Integrated genomic characterization of endometrial carcinoma

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Levine"],"publishedAt":1367366400,"publishedAtString":"2013-05-01","title":"Integrated genomic characterization of endometrial carcinoma","legacy":null,"publishedAtTime":null,"documentType":"aplusplus","subjects":"Cancer genomics,Endometrial cancer"},"journal":{"pcode":"nature","title":"nature","volume":"497","issue":"7447","id":41586,"publishingModel":"Hybrid Access"},"authorization":{"status":true},"features":[{"name":"furtherReadingSection","present":true}],"collection":{"id":"ffebghgeba"}},"page":{"category":{"pageType":"article"},"attributes":{"template":"mosaic","featureFlags":[{"name":"nature-onwards-journey","active":false}],"testGroup":null},"search":null},"privacy":{},"version":"1.0.0","product":null,"session":null,"user":null,"backHalfContent":true,"country":"HK","hasBody":true,"uneditedManuscript":false,"twitterId":["o3xnx","o43y9","o3ef7"],"baiduId":"d38bce82bcb44717ccc29a90c4b781ea","japan":false}]; window.dataLayer.push({ ga4MeasurementId: 'G-ERRNTNZ807', 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Uterine serous tumours and ∼25% of high-grade endometrioid tumours had extensive copy number alterations, few DNA methylation changes, low oestrogen receptor/progesterone receptor levels, and frequent TP53 mutations. Most endometrioid tumours had few copy number alterations or TP53 mutations, but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A and KRAS and novel mutations in the SWI/SNF chromatin remodelling complex gene ARID5B. A subset of endometrioid tumours that we identified had a markedly increased transversion mutation frequency and newly identified hotspot mutations in POLE. Our results classified endometrial cancers into four categories: POLE ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high. Uterine serous carcinomas share genomic features with ovarian serous and basal-like breast carcinomas. We demonstrated that the genomic features of endometrial carcinomas permit a reclassification that may affect post-surgical adjuvant treatment for women with aggressive tumours. An integrative genomic analysis of several hundred endometrial carcinomas shows that a minority of tumour samples carry copy number alterations or TP53 mutations and many contain key cancer-related gene mutations, such as those involved in canonical pathways and chromatin remodelling; a reclassification of endometrial tumours into four distinct types is proposed, which may have an effect on patient treatment regimes. This paper from The Cancer Genome Atlas Research Network presents an in-depth genome-wide analysis of endometrial (uterine) carcinomas from more than 350 patients. Based on a series of genomic features including newly identified hotspot mutations in the DNA polymerase gene POLE, and novel mutations in the ARID5B DNA-binding protein, the authors propose a reclassification of endometrial tumours into four distinct types. 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Levine","affiliation":[{"name":"Gynecology Service, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.","address":{"name":"Department of Surgery, Gynecology Service, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA., ","@type":"PostalAddress"},"@type":"Organization"}],"email":"levine2@mskcc.org","@type":"Person"}],"isAccessibleForFree":true,"@type":"ScholarlyArticle"},"@context":"https://schema.org","@type":"WebPage"}</script> <link rel="canonical" href="https://www.nature.com/articles/nature12113"> <meta name="journal_id" content="41586"/> <meta name="dc.title" content="Integrated genomic characterization of endometrial carcinoma"/> <meta name="dc.source" content="Nature 2013 497:7447"/> <meta name="dc.format" content="text/html"/> <meta name="dc.publisher" content="Nature Publishing Group"/> <meta name="dc.date" content="2013-05-01"/> <meta name="dc.type" content="OriginalPaper"/> <meta name="dc.language" content="En"/> <meta name="dc.copyright" content="2013 The Author(s)"/> <meta name="dc.rights" content="2013 The Author(s)"/> <meta name="dc.rightsAgent" content="journalpermissions@springernature.com"/> <meta name="dc.description" content="We performed an integrated genomic, transcriptomic and proteomic characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. Uterine serous tumours and ∼25% of high-grade endometrioid tumours had extensive copy number alterations, few DNA methylation changes, low oestrogen receptor/progesterone receptor levels, and frequent TP53 mutations. Most endometrioid tumours had few copy number alterations or TP53 mutations, but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A and KRAS and novel mutations in the SWI/SNF chromatin remodelling complex gene ARID5B. A subset of endometrioid tumours that we identified had a markedly increased transversion mutation frequency and newly identified hotspot mutations in POLE. Our results classified endometrial cancers into four categories: POLE ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high. Uterine serous carcinomas share genomic features with ovarian serous and basal-like breast carcinomas. We demonstrated that the genomic features of endometrial carcinomas permit a reclassification that may affect post-surgical adjuvant treatment for women with aggressive tumours. An integrative genomic analysis of several hundred endometrial carcinomas shows that a minority of tumour samples carry copy number alterations or TP53 mutations and many contain key cancer-related gene mutations, such as those involved in canonical pathways and chromatin remodelling; a reclassification of endometrial tumours into four distinct types is proposed, which may have an effect on patient treatment regimes. This paper from The Cancer Genome Atlas Research Network presents an in-depth genome-wide analysis of endometrial (uterine) carcinomas from more than 350 patients. Based on a series of genomic features including newly identified hotspot mutations in the DNA polymerase gene POLE, and novel mutations in the ARID5B DNA-binding protein, the authors propose a reclassification of endometrial tumours into four distinct types. 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class="c-context-bar__title"> Integrated genomic characterization of endometrial carcinoma </div> <div class="c-pdf-download u-clear-both js-pdf-download"> <a href="/articles/nature12113.pdf" class="u-button u-button--full-width u-button--primary u-justify-content-space-between c-pdf-download__link" data-article-pdf="true" data-readcube-pdf-url="true" data-test="download-pdf" data-draft-ignore="true" data-track="content_download" data-track-type="article pdf download" data-track-action="download pdf" data-track-label="link" data-track-external download> <span class="c-pdf-download__text">Download PDF</span> <svg aria-hidden="true" focusable="false" width="16" height="16" class="u-icon"><use xlink:href="#icon-download"/></svg> </a> </div> </div> </div> <article lang="en"> <div class="c-pdf-button__container u-mb-16 u-hide-at-lg js-context-bar-sticky-point-mobile"> <div class="c-pdf-container" data-track-context="article body"> <div class="c-pdf-download u-clear-both js-pdf-download"> <a href="/articles/nature12113.pdf" class="u-button u-button--full-width u-button--primary u-justify-content-space-between c-pdf-download__link" data-article-pdf="true" data-readcube-pdf-url="true" data-test="download-pdf" data-draft-ignore="true" data-track="content_download" data-track-type="article pdf download" data-track-action="download pdf" data-track-label="link" data-track-external download> <span class="c-pdf-download__text">Download PDF</span> <svg aria-hidden="true" focusable="false" width="16" height="16" class="u-icon"><use xlink:href="#icon-download"/></svg> </a> </div> </div> </div> <div class="c-article-header"> <header> <ul class="c-article-identifiers" data-test="article-identifier"> <li class="c-article-identifiers__item" data-test="article-category">Article</li> <li class="c-article-identifiers__item"> <a href="https://www.springernature.com/gp/open-research/about/the-fundamentals-of-open-access-and-open-research" data-track="click" data-track-action="open access" data-track-label="link" class="u-color-open-access" data-test="open-access">Open access</a> </li> <li class="c-article-identifiers__item">Published: <time datetime="2013-05-01">01 May 2013</time></li> </ul> <h1 class="c-article-title" data-test="article-title" data-article-title="">Integrated genomic characterization of endometrial carcinoma</h1> <ul class="c-article-author-list c-article-author-list--short" data-test="authors-list" data-component-authors-activator="authors-list"><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Douglas_A_-Levine-Aff51" data-author-popup="auth-Douglas_A_-Levine-Aff51" data-author-search="Levine, Douglas A." data-corresp-id="c1">Douglas A. Levine<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-mail-medium"></use></svg></a><sup class="u-js-hide"><a href="#Aff51">51</a></sup> & </li><li class="c-article-author-list__item"><a data-test="author-name" data-author-popup="group-1" href="#group-1">The Cancer Genome Atlas Research Network</a></li></ul> <p class="c-article-info-details" data-container-section="info"> <a data-test="journal-link" href="/" data-track="click" data-track-action="journal homepage" data-track-category="article body" data-track-label="link"><i data-test="journal-title">Nature</i></a> <b data-test="journal-volume"><span class="u-visually-hidden">volume</span> 497</b>, <span class="u-visually-hidden">pages </span>67–73 (<span data-test="article-publication-year">2013</span>)<a href="#citeas" class="c-article-info-details__cite-as u-hide-print" data-track="click" data-track-action="cite this article" data-track-label="link">Cite this article</a> </p> <div class="c-article-metrics-bar__wrapper u-clear-both"> <ul class="c-article-metrics-bar u-list-reset"> <li class=" c-article-metrics-bar__item" data-test="access-count"> <p class="c-article-metrics-bar__count">182k <span class="c-article-metrics-bar__label">Accesses</span></p> </li> <li class="c-article-metrics-bar__item" data-test="citation-count"> <p class="c-article-metrics-bar__count">3779 <span class="c-article-metrics-bar__label">Citations</span></p> </li> <li class="c-article-metrics-bar__item" data-test="altmetric-score"> <p class="c-article-metrics-bar__count">433 <span class="c-article-metrics-bar__label">Altmetric</span></p> </li> <li class="c-article-metrics-bar__item"> <p class="c-article-metrics-bar__details"><a href="/articles/nature12113/metrics" data-track="click" data-track-action="view metrics" data-track-label="link" rel="nofollow">Metrics <span class="u-visually-hidden">details</span></a></p> </li> </ul> </div> </header> <div class="u-js-hide" data-component="article-subject-links"> <h3 class="c-article__sub-heading">Subjects</h3> <ul class="c-article-subject-list"> <li class="c-article-subject-list__subject"><a href="/subjects/cancer-genomics" data-track="click" data-track-action="view subject" data-track-label="link">Cancer genomics</a></li><li class="c-article-subject-list__subject"><a href="/subjects/endometrial-cancer" data-track="click" data-track-action="view subject" data-track-label="link">Endometrial cancer</a></li> </ul> </div> <div class="u-mb-8 c-status-message c-status-message--boxed c-status-message--info"> <span class="c-status-message__icon"> <svg class="u-icon" width="18" height="18" aria-hidden="true" focusable="false"> <use xlink:href="#icon-eds-i-info-filled-medium"></use> </svg> </span> <p class="u-mt-0">An <a href="https://doi.org/10.1038/nature12325" class="relation-link" data-track="click" data-track-action="view linked article" data-track-label="link">Erratum</a> to this article was published on 12 June 2013</p> </div> <div class="u-mb-8 c-status-message c-status-message--boxed c-status-message--info"> <span class="c-status-message__icon"> <svg class="u-icon" width="18" height="18" aria-hidden="true" focusable="false"> <use xlink:href="#icon-eds-i-info-filled-medium"></use> </svg> </span> <p class="u-mt-0">This article has been <a href="#change-history">updated</a></p> </div> </div> <div class="c-article-body"> <section aria-labelledby="Abs1" data-title="Abstract" lang="en"><div class="c-article-section" id="Abs1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Abs1">Abstract</h2><div class="c-article-section__content" id="Abs1-content"><p>We performed an integrated genomic, transcriptomic and proteomic characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. Uterine serous tumours and <span class="stix">∼</span>25% of high-grade endometrioid tumours had extensive copy number alterations, few DNA methylation changes, low oestrogen receptor/progesterone receptor levels, and frequent <i>TP53</i> mutations. Most endometrioid tumours had few copy number alterations or <i>TP53</i> mutations, but frequent mutations in <i>PTEN</i>, <i>CTNNB1</i>, <i>PIK3CA</i>, <i>ARID1A</i> and <i>KRAS</i> and novel mutations in the SWI/SNF chromatin remodelling complex gene <i>ARID5B</i>. A subset of endometrioid tumours that we identified had a markedly increased transversion mutation frequency and newly identified hotspot mutations in <i>POLE</i>. Our results classified endometrial cancers into four categories: <i>POLE</i> ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high. Uterine serous carcinomas share genomic features with ovarian serous and basal-like breast carcinomas. We demonstrated that the genomic features of endometrial carcinomas permit a reclassification that may affect post-surgical adjuvant treatment for women with aggressive tumours.</p></div></div></section> <noscript> </noscript> <section aria-labelledby="inline-recommendations" data-title="Inline Recommendations" class="c-article-recommendations" data-track-component="inline-recommendations"> <h3 class="c-article-recommendations-title" id="inline-recommendations">Similar content being viewed by others</h3> <div class="c-article-recommendations-list"> <div class="c-article-recommendations-list__item"> <article class="c-article-recommendations-card" itemscope itemtype="http://schema.org/ScholarlyArticle"> <div class="c-article-recommendations-card__img"><img src="https://media.springernature.com/w215h120/springer-static/image/art%3A10.1038%2Fs41379-022-01066-y/MediaObjects/41379_2022_1066_Fig1_HTML.png" loading="lazy" alt=""></div> <div class="c-article-recommendations-card__main"> <h3 class="c-article-recommendations-card__heading" itemprop="name headline"> <a class="c-article-recommendations-card__link" itemprop="url" href="https://www.nature.com/articles/s41379-022-01066-y?fromPaywallRec=false" data-track="select_recommendations_1" data-track-context="inline recommendations" data-track-action="click recommendations inline - 1" data-track-label="10.1038/s41379-022-01066-y">Genomic landscape of endometrial carcinomas of no specific molecular profile </a> </h3> <div class="c-article-meta-recommendations" data-test="recommendation-info"> <span class="c-article-meta-recommendations__item-type">Article</span> <span class="c-article-meta-recommendations__date">01 April 2022</span> </div> </div> </article> </div> <div class="c-article-recommendations-list__item"> <article class="c-article-recommendations-card" itemscope itemtype="http://schema.org/ScholarlyArticle"> <div class="c-article-recommendations-card__img"><img src="https://media.springernature.com/w215h120/springer-static/image/art%3A10.1038%2Fs41388-022-02221-0/MediaObjects/41388_2022_2221_Fig1_HTML.png" loading="lazy" alt=""></div> <div class="c-article-recommendations-card__main"> <h3 class="c-article-recommendations-card__heading" itemprop="name headline"> <a class="c-article-recommendations-card__link" itemprop="url" href="https://www.nature.com/articles/s41388-022-02221-0?fromPaywallRec=false" data-track="select_recommendations_2" data-track-context="inline recommendations" data-track-action="click recommendations inline - 2" data-track-label="10.1038/s41388-022-02221-0">Intratumor genetic heterogeneity and clonal evolution to decode endometrial cancer progression </a> </h3> <div class="c-article-meta-recommendations" data-test="recommendation-info"> <span class="c-article-meta-recommendations__item-type">Article</span> <span class="c-article-meta-recommendations__access-type">Open access</span> <span class="c-article-meta-recommendations__date">10 February 2022</span> </div> </div> </article> </div> <div class="c-article-recommendations-list__item"> <article class="c-article-recommendations-card" itemscope itemtype="http://schema.org/ScholarlyArticle"> <div class="c-article-recommendations-card__img"><img src="https://media.springernature.com/w215h120/springer-static/image/art%3A10.1038%2Fs41379-020-00705-6/MediaObjects/41379_2020_705_Fig1_HTML.png" loading="lazy" alt=""></div> <div class="c-article-recommendations-card__main"> <h3 class="c-article-recommendations-card__heading" itemprop="name headline"> <a class="c-article-recommendations-card__link" itemprop="url" href="https://www.nature.com/articles/s41379-020-00705-6?fromPaywallRec=false" data-track="select_recommendations_3" data-track-context="inline recommendations" data-track-action="click recommendations inline - 3" data-track-label="10.1038/s41379-020-00705-6">Targeted RNA expression profiling identifies high-grade endometrial stromal sarcoma as a clinically relevant molecular subtype of uterine sarcoma </a> </h3> <div class="c-article-meta-recommendations" data-test="recommendation-info"> <span class="c-article-meta-recommendations__item-type">Article</span> <span class="c-article-meta-recommendations__date">19 October 2020</span> </div> </div> </article> </div> </div> </section> <script> window.dataLayer = window.dataLayer || []; window.dataLayer.push({ recommendations: { recommender: 'semantic', model: 'specter', policy_id: 'NA', timestamp: 1732422937, embedded_user: 'null' } }); </script> <div class="main-content"> <section data-title="Main"><div class="c-article-section" id="Sec1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec1">Main</h2><div class="c-article-section__content" id="Sec1-content"><p>Endometrial cancer arises from the lining of the uterus. It is the fourth most common malignancy among women in the United States, with an estimated 49,500 new cases and 8,200 deaths in 2013 (ref. <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 1" title="Siegel, R., Naishadham, D. & Jemal, A. Cancer statistics, 2013. CA Cancer J. Clin. 63, 11–30 (2013)" href="/articles/nature12113#ref-CR1" id="ref-link-section-d169765955e5159">1</a>). Most patients present with low-grade, early-stage disease. The majority of patients with more aggressive, high-grade tumours who have disease spread beyond the uterus will progress within 1 year (refs <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 2" title="Fleming, G. F. et al. Phase III trial of doxorubicin plus cisplatin with or without paclitaxel plus filgrastim in advanced endometrial carcinoma: a Gynecologic Oncology Group Study. J. Clin. Oncol. 22, 2159–2166 (2004)" href="/articles/nature12113#ref-CR2" id="ref-link-section-d169765955e5162">2</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Sutton, G. et al. Whole abdominal radiotherapy in the adjuvant treatment of patients with stage III and IV endometrial cancer: a gynecologic oncology group study. Gynecol. Oncol. 97, 755–763 (2005)" href="/articles/nature12113#ref-CR3" id="ref-link-section-d169765955e5165">3</a>). Endometrial cancers have been broadly classified into two groups<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 4" title="Lax, S. F. & Kurman, R. J. A dualistic model for endometrial carcinogenesis based on immunohistochemical and molecular genetic analyses. Verh. Dtsch. Ges. Pathol. 81, 228–232 (1997)" href="/articles/nature12113#ref-CR4" id="ref-link-section-d169765955e5169">4</a></sup>. Type I endometrioid tumours are linked to oestrogen excess, obesity, hormone-receptor positivity, and favourable prognosis compared with type II, primarily serous, tumours that are more common in older, non-obese women and have a worse outcome. Early-stage endometrioid cancers are often treated with adjuvant radiotherapy, whereas serous tumours are treated with chemotherapy, similar to advanced-stage cancers of either histological subtype. Therefore, proper subtype classification is crucial for selecting appropriate adjuvant therapy.</p><p>Several previous reports suggest that <i>PTEN</i> mutations occur early in the neoplastic process of type I tumours and co-exist frequently with other mutations in the phosphatidylinositol-3-OH kinase (PI(3)K)/AKT pathway<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 5" title="Cheung, L. W. et al. High frequency of PIK3R1 and PIK3R2 mutations in endometrial cancer elucidates a novel mechanism for regulation of PTEN protein stability. Cancer Discov. 1, 170–185 (2011)" href="/articles/nature12113#ref-CR5" id="ref-link-section-d169765955e5179">5</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 6" title="Levine, R. L. et al. PTEN mutations and microsatellite instability in complex atypical hyperplasia, a precursor lesion to uterine endometrioid carcinoma. Cancer Res. 58, 3254–3258 (1998)" href="/articles/nature12113#ref-CR6" id="ref-link-section-d169765955e5182">6</a></sup>. Other commonly mutated genes in type I tumours include <i>FGFR2</i>, <i>ARID1A</i>, <i>CTNNB1</i>, <i>PIK3CA</i>, <i>PIK3R1</i> and <i>KRAS</i><sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 7" title="McConechy, M. K. et al. Use of mutation profiles to refine the classification of endometrial carcinomas. J. Pathol. 228, 20–30 (2012)" href="/articles/nature12113#ref-CR7" id="ref-link-section-d169765955e5204">7</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 8" title="Byron, S. A. et al. FGFR2 point mutations in 466 endometrioid endometrial tumors: relationship with MSI, KRAS, PIK3CA, CTNNB1 mutations and clinicopathological features. PLoS ONE 7, e30801 (2012)" href="/articles/nature12113#ref-CR8" id="ref-link-section-d169765955e5207">8</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 9" title="Urick, M. E. et al. PIK3R1 (p85α) is somatically mutated at high frequency in primary endometrial cancer. Cancer Res. 71, 4061–4067 (2011)" href="/articles/nature12113#ref-CR9" id="ref-link-section-d169765955e5210">9</a></sup>. Microsatellite instability (MSI) is found in approximately one-third of type I tumours, but is infrequent in type II tumours<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 10" title="Zighelboim, I. et al. Microsatellite instability and epigenetic inactivation of MLH1 and outcome of patients with endometrial carcinomas of the endometrioid type. J. Clin. Oncol. 25, 2042–2048 (2007)" href="/articles/nature12113#ref-CR10" id="ref-link-section-d169765955e5214">10</a></sup>. <i>TP53</i>, <i>PIK3CA</i> and <i>PPP2R1A</i> mutations are frequent in type II tumours<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 11" title="Kuhn, E. et al. Identification of molecular pathway aberrations in uterine serous carcinoma by genome-wide analyses. J. Natl. Cancer Inst. 104, 1503–1513 (2012)" href="/articles/nature12113#ref-CR11" id="ref-link-section-d169765955e5228">11</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 12" title="Le Gallo, M. et al. Exome sequencing of serous endometrial tumors identifies recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes. Nature Genet. 44, 1310–1315 (2012)" href="/articles/nature12113#ref-CR12" id="ref-link-section-d169765955e5231">12</a></sup>. Most of these studies have been limited to DNA sequencing only with samples of heterogeneous histological subtypes and tumour grades. We present a comprehensive, multiplatform analysis of 373 endometrial carcinomas including low-grade endometrioid, high-grade endometrioid, and serous carcinomas. This integrated analysis provides key molecular insights into tumour classification, which may have a direct effect on treatment recommendations for patients, and provides opportunities for genome-guided clinical trials and drug development.</p></div></div></section><section data-title="Results"><div class="c-article-section" id="Sec2-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec2">Results</h2><div class="c-article-section__content" id="Sec2-content"><p>Tumour samples and corresponding germline DNA were collected from 373 patients, including 307 endometrioid and 66 serous (53) or mixed histology (13) cases. Local Institutional Review Boards approved all tissue acquisition. The clinical and pathological characteristics of the samples generally reflect a cross-section of individuals with recurrent endometrial cancer<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 2" title="Fleming, G. F. et al. Phase III trial of doxorubicin plus cisplatin with or without paclitaxel plus filgrastim in advanced endometrial carcinoma: a Gynecologic Oncology Group Study. J. Clin. Oncol. 22, 2159–2166 (2004)" href="/articles/nature12113#ref-CR2" id="ref-link-section-d169765955e5243">2</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Sutton, G. et al. Whole abdominal radiotherapy in the adjuvant treatment of patients with stage III and IV endometrial cancer: a gynecologic oncology group study. Gynecol. Oncol. 97, 755–763 (2005)" href="/articles/nature12113#ref-CR3" id="ref-link-section-d169765955e5246">3</a></sup> (<a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/nature12113#MOESM88">Supplementary Table 1.1</a>). The median follow-up of the cohort was 32 months (range, 1–195 months); 21% of the patients have recurred, and 11% have died. Comprehensive molecular analyses were performed at independent centres using six genomic or proteomic platforms (<a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/nature12113#MOESM88">Supplementary Table 1.2</a>). MSI testing performed on all samples using seven repeat loci (<a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/nature12113#MOESM88">Supplementary Table 1.3</a>) found MSI in 40% of endometrioid tumours and 2% of serous tumours.</p></div></div></section><section data-title="Somatic copy number alterations"><div class="c-article-section" id="Sec3-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec3">Somatic copy number alterations</h2><div class="c-article-section__content" id="Sec3-content"><p>Somatic copy number alterations (SCNAs) were assessed in 363 endometrial carcinomas. Unsupervised hierarchical clustering grouped the tumours into four clusters (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/nature12113#Fig1">Fig. 1a</a>). The first three copy-number clusters were composed almost exclusively (97%) of endometrioid tumours without significant differences in tumour grades. Cluster 1 tumours were nearly devoid of broad SCNAs, averaging less than 0.5% genome alteration, with no significant recurrent events. Cluster 1 tumours also had significantly increased non-synonymous mutation rates compared to all others (median 7.2 × 10<sup>−6</sup> versus 1.7 × 10<sup>−6</sup> mutations per megabase (Mb), <i>P</i> < 0.001). Copy-number clusters 2 and 3 consisted mainly of endometrioid tumours, distinguished by more frequent 1q amplification in cluster 3 than cluster 2 (100% of cluster 3 tumours versus 33% of cluster 2 tumours) and worse progression-free survival (<i>P</i> = 0.003, log-rank versus clusters 1 and 2; <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/nature12113#Fig1">Fig. 1b</a>).</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-1" data-title="SCNAs in endometrial carcinomas."><figure><figcaption><b id="Fig1" class="c-article-section__figure-caption" data-test="figure-caption-text">Figure 1: SCNAs in endometrial carcinomas.</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/nature12113/figures/1" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fnature12113/MediaObjects/41586_2013_Article_BFnature12113_Fig1_HTML.jpg?as=webp"><img aria-describedby="Fig1" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fnature12113/MediaObjects/41586_2013_Article_BFnature12113_Fig1_HTML.jpg" alt="figure 1" loading="lazy" width="685" height="910"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-1-desc"><p><b>a</b>, Tumours were hierarchically clustered into four groups based on SCNAs. The heat map shows SCNAs in each tumour (horizontal axis) plotted by chromosomal location (vertical axis). Chr., chromosome. <b>b</b>, Kaplan–Meier curves of progression-free survival for each copy-number cluster.</p><p> <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/nature12113#MOESM83">PowerPoint slide</a> </p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/nature12113/figures/1" data-track-dest="link:Figure1 Full size image" aria-label="Full size image figure 1" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p>Most of the serous (50 out of 53; 94%) and mixed histology (8 out of 13; 62%) tumours clustered with 36 (12%) of the 289 endometrioid tumours, including 24% of grade 3 and 5% of grade 1 or 2, into copy-number cluster 4; a single group characterized by a very high degree of SCNAs (<a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/nature12113#MOESM88">Supplementary Fig. 2.1</a>; focal SCNAs with false discovery rate (FDR) < 0.15, and <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/nature12113#MOESM88">Supplementary Data 2.1</a>). Cluster 4 tumours were characterized by significantly recurrent previously reported focal amplifications of the oncogenes <i>MYC</i> (8q24.12), <i>ERBB2</i> (17q12) and <i>CCNE1</i> (19q12)<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 13" title="Salvesen, H. B. et al. Integrated genomic profiling of endometrial carcinoma associates aggressive tumors with indicators of PI3 kinase activation. Proc. Natl Acad. Sci. USA 106, 4834–4839 (2009)" href="/articles/nature12113#ref-CR13" id="ref-link-section-d169765955e5334">13</a></sup>, and by SCNAs previously unreported in endometrial cancers including those containing <i>FGFR3</i> (4p16.3) and <i>SOX17</i> (8q11.23). Cluster 4 tumours also had frequent <i>TP53</i> mutations (90%), little MSI (6%), and fewer <i>PTEN</i> mutations (11%) than other endometrioid tumours (84%). Overall, these findings suggest that a subset of endometrial tumours contain distinct patterns of SCNAs and mutations that do not correlate with traditional tumour histology or grade.</p><p>As expected, tumours in the ‘serous-like’ cluster (cluster 4) had significantly worse progression-free survival than tumours in the endometrioid cluster groups (<i>P</i> = 0.003, log-rank, <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/nature12113#Fig1">Fig. 1b</a>). Potential therapeutically relevant SCNAs included the cluster 2 15q26.2 focal amplification, which contained <i>IGF1R</i>; and cluster 4 amplifications of <i>ERBB2</i>, <i>FGFR1</i> and <i>FGFR3</i>, and <i>LRP1B</i> deletion, which was recently associated with resistance to liposomal doxorubicin in serous ovarian cancer<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 14" title="Cowin, P. A. et al. LRP1B deletion in high-grade serous ovarian cancers is associated with acquired chemotherapy resistance to liposomal doxorubicin. Cancer Res. 72, 4060–4073 (2012)" href="/articles/nature12113#ref-CR14" id="ref-link-section-d169765955e5375">14</a></sup>.</p></div></div></section><section data-title="Exome sequence analysis"><div class="c-article-section" id="Sec4-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec4">Exome sequence analysis</h2><div class="c-article-section__content" id="Sec4-content"><p>We sequenced the exomes of 248 tumour/normal pairs. On the basis of a combination of somatic nucleotide substitutions, MSI and SCNAs, the endometrial tumours were classified into four groups (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/nature12113#Fig2">Fig. 2a, b</a>): (1) an ultramutated group with unusually high mutation rates (232 × 10<sup>−6</sup> mutations per Mb) and a unique nucleotide change spectrum; (2) a hypermutated group (18 × 10<sup>−6</sup> mutations per Mb) of MSI tumours, most with <i>MLH1</i> promoter methylation; (3) a group with lower mutation frequency (2.9 × 10<sup>−6</sup> mutations per Mb) and most of the microsatellite stable (MSS) endometrioid cancers; and (4) a group that consists primarily of serous-like cancers with extensive SCNA (copy-number cluster 4) and a low mutation rate (2.3 × 10<sup>−6</sup> mutations per Mb). The ultramutated group consisted of 17 (7%) tumours exemplified by an increased C→A transversion frequency, all with mutations in the exonuclease domain of <i>POLE</i>, and an improved progression-free survival (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/nature12113#Fig2">Fig. 2a, c</a>). <i>POLE</i> is a catalytic subunit of DNA polymerase epsilon involved in nuclear DNA replication and repair. We identified hotspot mutations in <i>POLE</i> at Pro286Arg and Val411Leu present in 13 (76%) of the 17 ultramutated samples. Significantly mutated genes (SMGs) identified at low FDRs (<i>Q</i>) in this subset included <i>PTEN</i> (94%, <i>Q</i> = 0), <i>PIK3R1</i> (65%, <i>Q</i> = 8.3 × 10<sup>−7</sup>), <i>PIK3CA</i> (71%, <i>Q</i> = 9.1 × 10<sup>−5</sup>), <i>FBXW7</i> (82%, <i>Q</i> = 1.4 × 10<sup>−4</sup>), <i>KRAS</i> (53%, <i>Q</i> = 9.2 × 10<sup>−4</sup>) and <i>POLE</i> (100%, <i>Q</i> = 4.2 × 10<sup>−3</sup>). Mutation rates in <i>POLE</i> mutant endometrial and previously reported ultramutated colorectal tumours exceeded those found in any other lineage including lung cancer and melanoma<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 15" title="The Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 487, 330–337 (2012)" href="/articles/nature12113#ref-CR15" id="ref-link-section-d169765955e5470">15</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 16" title="Govindan, R. et al. Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell 150, 1121–1134 (2012)" href="/articles/nature12113#ref-CR16" id="ref-link-section-d169765955e5473">16</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 17" title="Pleasance, E. D. et al. A comprehensive catalogue of somatic mutations from a human cancer genome. Nature 463, 191–196 (2010)" href="/articles/nature12113#ref-CR17" id="ref-link-section-d169765955e5476">17</a></sup>. Germline susceptibility variants have been reported in <i>POLE</i> (Leu424Val) and <i>POLD1</i> (Ser478Asn), but were not found in our endometrial normal exome-seq reads<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 18" title="Palles, C. et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nature Genet. 45, 136–144 (2013)" href="/articles/nature12113#ref-CR18" id="ref-link-section-d169765955e5486">18</a></sup>.</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-2" data-title="Mutation spectra across endometrial carcinomas."><figure><figcaption><b id="Fig2" class="c-article-section__figure-caption" data-test="figure-caption-text">Figure 2: Mutation spectra across endometrial carcinomas.</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/nature12113/figures/2" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fnature12113/MediaObjects/41586_2013_Article_BFnature12113_Fig2_HTML.jpg?as=webp"><img aria-describedby="Fig2" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fnature12113/MediaObjects/41586_2013_Article_BFnature12113_Fig2_HTML.jpg" alt="figure 2" loading="lazy" width="685" height="391"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-2-desc"><p><b>a</b>, Mutation frequencies (vertical axis, top panel) plotted for each tumour (horizontal axis). Nucleotide substitutions are shown in the middle panel, with a high frequency of C-to-A transversions in the samples with <i>POLE</i> exonuclease mutations. CN, copy number. <b>b</b>, Tumours were stratified into the four groups by (1) nucleotide substitution frequencies and patterns, (2) MSI status, and (3) copy-number cluster. SNV, single nucleotide variant. <b>c</b>, <i>POLE</i>-mutant tumours have significantly better progression-free survival, whereas copy-number high tumours have the poorest outcome. <b>d</b>, Recurrently mutated genes are different between the four subgroups. Shown are the mutation frequencies of all genes that were significantly mutated in at least one of the four subgroups (MUSiC, asterisk denotes FDR < 0.05).</p><p> <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/nature12113#MOESM84">PowerPoint slide</a> </p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/nature12113/figures/2" data-track-dest="link:Figure2 Full size image" aria-label="Full size image figure 2" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p>The MSI endometrioid tumours had a mutation frequency approximately tenfold greater than MSS endometrioid tumours, few SCNAs, frameshift deletions in <i>RPL22</i>, frequent non-synonymous <i>KRAS</i> mutations, and few mutations in <i>FBXW7</i>, <i>CTNNB1</i>, <i>PPP2R1A</i> and <i>TP53</i>. The MSS, copy-number low, endometrioid tumours had an unusually high frequency of <i>CTNNB1</i> mutations (52%); the only gene with a higher mutation frequency than the MSI samples. The copy-number high group contained all of the remaining serous cases and one-quarter of the grade 3 endometrioid cases. Most of these tumours had <i>TP53</i> mutations and a high frequency of <i>FBXW7</i> (22%, <i>Q</i> = 0) and <i>PPP2R1A</i> (22%, <i>Q</i> = 1.7 × 10<sup>−16</sup>) mutations, previously reported as common in uterine serous but not endometrioid carcinomas. Thus, a subset of high-grade endometrioid tumours had similar SCNAs and mutation spectra as uterine serous carcinomas, suggesting that these patients might benefit from treatment approaches that parallel those for serous tumours.</p><p>There were 48 genes with differential mutation frequencies across the four groups (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/nature12113#Fig2">Fig. 2d</a> and <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/nature12113#MOESM88">Supplementary Data 3.1</a>). <i>ARID5B</i>, a member of the same AT-rich interaction domain (ARID) family as <i>ARID1A</i>, was more frequently mutated in MSI (23.1%) than in either MSS endometrioid (5.6%) or high SCNA serous tumours (0%), a novel finding for endometrial cancer. Frameshifting <i>RPL22</i> indels near a homopolymer at Lys 15 were almost exclusively found in the MSI group (36.9%). The <i>TP53</i> mutation frequency (>90%) in serous tumours differentiated them from the endometrioid subtypes (11.4%). However, many (10 out of 20; 50%) endometrioid tumours with a non-silent <i>TP53</i> mutation also had non-silent mutations in <i>PTEN</i>, compared to only 1 out of 39 (2.6%) serous tumours with non-silent <i>TP53</i> mutations. Although <i>TP53</i> mutations are not restricted to serous tumours, the co-existing <i>PTEN</i> mutations in the endometrioid cases suggest a distinct tumorigenic mechanism.</p><p>Comparisons of 66 SMGs between traditional histological subtypes are provided (<a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/nature12113#MOESM88">Supplementary Methods 3</a>), and SMGs across other subcohorts can be found in <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/nature12113#MOESM88">Supplementary Data 3.2</a>. The spectrum of <i>PIK3CA</i> and <i>PTEN</i> mutations in endometrial cancer also differed from other solid tumours (<a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/nature12113#MOESM88">Supplementary Methods 3</a>). Integrated analysis may be useful for identifying histologically misclassified cases. For example, a single serous case was identified without a <i>TP53</i> mutation or extensive SCNAs and with a <i>KRAS</i> mutation and high mutation rate. After re-review of the histological section, the case was deemed consistent with a grade 3 endometrioid tumour, demonstrating how molecular analysis could reclassify tumour histology and potentially affect treatment decisions.</p></div></div></section><section data-title="Multiplatform subtype classifications"><div class="c-article-section" id="Sec5-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec5">Multiplatform subtype classifications</h2><div class="c-article-section__content" id="Sec5-content"><p>All of the endometrial tumours were examined for messenger RNA expression (<i>n</i> = 333), protein expression (<i>n</i> = 293), microRNA expression (<i>n</i> = 367), and DNA methylation (<i>n</i> = 373) (<a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/nature12113#MOESM88">Supplementary Methods 4–7</a>). Unsupervised <i>k</i>-means clustering of mRNA expression from RNA sequencing identified three robust clusters termed ‘mitotic’, ‘hormonal’ and ‘immunoreactive’ (<a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/nature12113#MOESM88">Supplementary Fig. 4.1</a>) that were significantly correlated with the four integrated clusters; <i>POLE</i>, MSI, copy-number low and copy-number high (<i>P</i> < 0.0001). Supervised analysis identified signature genes of the <i>POLE</i> cluster (<i>n</i> = 17) mostly involved in cellular metabolism (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/nature12113#Fig3">Fig. 3a</a>). Among the few signature genes in the MSI cluster was decreased <i>MLH1</i> mRNA expression, probably due to its promoter methylation. Increased progesterone receptor (<i>PGR</i>) expression was noted in the copy-number low cluster, suggesting responsiveness to hormonal therapy. The copy-number high cluster, which included most of the serous and serous-like endometrioid tumours, exhibited the greatest transcriptional activity exemplified by increased cell cycle deregulation (for example, <i>CCNE1</i>, <i>PIK3CA</i>, <i>MYC</i> and <i>CDKN2A</i>) and <i>TP53</i> mutation (<a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/nature12113#MOESM88">Supplementary Figs 4.2 and 4.3</a>). This is consistent with reports that increased CDKN2A can distinguish serous from endometrioid carcinomas<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 19" title="Bartosch, C. et al. Endometrial carcinomas: a review emphasizing overlapping and distinctive morphological and immunohistochemical features. Adv. Anat. Pathol. 18, 415–437 (2011)" href="/articles/nature12113#ref-CR19" id="ref-link-section-d169765955e5709">19</a></sup>. Approximately 85% of cases in the copy-number high cluster shared membership with the ‘mitotic’ mRNA subtype.</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-3" data-title="Gene expression across integrated subtypes in endometrial carcinomas."><figure><figcaption><b id="Fig3" class="c-article-section__figure-caption" data-test="figure-caption-text">Figure 3: Gene expression across integrated subtypes in endometrial carcinomas.</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/nature12113/figures/3" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fnature12113/MediaObjects/41586_2013_Article_BFnature12113_Fig3_HTML.jpg?as=webp"><img aria-describedby="Fig3" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fnature12113/MediaObjects/41586_2013_Article_BFnature12113_Fig3_HTML.jpg" alt="figure 3" loading="lazy" width="685" height="1062"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-3-desc"><p><b>a</b>, Supervised analysis of <span class="stix">∼</span>1,500 genes significantly associated with integrated subtypes. <b>b</b>, Heat map of protein expression clusters, supervised by integrated subtypes. Samples are in columns; genes or proteins are in rows.</p><p> <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/nature12113#MOESM85">PowerPoint slide</a> </p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/nature12113/figures/3" data-track-dest="link:Figure3 Full size image" aria-label="Full size image figure 3" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p>Supervised clustering of the reverse phase protein array (RPPA) expression data was consistent with loss of function for many of the mutated genes (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/nature12113#Fig3">Fig. 3b</a>). <i>TP53</i> was frequently mutated in the copy-number high group (<i>P</i> = 2.5 × 10<sup>−27</sup>) and its protein expression was also increased, suggesting that these mutations are associated with increased expression. By contrast, <i>PTEN</i> (<i>P</i> = 2.8 × 10<sup>−19</sup>) and <i>ARID1A</i> (<i>P</i> = 1.2 × 10<sup>−6</sup>) had high mutation rates in the remaining groups, but their expression was decreased, suggesting inactivating mutations in both genes. The copy-number high group also had decreased levels of phospho-AKT, consistent with downregulation of the AKT pathway. The copy-number low group had raised RAD50 expression, which is associated with DNA repair, explaining some of the differences between the copy-number high and low groups. The <i>POLE</i> group had high expression of ASNS and CCNB1, whereas the MSI tumours had both high phospho-AKT and low PTEN expression.</p><p>Unsupervised clustering of DNA methylation data generated from Illumina Infinium DNA methylation arrays revealed four unique subtypes (MC1–4) that support the four integrative clusters. A heavily methylated subtype (MC1) reminiscent of the CpG island methylator phenotype (CIMP) described in colon cancers and glioblastomas<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 20" title="Toyota, M. et al. CpG island methylator phenotype in colorectal cancer. Proc. Natl Acad. Sci. USA 96, 8681–8686 (1999)" href="/articles/nature12113#ref-CR20" id="ref-link-section-d169765955e5781">20</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 21" title="Hinoue, T. et al. Genome-scale analysis of aberrant DNA methylation in colorectal cancer. Genome Res. 22, 271–282 (2012)" href="/articles/nature12113#ref-CR21" id="ref-link-section-d169765955e5784">21</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 22" title="Noushmehr, H. et al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17, 510–522 (2010)" href="/articles/nature12113#ref-CR22" id="ref-link-section-d169765955e5787">22</a></sup> was associated with the MSI subtype and attributable to promoter hypermethylation of <i>MLH1</i>. A serous-like cluster (MC3) with minimal DNA methylation changes was composed primarily of serous tumours and some endometrioid tumours (<a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/nature12113#MOESM88">Supplementary Fig. 7.1</a>) and contained most of the copy-number high tumours.</p><p>Integrative clustering using the iCluster framework returned two major clusters split primarily on serous and endometrioid histology highlighting <i>TP53</i> mutations, lack of <i>PTEN</i> mutation and encompassing almost exclusively copy-number high tumours<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 23" title="Shen, R., Olshen, A. B. & Ladanyi, M. Integrative clustering of multiple genomic data types using a joint latent variable model with application to breast and lung cancer subtype analysis. Bioinformatics 25, 2906–2912 (2009)" href="/articles/nature12113#ref-CR23" id="ref-link-section-d169765955e5806">23</a></sup> (<a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/nature12113#MOESM88">Supplementary Fig. 8.1</a>). We developed a new clustering algorithm, called SuperCluster, to derive overall subtypes based on sample cluster memberships across all data types (<a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/nature12113#MOESM88">Supplementary Fig. 9.1</a>). SuperCluster identified four clusters that generally confirmed the contributions of individual platforms to the overall integrated clusters. No major batch effects were identified for any platform (<a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/nature12113#MOESM88">Supplementary Methods 10</a>).</p></div></div></section><section data-title="Structural aberrations"><div class="c-article-section" id="Sec6-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec6">Structural aberrations</h2><div class="c-article-section__content" id="Sec6-content"><p>To identify somatic chromosomal aberrations, we performed low-pass, paired-end, whole-genome sequencing on 106 tumours with matched normals. We found recurrent translocations involving genes in several pathways including WNT, EGFR–RAS–MAPK, PI(3)K, protein kinase A, retinoblastoma and apoptosis. The most frequent translocations (5 out of 106) involved a member of the BCL family (<i>BCL2</i>, <i>BCL7A</i>, <i>BCL9</i> and <i>BCL2L11</i>). Four of these were confirmed by identification of the translocation junction point and two were also confirmed by high-throughput RNA sequencing (RNA-Seq). In all cases the translocations result in in-frame fusions and are predicted to result in activation or increased expression of the BCL family members (<a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/nature12113#MOESM88">Supplementary Fig. 3.2</a>). Translocations involving members of the BCL family leading to reduced apoptosis have been described in other tumour types<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 24" title="Hockenbery, D., Nunez, G., Milliman, C., Schreiber, R. D. & Korsmeyer, S. J. Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 348, 334–336 (1990)" href="/articles/nature12113#ref-CR24" id="ref-link-section-d169765955e5845">24</a></sup> and our results suggest that similar mechanisms may be operative here.</p></div></div></section><section data-title="Pathway alterations"><div class="c-article-section" id="Sec7-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec7">Pathway alterations</h2><div class="c-article-section__content" id="Sec7-content"><p>Multiple platform data were integrated to identify recurrently altered pathways in the four endometrial cancer integrated subgroups. Because of the high background mutation rate and small sample size, we excluded the <i>POLE</i> subgroup from this analysis. Considering all recurrently mutated, homozygously deleted, and amplified genes, we used MEMo<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 25" title="Ciriello, G., Cerami, E., Sander, C. & Schultz, N. Mutual exclusivity analysis identifies oncogenic network modules. Genome Res. 22, 398–406 (2012)" href="/articles/nature12113#ref-CR25" id="ref-link-section-d169765955e5860">25</a></sup> to identify gene networks with mutually exclusive alteration patterns in each subgroup. The most significant module was found in the copy-number low group and contained <i>CTNNB1</i>, <i>KRAS</i> and <i>SOX17</i> (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/nature12113#Fig4">Fig. 4a</a>). The very strong mutual exclusivity between mutations in these three genes suggests that alternative mechanisms activate WNT signalling in endometrioid endometrial cancer. Activating <i>KRAS</i> mutations have been shown to increase the stability of β-catenin via glycogen synthase kinase 3β (GSK-3β), leading to an alternative mechanism of β-catenin activation other than adenomatous polyposis coli degradation<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 26" title="Li, J., Mizukami, Y., Zhang, X., Jo, W. S. & Chung, D. C. Oncogenic K-ras stimulates Wnt signaling in colon cancer through inhibition of GSK-3β. Gastroenterology 128, 1907–1918 (2005)" href="/articles/nature12113#ref-CR26" id="ref-link-section-d169765955e5880">26</a></sup>. <i>SOX17</i>, which mediates proteasomal degradation of β-catenin<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 27" title="Zorn, A. M. et al. Regulation of Wnt signaling by Sox proteins: XSox17 α/β and XSox3 physically interact with β-catenin. Mol. Cell 4, 487–498 (1999)" href="/articles/nature12113#ref-CR27" id="ref-link-section-d169765955e5887">27</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 28" title="Sinner, D. et al. Sox17 and Sox4 differentially regulate β-catenin/T-cell factor activity and proliferation of colon carcinoma cells. Mol. Cell. Biol. 27, 7802–7815 (2007)" href="/articles/nature12113#ref-CR28" id="ref-link-section-d169765955e5890">28</a></sup>, is mutated exclusively in the copy-number low group (8%) at recurrent positions (Ala96Gly and Ser403Ile) not previously described. Other genes with mutually exclusive alteration patterns in this module were <i>FBXW7</i>, <i>FGFR2</i> and <i>ERBB2</i> (ref. <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 29" title="Pollock, P. M. et al. Frequent activating FGFR2 mutations in endometrial carcinomas parallel germline mutations associated with craniosynostosis and skeletal dysplasia syndromes. Oncogene 26, 7158–7162 (2007)" href="/articles/nature12113#ref-CR29" id="ref-link-section-d169765955e5903">29</a>). <i>ERBB2</i> was focally amplified with protein overexpression in 25% of the serous or serous-like tumours, suggesting a potential role for human epidermal growth factor receptor 2 (HER2)-targeted inhibitors. A small clinical trial of trastuzumab found no activity in endometrial carcinoma, but accrued few HER2 fluorescence <i>in situ</i> hybridization (FISH)-amplified serous carcinomas<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 30" title="Fleming, G. F. et al. Phase II trial of trastuzumab in women with advanced or recurrent, HER2-positive endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol. Oncol. 116, 15–20 (2010)" href="/articles/nature12113#ref-CR30" id="ref-link-section-d169765955e5913">30</a></sup>.</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-4" data-title="Pathway alterations in endometrial carcinomas."><figure><figcaption><b id="Fig4" class="c-article-section__figure-caption" data-test="figure-caption-text">Figure 4: Pathway alterations in endometrial carcinomas.</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/nature12113/figures/4" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fnature12113/MediaObjects/41586_2013_Article_BFnature12113_Fig4_HTML.jpg?as=webp"><img aria-describedby="Fig4" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fnature12113/MediaObjects/41586_2013_Article_BFnature12113_Fig4_HTML.jpg" alt="figure 4" loading="lazy" width="685" height="256"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-4-desc"><p><b>a</b>, The RTK/RAS/β-catenin pathway is altered through several mechanisms that exhibit mutually exclusive patterns. Alteration frequencies are expressed as a percentage of all cases. The right panel shows patterns of occurrence. <b>b</b>, The PI(3)K pathway has mutually exclusive <i>PIK3CA</i> and <i>PIK3R1</i> alterations that frequently co-occur with <i>PTEN</i> alterations in the MSI and copy-number low subgroups. <b>c</b>, Heat map display of top 1,000 varying pathway features within PARADIGM consensus clusters. Samples were arranged in order of their consensus cluster membership. The genomic subtype for each sample is displayed below the consensus clusters.</p><p> <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/nature12113#MOESM86">PowerPoint slide</a> </p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/nature12113/figures/4" data-track-dest="link:Figure4 Full size image" aria-label="Full size image figure 4" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p><i>PIK3CA</i> and <i>PIK3R1</i> mutations were frequent and showed a strong tendency for mutual exclusivity in all subgroups, but unlike other tumour types, they co-occurred with <i>PTEN</i> mutations in the MSI and copy-number low subgroups as previously reported<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 5" title="Cheung, L. W. et al. High frequency of PIK3R1 and PIK3R2 mutations in endometrial cancer elucidates a novel mechanism for regulation of PTEN protein stability. Cancer Discov. 1, 170–185 (2011)" href="/articles/nature12113#ref-CR5" id="ref-link-section-d169765955e5972">5</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 9" title="Urick, M. E. et al. PIK3R1 (p85α) is somatically mutated at high frequency in primary endometrial cancer. Cancer Res. 71, 4061–4067 (2011)" href="/articles/nature12113#ref-CR9" id="ref-link-section-d169765955e5975">9</a></sup> (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/nature12113#Fig4">Fig. 4b</a>). The copy-number high subgroup showed mutual exclusivity between alterations of all three genes. Overall, 93% of endometrioid tumours had mutations that suggested potential for targeted therapy with PI(3)K/AKT pathway inhibitors.</p><p>Consensus clustering of copy number, mRNA expression and pathway interaction data for 324 samples yielded five PARADIGM clusters with distinct pathway activation patterns<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 31" title="Vaske, C. J. et al. Inference of patient-specific pathway activities from multi-dimensional cancer genomics data using PARADIGM. Bioinformatics 26, i237–i245 (2010)" href="/articles/nature12113#ref-CR31" id="ref-link-section-d169765955e5985">31</a></sup> (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/nature12113#Fig4">Fig. 4c</a> and <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/nature12113#MOESM88">Supplementary Methods 11</a>). PARADIGM cluster 1 had the lowest level of MYC pathway activation and highest level of WNT pathway activation, consistent with its composition of copy-number low cases having frequent <i>CTNNB1</i> mutations. PARADIGM cluster 3 was composed predominantly of the copy-number high cases, with relatively high MYC/MAX signalling but low oestrogen receptor/FOXA1 signalling and p53 activity. Only <i>TP53</i> truncation and not missense mutations were implicated as loss-of-function mutations, suggesting different classes of p53 mutations may have distinct signalling consequences. PARADIGM cluster 5 was enriched for hormone receptor expression.</p></div></div></section><section data-title="Comparison to ovarian and breast cancers"><div class="c-article-section" id="Sec8-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec8">Comparison to ovarian and breast cancers</h2><div class="c-article-section__content" id="Sec8-content"><p>The clinical and pathologic features of uterine serous carcinoma and high-grade serous ovarian carcinoma (HGSOC) are quite similar. HGSOC shares many similar molecular features with basal-like breast carcinoma<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 32" title="The Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 490, 61–70 (2012)" href="/articles/nature12113#ref-CR32" id="ref-link-section-d169765955e6009">32</a></sup>. Focal SCNA patterns were similar between these three tumour subtypes and unsupervised clustering identified relatedness (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/nature12113#Fig5">Fig. 5a</a> and <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/nature12113#MOESM88">Supplementary Fig. 12.1</a>). Supervised analysis of transcriptome data sets showed high correlation between tumour subtypes (<a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/nature12113#MOESM88">Supplementary Fig. 12.2</a>). The MC3 DNA methylation subtype with minimal DNA methylation changes was also similar to basal-like breast and HGSOCs (<a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/nature12113#MOESM88">Supplementary Fig. 12.3</a>). A high frequency of <i>TP53</i> mutations is shared across these tumour subtypes (uterine serous, 91%; HGSOC, 96%; basal-like breast, 84%)<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 33" title="The Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 474, 609–615 (2011)" href="/articles/nature12113#ref-CR33" id="ref-link-section-d169765955e6029">33</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 34" title="Clarke, B. A. & Gilks, C. B. Endometrial carcinoma: controversies in histopathological assessment of grade and tumour cell type. J. Clin. Pathol. 63, 410–415 (2010)" href="/articles/nature12113#ref-CR34" id="ref-link-section-d169765955e6032">34</a></sup>, as is the very low frequency of <i>PTEN</i> mutations (uterine serous, 2%; HGSOC, 1%; basal-like breast, 1%). Differences included a higher frequency of <i>FBXW7</i>, <i>PPP2R1A</i> and <i>PIK3CA</i> mutations in uterine serous compared to basal-like breast and HGSOCs (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/nature12113#Fig5">Fig. 5b</a>). We showed that uterine serous carcinomas share many molecular features with both HGSOCs and basal-like breast carcinomas, despite more frequent mutations, suggesting new opportunities for overlapping treatment paradigms.</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-5" data-title="Genomic relationships between endometrial serous-like, ovarian serous, and basal-like breast carcinomas."><figure><figcaption><b id="Fig5" class="c-article-section__figure-caption" data-test="figure-caption-text">Figure 5: Genomic relationships between endometrial serous-like, ovarian serous, and basal-like breast carcinomas.</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/nature12113/figures/5" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fnature12113/MediaObjects/41586_2013_Article_BFnature12113_Fig5_HTML.jpg?as=webp"><img aria-describedby="Fig5" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fnature12113/MediaObjects/41586_2013_Article_BFnature12113_Fig5_HTML.jpg" alt="figure 5" loading="lazy" width="685" height="902"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-5-desc"><p><b>a</b>, SCNAs for each tumour type. <b>b</b>, Frequency of genomic alterations present in at least 10% of one tumour type.</p><p> <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/nature12113#MOESM87">PowerPoint slide</a> </p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/nature12113/figures/5" data-track-dest="link:Figure5 Full size image" aria-label="Full size image figure 5" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div></div></div></section><section data-title="Discussion"><div class="c-article-section" id="Sec9-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec9">Discussion</h2><div class="c-article-section__content" id="Sec9-content"><p>This integrated genomic and proteomic analysis of 373 endometrial cancers provides insights into disease biology and diagnostic classification that could have immediate therapeutic application. Our analysis identified four new groups of tumours based on integrated genomic data, including a novel <i>POLE</i> subtype in <span class="stix">∼</span>10% of endometrioid tumours. Ultrahigh somatic mutation frequency, MSS, and common, newly identified hotspot mutations in the exonuclease domain of <i>POLE</i> characterize this subtype. SCNAs add a layer of resolution, revealing that most endometrioid tumours have few SCNAs, most serous and serous-like tumours exhibit extensive SCNAs, and the extent of SCNA roughly correlates with progression-free survival.</p><p>Endometrial cancer has more frequent mutations in the PI(3)K/AKT pathway than any other tumour type studied by The Cancer Genome Atlas (TCGA) so far. Endometrioid endometrial carcinomas share many characteristics with colorectal carcinoma including a high frequency of MSI (40% and 11%, respectively), <i>POLE</i> mutations (7% and 3%, respectively) leading to ultrahigh mutation rates, and frequent activation of WNT/CTNNB1 signalling; yet endometrial carcinomas have novel exclusivity of <i>KRAS</i> and <i>CTNNB1</i> mutations and a distinct mechanism of pathway activation. Uterine serous carcinomas share many similar characteristics with basal-like breast and HGSOCs; three tumour types with high-frequency non-silent <i>TP53</i> mutations and extensive SCNA. However, the high frequency of <i>PIK3CA</i>, <i>FBXW7</i>, <i>PPP2R1A</i> and <i>ARID1A</i> mutations in uterine serous carcinomas are not found in basal-like breast and HGSOCs. The frequency of mutations in <i>PIK3CA</i>, <i>FBXW7</i> and <i>PPP2R1A</i> was <span class="stix">∼</span>30% higher than in a recently reported study of 76 uterine serous carcinomas<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 11" title="Kuhn, E. et al. Identification of molecular pathway aberrations in uterine serous carcinoma by genome-wide analyses. J. Natl. Cancer Inst. 104, 1503–1513 (2012)" href="/articles/nature12113#ref-CR11" id="ref-link-section-d169765955e6135">11</a></sup>, but similar to another study<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 12" title="Le Gallo, M. et al. Exome sequencing of serous endometrial tumors identifies recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes. Nature Genet. 44, 1310–1315 (2012)" href="/articles/nature12113#ref-CR12" id="ref-link-section-d169765955e6139">12</a></sup>. Uterine serous carcinomas have <i>ERBB2</i> amplification in 27% of tumours and <i>PIK3CA</i> mutations in 42%, which provide translational opportunities for targeted therapeutics.</p><p>Early stage type I endometrioid tumours are often treated with adjuvant radiotherapy, whereas similarly staged type II serous tumours are treated with chemotherapy. High-grade serous and endometrioid endometrial carcinomas are difficult to subtype correctly, and intra-observer concordance among speciality pathologists is low<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 7" title="McConechy, M. K. et al. Use of mutation profiles to refine the classification of endometrial carcinomas. J. Pathol. 228, 20–30 (2012)" href="/articles/nature12113#ref-CR7" id="ref-link-section-d169765955e6152">7</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 34" title="Clarke, B. A. & Gilks, C. B. Endometrial carcinoma: controversies in histopathological assessment of grade and tumour cell type. J. Clin. Pathol. 63, 410–415 (2010)" href="/articles/nature12113#ref-CR34" id="ref-link-section-d169765955e6155">34</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 35" title="Yemelyanova, A. et al. Utility of p16 expression for distinction of uterine serous carcinomas from endometrial endometrioid and endocervical adenocarcinomas: immunohistochemical analysis of 201 cases. Am. J. Surg. Pathol. 33, 1504–1514 (2009)" href="/articles/nature12113#ref-CR35" id="ref-link-section-d169765955e6158">35</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 36" title="Gilks, C. B., Oliva, E. & Soslow, R. A. Poor inter-observer reproducibility in the diagnosis of high-grade endometrial carcinoma. Am. J. Surg. Pathol. 91, 248A (2012)" href="/articles/nature12113#ref-CR36" id="ref-link-section-d169765955e6161">36</a></sup>. Our molecular characterization data demonstrate that <span class="stix">∼</span>25% of tumours classified as high-grade endometrioid by pathologists have a molecular phenotype similar to uterine serous carcinomas, including frequent <i>TP53</i> mutations and extensive SCNA. The compelling similarities between this subset of endometrioid tumours and uterine serous carcinomas suggest that genomic-based classification may lead to improved management of these patients. Clinicians should carefully consider treating copy-number-altered endometrioid patients with chemotherapy rather than adjuvant radiotherapy and formally test such hypotheses in prospective clinical trials. Furthermore, the marked molecular differences between endometrioid and serous-like tumours suggest that these tumours warrant separate clinical trials to develop the independent treatment paradigms that have improved outcomes in other tumour types, such as breast cancer.</p></div></div></section><section data-title="Methods Summary"><div class="c-article-section" id="Sec10-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec10">Methods Summary</h2><div class="c-article-section__content" id="Sec10-content"><p>Biospecimens were obtained from 373 patients after Institutional Review Board-approved consents. DNA and RNA were co-isolated using a modified AllPrep kit (Qiagen). We used Affymetrix SNP 6.0 microarrays to detect SCNAs in 363 samples and GISTIC analysis to identify recurrent events<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 37" title="Mermel, C. H. et al. GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. Genome Biol. 12, R41 (2011)" href="/articles/nature12113#ref-CR37" id="ref-link-section-d169765955e6176">37</a></sup>. The exomes of 248 tumours were sequenced to a read-depth of at least ×20. We performed low-pass whole-genome sequencing on 107 tumours to a mean depth of ×6. Consensus clustering was used to analyse mRNA, miRNA, RPPA and methylation data with methods previously described<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 38" title="Gaujoux, R. & Seoighe, C. A flexible R package for nonnegative matrix factorization. BMC Bioinformatics 11, 367 (2010)" href="/articles/nature12113#ref-CR38" id="ref-link-section-d169765955e6180">38</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 39" title="Houseman, E. A. et al. Model-based clustering of DNA methylation array data: a recursive-partitioning algorithm for high-dimensional data arising as a mixture of beta distributions. BMC Bioinformatics 9, 365 (2008)" href="/articles/nature12113#ref-CR39" id="ref-link-section-d169765955e6183">39</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 40" title="Brunet, J. P., Tamayo, P., Golub, T. R. & Mesirov, J. P. Metagenes and molecular pattern discovery using matrix factorization. Proc. Natl Acad. Sci. USA 101, 4164–4169 (2004)" href="/articles/nature12113#ref-CR40" id="ref-link-section-d169765955e6186">40</a></sup>. Integrated cross-platform analyses were performed using MEMo, iCluster and PARADIGM<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 25" title="Ciriello, G., Cerami, E., Sander, C. & Schultz, N. Mutual exclusivity analysis identifies oncogenic network modules. Genome Res. 22, 398–406 (2012)" href="/articles/nature12113#ref-CR25" id="ref-link-section-d169765955e6190">25</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 31" title="Vaske, C. J. et al. Inference of patient-specific pathway activities from multi-dimensional cancer genomics data using PARADIGM. Bioinformatics 26, i237–i245 (2010)" href="/articles/nature12113#ref-CR31" id="ref-link-section-d169765955e6193">31</a></sup>.</p></div></div></section> </div> <div> <section data-title="Change history"><div class="c-article-section" id="change-history-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="change-history">Change history</h2><div class="c-article-section__content" id="change-history-content"><ul class="c-article-change-list"><li class="c-article-change-list__item u-mb-24" id="chg1"><ins datetime="2013-06-12"><h3 class="c-article-change-list__heading u-h3 u-pr-8 u-display-inline">12 June 2013</h3><div class="c-article-change-list__details"><p>Nature 497, 67–73 (2013); doi:10.1038/nature12113 In the ‘Results’ section of this Article, the range in the sentence “The median follow-up of the cohort was 32 months (range, 1–19 months); 21% of the patients have recurred, and 11% have died.” should have been 1–195 months. This error has been corrected in the HTML and PDF versions of the paper.</p></div></ins></li></ul></div></div></section><div id="MagazineFulltextArticleBodySuffix"><section aria-labelledby="Bib1" data-title="References"><div class="c-article-section" id="Bib1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Bib1">References</h2><div class="c-article-section__content" id="Bib1-content"><div data-container-section="references"><ol class="c-article-references" data-track-component="outbound reference" data-track-context="references section"><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="1"><p class="c-article-references__text" id="ref-CR1">Siegel, R., Naishadham, D. & Jemal, A. Cancer statistics, 2013. <i>CA Cancer J. 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We thank M. Sheth and L. Lund for administrative coordination of TCGA activities, G. Monemvasitis for editing the manuscript, and C. Gunter for critical reading of the manuscript. This work was supported by the following grants from the US National Institutes of Health: 5U24CA143799-04, 5U24CA143835-04, 5U24CA143840-04, 5U24CA143843-04, 5U24CA143845-04, 5U24CA143848-04, 5U24CA143858-04, 5U24CA143866-04, 5U24CA143867-04, 5U24CA143882-04, 5U24CA143883-04, 5U24CA144025-04, U54HG003067-11, U54HG003079-10 and U54HG003273-10.</p></div></div></section><section aria-labelledby="author-information" data-title="Author information"><div class="c-article-section" id="author-information-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="author-information">Author information</h2><div class="c-article-section__content" id="author-information-content"><h3 class="c-article__sub-heading" id="affiliations">Authors and Affiliations</h3><ol class="c-article-author-affiliation__list"><li id="Aff1"><p class="c-article-author-affiliation__address">The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University Cambridge, Massachusetts 02142, USA., </p><p class="c-article-author-affiliation__authors-list">Gad Getz, Stacey B. Gabriel, Kristian Cibulskis, Eric Lander, Andrey Sivachenko, Carrie Sougnez, Mike Lawrence, Andrew D. Cherniack, Itai Pashtan, Gordon Saksena, Robert C. Onofrio, Steven E. Schumacher, Barbara Tabak, Scott L. Carter, Bryan Hernandez, Jeff Gentry, Helga B. Salvesen, Kristin Ardlie, Gad Getz, Wendy Winckler, Rameen Beroukhim, Stacey B. Gabriel, Matthew Meyerson, Lynda Chin, Lynda Chin, Gad Getz, Juok Cho, Daniel DiCara, Scott Frazer, David Heiman, Rui Jing, Pei Lin, Will Mallard, Doug Voet, Hailei Zhang, Lihua Zou, Michael Noble, Mike Lawrence, Andrew D. Cherniack, Rameen Beroukhim, Itai Pashtan, Helga B. Salvesen, Michael Noble, Andrew D. Cherniack & Itai Pashtan</p></li><li id="Aff2"><p class="c-article-author-affiliation__address">The Genome Institute, Washington University, St Louis, Missouri, 63108, USA</p><p class="c-article-author-affiliation__authors-list">Cyriac Kandoth, David Dooling, Robert Fulton, Lucinda Fulton, Joelle Kalicki-Veizer, Michael D. McLellan, Michelle O’Laughlin, Heather Schmidt, Richard K. Wilson, Kai Ye, Li Ding, Elaine R. Mardis, Li Ding, Cyriac Kandoth, Elaine R. Mardis, Cyriac Kandoth, Li Ding & Elaine R. Mardis</p></li><li id="Aff3"><p class="c-article-author-affiliation__address">Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z, Canada., </p><p class="c-article-author-affiliation__authors-list">Adrian Ally, Miruna Balasundaram, Inanc Birol, Yaron S. N. Butterfield, Rebecca Carlsen, Candace Carter, Andy Chu, Eric Chuah, Hye-Jung E. Chun, Noreen Dhalla, Ranabir Guin, Carrie Hirst, Robert A. Holt, Steven J. M. Jones, Darlene Lee, Haiyan I. Li, Marco A. Marra, Michael Mayo, Richard A. Moore, Andrew J. Mungall, Patrick Plettner, Jacqueline E. Schein, Payal Sipahimalani, Angela Tam, Richard J. Varhol, A. Gordon Robertson, A. Gordon Robertson & A. Gordon Robertson</p></li><li id="Aff4"><p class="c-article-author-affiliation__address">Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA., </p><p class="c-article-author-affiliation__authors-list">Itai Pashtan, Itai Pashtan & Itai Pashtan</p></li><li id="Aff5"><p class="c-article-author-affiliation__address">Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA., </p><p class="c-article-author-affiliation__authors-list">Itai Pashtan, Itai Pashtan & Itai Pashtan</p></li><li id="Aff6"><p class="c-article-author-affiliation__address">Department of Obstetrics and Gynecology, Haukeland University Hospital, 5021 Bergen, Norway., </p><p class="c-article-author-affiliation__authors-list">Helga B. Salvesen & Helga B. Salvesen</p></li><li id="Aff7"><p class="c-article-author-affiliation__address">Department of Clinical Medicine, University of Bergen, 5020, Bergen, Norway</p><p class="c-article-author-affiliation__authors-list">Helga B. Salvesen & Helga B. Salvesen</p></li><li id="Aff8"><p class="c-article-author-affiliation__address">Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA., </p><p class="c-article-author-affiliation__authors-list">Rameen Beroukhim, Matthew Meyerson & Rameen Beroukhim</p></li><li id="Aff9"><p class="c-article-author-affiliation__address">Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA., </p><p class="c-article-author-affiliation__authors-list">Angela Hadjipanayis, Xiaojia Ren, Raju Kucherlapati, Raju Kucherlapati & Raju Kucherlapati</p></li><li id="Aff10"><p class="c-article-author-affiliation__address">Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA., </p><p class="c-article-author-affiliation__authors-list">Semin Lee, Peter Park, Ruibin Xi & Lixing Yang</p></li><li id="Aff11"><p class="c-article-author-affiliation__address">Department of Genomic Medicine, Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA., </p><p class="c-article-author-affiliation__authors-list">Harshad S. Mahadeshwar, Alexei Protopopov, Sahil Seth, Xingzhi Song, Jiabin Tang, Dong Zeng, Lynda Chin, Jianhua Zhang, Lynda Chin & Jianhua Zhang</p></li><li id="Aff12"><p class="c-article-author-affiliation__address">Informatics Program, Boston Children’s Hospital, Boston, Massachusetts 02115, USA., </p><p class="c-article-author-affiliation__authors-list">Peter Park</p></li><li id="Aff13"><p class="c-article-author-affiliation__address">Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA., </p><p class="c-article-author-affiliation__authors-list">J. Todd Auman</p></li><li id="Aff14"><p class="c-article-author-affiliation__address">Institute for Pharmacogenetics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA., </p><p class="c-article-author-affiliation__authors-list">J. Todd Auman</p></li><li id="Aff15"><p class="c-article-author-affiliation__address">Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA., </p><p class="c-article-author-affiliation__authors-list">Saianand Balu, Tom Bodenheimer, Elizabeth Buda, D. Neil Hayes, Alan P. Hoyle, Stuart R. Jefferys, Shaowu Meng, Lisle E. Mose, Joel S. Parker, Charles M. Perou, Yan Shi, Janae V. Simons, Mathew G. Soloway, Donghui Tan, Michael D. Topal, Scot Waring, Junyuan Wu, Katherine A. Hoadley, W. Kimryn Rathmell & Katherine A. Hoadley</p></li><li id="Aff16"><p class="c-article-author-affiliation__address">Department of Internal Medicine, Division of Medical Oncology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA., </p><p class="c-article-author-affiliation__authors-list">D. Neil Hayes</p></li><li id="Aff17"><p class="c-article-author-affiliation__address">Department of Biology, University of North Carolina at Chapel Hill, North Carolina 27599, USA., </p><p class="c-article-author-affiliation__authors-list">Corbin D. Jones</p></li><li id="Aff18"><p class="c-article-author-affiliation__address">Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA., </p><p class="c-article-author-affiliation__authors-list">Piotr A. Mieczkowski, Charles M. Perou, Katherine A. Hoadley & Katherine A. Hoadley</p></li><li id="Aff19"><p class="c-article-author-affiliation__address">Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA., </p><p class="c-article-author-affiliation__authors-list">Charles M. Perou & Michael D. Topal</p></li><li id="Aff20"><p class="c-article-author-affiliation__address">Research Computing Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA., </p><p class="c-article-author-affiliation__authors-list">Jeff Roach</p></li><li id="Aff21"><p class="c-article-author-affiliation__address">Cancer Biology Division, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, Maryland 21231, USA., </p><p class="c-article-author-affiliation__authors-list">Stephen B. Baylin</p></li><li id="Aff22"><p class="c-article-author-affiliation__address">University of Southern California Epigenome Center, University of Southern California, Los Angeles, California 90089, USA., </p><p class="c-article-author-affiliation__authors-list">Moiz S. Bootwalla, Phillip H. Lai, Timothy J. Triche Jr, David J. Van Den Berg, Daniel J. Weisenberger, Peter W. Laird, Hui Shen, Hui Shen, Peter W. Laird, Hui Shen & Peter W. Laird</p></li><li id="Aff23"><p class="c-article-author-affiliation__address">Institute for Systems Biology, Seattle, Washington 98109, USA., </p><p class="c-article-author-affiliation__authors-list">Sheila M. Reynolds & Ilya Shmulevich</p></li><li id="Aff24"><p class="c-article-author-affiliation__address">Computational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA., </p><p class="c-article-author-affiliation__authors-list">B. Arman Aksoy, Yevgeniy Antipin, Giovanni Ciriello, Gideon Dresdner, Jianjiong Gao, Benjamin Gross, Anders Jacobsen, Boris Reva, Chris Sander, Rileen Sinha, S. Onur Sumer, Ethan Cerami, Nils Weinhold, Nikolaus Schultz, Nikolaus Schultz, Ethan Cerami, Nils Weinhold & Nikolaus Schultz</p></li><li id="Aff25"><p class="c-article-author-affiliation__address">Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA., </p><p class="c-article-author-affiliation__authors-list">Marc Ladanyi</p></li><li id="Aff26"><p class="c-article-author-affiliation__address">Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California 94158, USA., </p><p class="c-article-author-affiliation__authors-list">Barry S. Taylor</p></li><li id="Aff27"><p class="c-article-author-affiliation__address">Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA., </p><p class="c-article-author-affiliation__authors-list">Ronglai Shen & Ronglai Shen</p></li><li id="Aff28"><p class="c-article-author-affiliation__address">Department of Biomolecular Engineering and Center for Biomolecular Science and Engineering, University of California Santa Cruz, Santa Cruz, California 95064, USA., </p><p class="c-article-author-affiliation__authors-list">Stephen Benz, Ted Goldstein, David Haussler, Sam Ng, Christopher Szeto, Joshua Stuart & Joshua Stuart</p></li><li id="Aff29"><p class="c-article-author-affiliation__address">Buck Institute for Age Research, Novato, California 94945, USA., </p><p class="c-article-author-affiliation__authors-list">Christopher C. Benz, Christina Yau, Christopher C. Benz & Christina Yau</p></li><li id="Aff30"><p class="c-article-author-affiliation__address">Cancer Genomics Core Laboratory, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA., </p><p class="c-article-author-affiliation__authors-list">Wei Zhang, Matti Annala, Guoyan Liu, Yuexin Liu, Yuexin Liu, Wei Zhang, Yuexin Liu & Wei Zhang</p></li><li id="Aff31"><p class="c-article-author-affiliation__address">Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA., </p><p class="c-article-author-affiliation__authors-list">Wei Zhang, Matti Annala, Guoyan Liu, Yuexin Liu, Russell Broaddus, Russell Broaddus, Yuexin Liu, Russell Broaddus, Wei Zhang, Yuexin Liu & Wei Zhang</p></li><li id="Aff32"><p class="c-article-author-affiliation__address">Tampere University of Technology Korkeakoulunkatu 10, FI-33720 Tampere, Finland., </p><p class="c-article-author-affiliation__authors-list">Matti Annala</p></li><li id="Aff33"><p class="c-article-author-affiliation__address">Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA., </p><p class="c-article-author-affiliation__authors-list">Bradley M. Broom, Tod D. Casasent, Zhenlin Ju, Han Liang, Anna K. Unruh, Chris Wakefield, John N. Weinstein, Nianxiang Zhang, Rehan Akbani, Rehan Akbani & Rehan Akbani</p></li><li id="Aff34"><p class="c-article-author-affiliation__address">Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA., </p><p class="c-article-author-affiliation__authors-list">Yiling Lu, Gordon B. Mills, Gordon B. Mills & Gordon B. Mills</p></li><li id="Aff35"><p class="c-article-author-affiliation__address">The Research Institute at Nationwide Children’s Hospital, Columbus, Ohio 43205, USA., </p><p class="c-article-author-affiliation__authors-list">Christopher Adams, Thomas Barr, Aaron D. Black, Jay Bowen, John Deardurff, Jessica Frick, Julie M. Gastier-Foster, Thomas Grossman, Hollie A. Harper, Melissa Hart-Kothari, Carmen Helsel, Aaron Hobensack, Harkness Kuck, Kelley Kneile, Kristen M. Leraas, Tara M. Lichtenberg, Cynthia McAllister, Robert E. Pyatt, Nilsa C. Ramirez, Teresa R. Tabler, Nathan Vanhoose, Peter White, Lisa Wise & Erik Zmuda</p></li><li id="Aff36"><p class="c-article-author-affiliation__address">The Ohio State University, Columbus, Ohio 43210, USA., </p><p class="c-article-author-affiliation__authors-list">Julie M. Gastier-Foster, Nilsa C. Ramirez, Paul J. Goodfellow & Paul J. Goodfellow</p></li><li id="Aff37"><p class="c-article-author-affiliation__address">Asterand, Detroit, Michigan 48202, USA., </p><p class="c-article-author-affiliation__authors-list">Nandita Barnabas, Charlenia Berry-Green, Victoria Blanc, Michael Button, Adam Farkas, Alex Green, Jean MacKenzie & Dana Nicholson</p></li><li id="Aff38"><p class="c-article-author-affiliation__address">University of North Carolina, Chapel Hill, North Carolina 27599, USA., </p><p class="c-article-author-affiliation__authors-list">Lori Boice, Jennifer Fisher, Mei Huang, Leigh Thorne & Linda Van Le</p></li><li id="Aff39"><p class="c-article-author-affiliation__address">OvCaRe British Columbia, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 4E6, Canada., </p><p class="c-article-author-affiliation__authors-list">Steve E. Kalloger, C. Blake Gilks & C. Blake Gilks</p></li><li id="Aff40"><p class="c-article-author-affiliation__address">Department of Pathology & Laboratory Medicine, The University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada., </p><p class="c-article-author-affiliation__authors-list">Steve E. Kalloger, C. Blake Gilks & C. Blake Gilks</p></li><li id="Aff41"><p class="c-article-author-affiliation__address">Women’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA., </p><p class="c-article-author-affiliation__authors-list">Beth Y. Karlan, Jenny Lester, Sandra Orsulic & Beth Y. Karlan</p></li><li id="Aff42"><p class="c-article-author-affiliation__address">Helen F Graham Cancer Center at Christiana Care, Newark, Delaware 19713, USA., </p><p class="c-article-author-affiliation__authors-list">Mark Borowsky, Mark Cadungog, Christine Czerwinski, Lori Huelsenbeck-Dill, Mary Iacocca, Nicholas Petrelli, Brenda Rabeno & Gary Witkin</p></li><li id="Aff43"><p class="c-article-author-affiliation__address">Cureline, Inc., South San Francisco, California 94080, USA., </p><p class="c-article-author-affiliation__authors-list">Elena Nemirovich-Danchenko, Olga Potapova & Daniil Rotin</p></li><li id="Aff44"><p class="c-article-author-affiliation__address">Duke University Medical Center, Duke Cancer Institute, Durham, North Carolina 27710, USA., </p><p class="c-article-author-affiliation__authors-list">Andrew Berchuck & Andrew Berchuck</p></li><li id="Aff45"><p class="c-article-author-affiliation__address">Harvard Medical School, Massachusetts General Hospital Cancer Center, Boston, Massachusetts 02114, USA., </p><p class="c-article-author-affiliation__authors-list">Michael Birrer</p></li><li id="Aff46"><p class="c-article-author-affiliation__address">University of California Medical Center, Irvine, Orange California 92868, USA., </p><p class="c-article-author-affiliation__authors-list">Phillip DiSaia</p></li><li id="Aff47"><p class="c-article-author-affiliation__address">GOG Tissue Bank, The Research Institute at Nationwide Children’s Hospital, Columbus, Ohio 43205, USA., </p><p class="c-article-author-affiliation__authors-list">Laura Monovich</p></li><li id="Aff48"><p class="c-article-author-affiliation__address">International Genomics Consortium, Phoenix, Arizona 85004, USA., </p><p class="c-article-author-affiliation__authors-list">Erin Curley, Johanna Gardner, David Mallery & Robert Penny</p></li><li id="Aff49"><p class="c-article-author-affiliation__address">Department of OB Gyn, Division of Gynecologic Oncology, Mayo Clinic, Rochester, Minnesota 55905, USA., </p><p class="c-article-author-affiliation__authors-list">Sean C. Dowdy, Boris Winterhoff, Bobbie Gostout, Alexandra Meuter, Attila Teoman, Sean C. Dowdy & Boris Winterhoff</p></li><li id="Aff50"><p class="c-article-author-affiliation__address">Department of Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA., </p><p class="c-article-author-affiliation__authors-list">Linda Dao</p></li><li id="Aff51"><p class="c-article-author-affiliation__address">Department of Surgery, Gynecology Service, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA., </p><p class="c-article-author-affiliation__authors-list">Douglas A. Levine, Fanny Dao, Narciso Olvera, Faina Bogomolniy, Douglas A. Levine, Douglas A. Levine & Douglas A. Levine</p></li><li id="Aff52"><p class="c-article-author-affiliation__address">Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA., </p><p class="c-article-author-affiliation__authors-list">Karuna Garg, Robert A. Soslow & Robert A. Soslow</p></li><li id="Aff53"><p class="c-article-author-affiliation__address">N. N. Blokhin Russian Cancer Research Center RAMS, Moscow 115478, Russia., </p><p class="c-article-author-affiliation__authors-list">Mikhail Abramov</p></li><li id="Aff54"><p class="c-article-author-affiliation__address">Ontario Tumour Bank, Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada., </p><p class="c-article-author-affiliation__authors-list">John M. S. Bartlett & Sugy Kodeeswaran</p></li><li id="Aff55"><p class="c-article-author-affiliation__address">Ontario Tumour Bank, London Health Sciences Centre, London, Ontario N6A 5A5, Canada., </p><p class="c-article-author-affiliation__authors-list">Jeremy Parfitt</p></li><li id="Aff56"><p class="c-article-author-affiliation__address">St Petersburg Academic University, St Petersburg 199034, Russia., </p><p class="c-article-author-affiliation__authors-list">Fedor Moiseenko</p></li><li id="Aff57"><p class="c-article-author-affiliation__address">Department of Pathology, University Health Network, Toronto, Ontario M5G 2C4, Canada., </p><p class="c-article-author-affiliation__authors-list">Blaise A. Clarke</p></li><li id="Aff58"><p class="c-article-author-affiliation__address">University of Hawaii, Honolulu, Hawaii 96813, USA., </p><p class="c-article-author-affiliation__authors-list">Marc T. Goodman, Michael E. Carney, Rayna K. Matsuno & Marc T. Goodman</p></li><li id="Aff59"><p class="c-article-author-affiliation__address">Cedars-Sinai Medical Center, Los Angeles, California 90024, USA., </p><p class="c-article-author-affiliation__authors-list">Marc T. Goodman & Marc T. Goodman</p></li><li id="Aff60"><p class="c-article-author-affiliation__address">University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA., </p><p class="c-article-author-affiliation__authors-list">Rajiv Dhir, Robert Edwards, Esther Elishaev & Kristin Zorn</p></li><li id="Aff61"><p class="c-article-author-affiliation__address">Washington University School of Medicine, St Louis, Missouri 63110, USA., </p><p class="c-article-author-affiliation__authors-list">Paul J. Goodfellow, David Mutch, Paul J. Goodfellow & David Mutch</p></li><li id="Aff62"><p class="c-article-author-affiliation__address">SRA International, Fairfax, Virgina 22033, USA., </p><p class="c-article-author-affiliation__authors-list">Ari B. Kahn, Brenda Ayala, Anna L. Chu, Mark A. Jensen, Prachi Kothiyal, Todd D. Pihl, Joan Pontius, David A. Pot, Eric E. Snyder, Deepak Srinivasan & Ari B. Kahn</p></li><li id="Aff63"><p class="c-article-author-affiliation__address">Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA., </p><p class="c-article-author-affiliation__authors-list">Daphne W. Bell</p></li><li id="Aff64"><p class="c-article-author-affiliation__address">Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane 4059, Australia., </p><p class="c-article-author-affiliation__authors-list">Pamela M. Pollock</p></li><li id="Aff65"><p class="c-article-author-affiliation__address">Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota 55905, USA., </p><p class="c-article-author-affiliation__authors-list">Chen Wang</p></li><li id="Aff66"><p class="c-article-author-affiliation__address">Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA., </p><p class="c-article-author-affiliation__authors-list">David A.Wheeler & Eve Shinbrot</p></li><li id="Aff67"><p class="c-article-author-affiliation__address">The Cancer Genome Atlas Program Office, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA., </p><p class="c-article-author-affiliation__authors-list">Kenna R. Mills Shaw, Margi Sheth, Tanja Davidsen, John A. Demchok & Liming Yang</p></li><li id="Aff68"><p class="c-article-author-affiliation__address">Scimentis, LLC, Atlanta, Georgia 30666, USA., </p><p class="c-article-author-affiliation__authors-list">Greg Eley Martin L. Ferguson</p></li><li id="Aff69"><p class="c-article-author-affiliation__address">MLF Consulting, Arlington, Maryland 02474, USA., </p><p class="c-article-author-affiliation__authors-list">Greg Eley Martin L. Ferguson</p></li><li id="Aff70"><p class="c-article-author-affiliation__address">National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA., </p><p class="c-article-author-affiliation__authors-list">Mark S. Guyer, Bradley A. Ozenberger & Heidi J. Sofia</p></li></ol><div class="u-js-hide u-hide-print" data-test="author-info"><span class="c-article__sub-heading">Authors</span><ol class="c-article-authors-search u-list-reset"><li id="auth-Douglas_A_-Levine-Aff51"><span class="c-article-authors-search__title u-h3 js-search-name">Douglas A. Levine</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="/search?author=Douglas%20A.%20Levine" class="c-article-button" data-track="click" data-track-action="author link - publication" data-track-label="link" rel="nofollow">View author publications</a></div><div class="c-article-authors-search__item c-article-authors-search__list-item--right"><p class="search-in-title-js c-article-authors-search__text">You can also search for this author in <span class="c-article-identifiers"><a class="c-article-identifiers__item" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&term=Douglas%20A.%20Levine" data-track="click" data-track-action="author link - pubmed" data-track-label="link" rel="nofollow">PubMed</a><span class="u-hide"> </span><a class="c-article-identifiers__item" href="http://scholar.google.co.uk/scholar?as_q=&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_sauthors=%22Douglas%20A.%20Levine%22&as_publication=&as_ylo=&as_yhi=&as_allsubj=all&hl=en" data-track="click" data-track-action="author link - scholar" data-track-label="link" rel="nofollow">Google Scholar</a></span></p></div></div></li></ol></div><h3 class="c-article__sub-heading" id="groups">Consortia</h3><div class="c-article-author-institutional-author" id="group-1"><h3 class="c-article-author-institutional-author__name u-h3">The Cancer Genome Atlas Research Network</h3><ul class="c-article-author-institutional-author__author-list"><li class="c-article-author-institutional-author__author-name"><h4 class="c-article-author-institutional-author__sub-division">Genome sequencing centres: Broad Institute</h4><ul class="c-article-author-institutional-author__author-list"><li class="c-article-author-institutional-author__author-name">Gad Getz</li><li class="c-article-author-institutional-author__author-name">, Stacey B. Gabriel</li><li class="c-article-author-institutional-author__author-name">, Kristian Cibulskis</li><li class="c-article-author-institutional-author__author-name">, Eric Lander</li><li class="c-article-author-institutional-author__author-name">, Andrey Sivachenko</li><li class="c-article-author-institutional-author__author-name">, Carrie Sougnez</li><li class="c-article-author-institutional-author__author-name"> & Mike Lawrence</li></ul></li><li class="c-article-author-institutional-author__author-name"><h4 class="c-article-author-institutional-author__sub-division">Washington University in St Louis</h4><ul class="c-article-author-institutional-author__author-list"><li class="c-article-author-institutional-author__author-name">Cyriac Kandoth</li><li class="c-article-author-institutional-author__author-name">, David Dooling</li><li class="c-article-author-institutional-author__author-name">, Robert Fulton</li><li class="c-article-author-institutional-author__author-name">, Lucinda Fulton</li><li class="c-article-author-institutional-author__author-name">, Joelle Kalicki-Veizer</li><li class="c-article-author-institutional-author__author-name">, Michael D. McLellan</li><li class="c-article-author-institutional-author__author-name">, Michelle O’Laughlin</li><li class="c-article-author-institutional-author__author-name">, Heather Schmidt</li><li class="c-article-author-institutional-author__author-name">, Richard K. Wilson</li><li class="c-article-author-institutional-author__author-name">, Kai Ye</li><li class="c-article-author-institutional-author__author-name">, Li Ding</li><li class="c-article-author-institutional-author__author-name"> & Elaine R. Mardis</li></ul></li><li class="c-article-author-institutional-author__author-name"><h4 class="c-article-author-institutional-author__sub-division">Genome characterization centres: British Columbia Cancer Agency</h4><ul class="c-article-author-institutional-author__author-list"><li class="c-article-author-institutional-author__author-name">Adrian Ally</li><li class="c-article-author-institutional-author__author-name">, Miruna Balasundaram</li><li class="c-article-author-institutional-author__author-name">, Inanc Birol</li><li class="c-article-author-institutional-author__author-name">, Yaron S. N. Butterfield</li><li class="c-article-author-institutional-author__author-name">, Rebecca Carlsen</li><li class="c-article-author-institutional-author__author-name">, Candace Carter</li><li class="c-article-author-institutional-author__author-name">, Andy Chu</li><li class="c-article-author-institutional-author__author-name">, Eric Chuah</li><li class="c-article-author-institutional-author__author-name">, Hye-Jung E. Chun</li><li class="c-article-author-institutional-author__author-name">, Noreen Dhalla</li><li class="c-article-author-institutional-author__author-name">, Ranabir Guin</li><li class="c-article-author-institutional-author__author-name">, Carrie Hirst</li><li class="c-article-author-institutional-author__author-name">, Robert A. Holt</li><li class="c-article-author-institutional-author__author-name">, Steven J. M. Jones</li><li class="c-article-author-institutional-author__author-name">, Darlene Lee</li><li class="c-article-author-institutional-author__author-name">, Haiyan I. Li</li><li class="c-article-author-institutional-author__author-name">, Marco A. Marra</li><li class="c-article-author-institutional-author__author-name">, Michael Mayo</li><li class="c-article-author-institutional-author__author-name">, Richard A. Moore</li><li class="c-article-author-institutional-author__author-name">, Andrew J. Mungall</li><li class="c-article-author-institutional-author__author-name">, Patrick Plettner</li><li class="c-article-author-institutional-author__author-name">, Jacqueline E. Schein</li><li class="c-article-author-institutional-author__author-name">, Payal Sipahimalani</li><li class="c-article-author-institutional-author__author-name">, Angela Tam</li><li class="c-article-author-institutional-author__author-name">, Richard J. Varhol</li><li class="c-article-author-institutional-author__author-name"> & A. Gordon Robertson</li></ul></li><li class="c-article-author-institutional-author__author-name"><h4 class="c-article-author-institutional-author__sub-division">Broad Institute</h4><ul class="c-article-author-institutional-author__author-list"><li class="c-article-author-institutional-author__author-name">Andrew D. Cherniack</li><li class="c-article-author-institutional-author__author-name">, Itai Pashtan</li><li class="c-article-author-institutional-author__author-name">, Gordon Saksena</li><li class="c-article-author-institutional-author__author-name">, Robert C. Onofrio</li><li class="c-article-author-institutional-author__author-name">, Steven E. Schumacher</li><li class="c-article-author-institutional-author__author-name">, Barbara Tabak</li><li class="c-article-author-institutional-author__author-name">, Scott L. Carter</li><li class="c-article-author-institutional-author__author-name">, Bryan Hernandez</li><li class="c-article-author-institutional-author__author-name">, Jeff Gentry</li><li class="c-article-author-institutional-author__author-name">, Helga B. Salvesen</li><li class="c-article-author-institutional-author__author-name">, Kristin Ardlie</li><li class="c-article-author-institutional-author__author-name">, Gad Getz</li><li class="c-article-author-institutional-author__author-name">, Wendy Winckler</li><li class="c-article-author-institutional-author__author-name">, Rameen Beroukhim</li><li class="c-article-author-institutional-author__author-name">, Stacey B. Gabriel</li><li class="c-article-author-institutional-author__author-name"> & Matthew Meyerson</li></ul></li><li class="c-article-author-institutional-author__author-name"><h4 class="c-article-author-institutional-author__sub-division">Harvard Medical School/Brigham & Women’s Hospital/MD Anderson Cancer Center</h4><ul class="c-article-author-institutional-author__author-list"><li class="c-article-author-institutional-author__author-name">Angela Hadjipanayis</li><li class="c-article-author-institutional-author__author-name">, Semin Lee</li><li class="c-article-author-institutional-author__author-name">, Harshad S. Mahadeshwar</li><li class="c-article-author-institutional-author__author-name">, Peter Park</li><li class="c-article-author-institutional-author__author-name">, Alexei Protopopov</li><li class="c-article-author-institutional-author__author-name">, Xiaojia Ren</li><li class="c-article-author-institutional-author__author-name">, Sahil Seth</li><li class="c-article-author-institutional-author__author-name">, Xingzhi Song</li><li class="c-article-author-institutional-author__author-name">, Jiabin Tang</li><li class="c-article-author-institutional-author__author-name">, Ruibin Xi</li><li class="c-article-author-institutional-author__author-name">, Lixing Yang</li><li class="c-article-author-institutional-author__author-name">, Dong Zeng</li><li class="c-article-author-institutional-author__author-name">, Raju Kucherlapati</li><li class="c-article-author-institutional-author__author-name">, Lynda Chin</li><li class="c-article-author-institutional-author__author-name"> & Jianhua Zhang</li></ul></li><li class="c-article-author-institutional-author__author-name"><h4 class="c-article-author-institutional-author__sub-division">University of North Carolina</h4><ul class="c-article-author-institutional-author__author-list"><li class="c-article-author-institutional-author__author-name">J. Todd Auman</li><li class="c-article-author-institutional-author__author-name">, Saianand Balu</li><li class="c-article-author-institutional-author__author-name">, Tom Bodenheimer</li><li class="c-article-author-institutional-author__author-name">, Elizabeth Buda</li><li class="c-article-author-institutional-author__author-name">, D. Neil Hayes</li><li class="c-article-author-institutional-author__author-name">, Alan P. Hoyle</li><li class="c-article-author-institutional-author__author-name">, Stuart R. Jefferys</li><li class="c-article-author-institutional-author__author-name">, Corbin D. Jones</li><li class="c-article-author-institutional-author__author-name">, Shaowu Meng</li><li class="c-article-author-institutional-author__author-name">, Piotr A. Mieczkowski</li><li class="c-article-author-institutional-author__author-name">, Lisle E. Mose</li><li class="c-article-author-institutional-author__author-name">, Joel S. Parker</li><li class="c-article-author-institutional-author__author-name">, Charles M. Perou</li><li class="c-article-author-institutional-author__author-name">, Jeff Roach</li><li class="c-article-author-institutional-author__author-name">, Yan Shi</li><li class="c-article-author-institutional-author__author-name">, Janae V. Simons</li><li class="c-article-author-institutional-author__author-name">, Mathew G. Soloway</li><li class="c-article-author-institutional-author__author-name">, Donghui Tan</li><li class="c-article-author-institutional-author__author-name">, Michael D. Topal</li><li class="c-article-author-institutional-author__author-name">, Scot Waring</li><li class="c-article-author-institutional-author__author-name">, Junyuan Wu</li><li class="c-article-author-institutional-author__author-name"> & Katherine A. Hoadley</li></ul></li><li class="c-article-author-institutional-author__author-name"><h4 class="c-article-author-institutional-author__sub-division">University of Southern California & Johns Hopkins</h4><ul class="c-article-author-institutional-author__author-list"><li class="c-article-author-institutional-author__author-name">Stephen B. Baylin</li><li class="c-article-author-institutional-author__author-name">, Moiz S. Bootwalla</li><li class="c-article-author-institutional-author__author-name">, Phillip H. Lai</li><li class="c-article-author-institutional-author__author-name">, Timothy J. Triche Jr</li><li class="c-article-author-institutional-author__author-name">, David J. Van Den Berg</li><li class="c-article-author-institutional-author__author-name">, Daniel J. Weisenberger</li><li class="c-article-author-institutional-author__author-name">, Peter W. Laird</li><li class="c-article-author-institutional-author__author-name"> & Hui Shen</li></ul></li><li class="c-article-author-institutional-author__author-name"><h4 class="c-article-author-institutional-author__sub-division">Genome data analysis centres: Broad Institute</h4><ul class="c-article-author-institutional-author__author-list"><li class="c-article-author-institutional-author__author-name">Lynda Chin</li><li class="c-article-author-institutional-author__author-name">, Jianhua Zhang</li><li class="c-article-author-institutional-author__author-name">, Gad Getz</li><li class="c-article-author-institutional-author__author-name">, Juok Cho</li><li class="c-article-author-institutional-author__author-name">, Daniel DiCara</li><li class="c-article-author-institutional-author__author-name">, Scott Frazer</li><li class="c-article-author-institutional-author__author-name">, David Heiman</li><li class="c-article-author-institutional-author__author-name">, Rui Jing</li><li class="c-article-author-institutional-author__author-name">, Pei Lin</li><li class="c-article-author-institutional-author__author-name">, Will Mallard</li><li class="c-article-author-institutional-author__author-name">, Petar Stojanov</li><li class="c-article-author-institutional-author__author-name">, Doug Voet</li><li class="c-article-author-institutional-author__author-name">, Hailei Zhang</li><li class="c-article-author-institutional-author__author-name">, Lihua Zou</li><li class="c-article-author-institutional-author__author-name">, Michael Noble</li><li class="c-article-author-institutional-author__author-name"> & Mike Lawrence</li></ul></li><li class="c-article-author-institutional-author__author-name"><h4 class="c-article-author-institutional-author__sub-division">Institute for Systems Biology</h4><ul class="c-article-author-institutional-author__author-list"><li class="c-article-author-institutional-author__author-name">Sheila M. Reynolds</li><li class="c-article-author-institutional-author__author-name"> & Ilya Shmulevich</li></ul></li><li class="c-article-author-institutional-author__author-name"><h4 class="c-article-author-institutional-author__sub-division">Memorial Sloan-Kettering Cancer Center</h4><ul class="c-article-author-institutional-author__author-list"><li class="c-article-author-institutional-author__author-name">B. Arman Aksoy</li><li class="c-article-author-institutional-author__author-name">, Yevgeniy Antipin</li><li class="c-article-author-institutional-author__author-name">, Giovanni Ciriello</li><li class="c-article-author-institutional-author__author-name">, Gideon Dresdner</li><li class="c-article-author-institutional-author__author-name">, Jianjiong Gao</li><li class="c-article-author-institutional-author__author-name">, Benjamin Gross</li><li class="c-article-author-institutional-author__author-name">, Anders Jacobsen</li><li class="c-article-author-institutional-author__author-name">, Marc Ladanyi</li><li class="c-article-author-institutional-author__author-name">, Boris Reva</li><li class="c-article-author-institutional-author__author-name">, Chris Sander</li><li class="c-article-author-institutional-author__author-name">, Rileen Sinha</li><li class="c-article-author-institutional-author__author-name">, S. Onur Sumer</li><li class="c-article-author-institutional-author__author-name">, Barry S. Taylor</li><li class="c-article-author-institutional-author__author-name">, Ethan Cerami</li><li class="c-article-author-institutional-author__author-name">, Nils Weinhold</li><li class="c-article-author-institutional-author__author-name">, Nikolaus Schultz</li><li class="c-article-author-institutional-author__author-name"> & Ronglai Shen</li></ul></li><li class="c-article-author-institutional-author__author-name"><h4 class="c-article-author-institutional-author__sub-division">University of California, Santa Cruz/Buck Institute</h4><ul class="c-article-author-institutional-author__author-list"><li class="c-article-author-institutional-author__author-name">Stephen Benz</li><li class="c-article-author-institutional-author__author-name">, Ted Goldstein</li><li class="c-article-author-institutional-author__author-name">, David Haussler</li><li class="c-article-author-institutional-author__author-name">, Sam Ng</li><li class="c-article-author-institutional-author__author-name">, Christopher Szeto</li><li class="c-article-author-institutional-author__author-name">, Joshua Stuart</li><li class="c-article-author-institutional-author__author-name">, Christopher C. Benz</li><li class="c-article-author-institutional-author__author-name"> & Christina Yau</li></ul></li><li class="c-article-author-institutional-author__author-name"><h4 class="c-article-author-institutional-author__sub-division">The University of Texas MD Anderson Cancer Center</h4><ul class="c-article-author-institutional-author__author-list"><li class="c-article-author-institutional-author__author-name">Wei Zhang</li><li class="c-article-author-institutional-author__author-name">, Matti Annala</li><li class="c-article-author-institutional-author__author-name">, Bradley M. Broom</li><li class="c-article-author-institutional-author__author-name">, Tod D. Casasent</li><li class="c-article-author-institutional-author__author-name">, Zhenlin Ju</li><li class="c-article-author-institutional-author__author-name">, Han Liang</li><li class="c-article-author-institutional-author__author-name">, Guoyan Liu</li><li class="c-article-author-institutional-author__author-name">, Yiling Lu</li><li class="c-article-author-institutional-author__author-name">, Anna K. Unruh</li><li class="c-article-author-institutional-author__author-name">, Chris Wakefield</li><li class="c-article-author-institutional-author__author-name">, John N. Weinstein</li><li class="c-article-author-institutional-author__author-name">, Nianxiang Zhang</li><li class="c-article-author-institutional-author__author-name">, Yuexin Liu</li><li class="c-article-author-institutional-author__author-name">, Russell Broaddus</li><li class="c-article-author-institutional-author__author-name">, Rehan Akbani</li><li class="c-article-author-institutional-author__author-name"> & Gordon B. Mills</li></ul></li><li class="c-article-author-institutional-author__author-name"><h4 class="c-article-author-institutional-author__sub-division">Biospecimen core resource: Nationwide Children’s Hospital</h4><ul class="c-article-author-institutional-author__author-list"><li class="c-article-author-institutional-author__author-name">Christopher Adams</li><li class="c-article-author-institutional-author__author-name">, Thomas Barr</li><li class="c-article-author-institutional-author__author-name">, Aaron D. Black</li><li class="c-article-author-institutional-author__author-name">, Jay Bowen</li><li class="c-article-author-institutional-author__author-name">, John Deardurff</li><li class="c-article-author-institutional-author__author-name">, Jessica Frick</li><li class="c-article-author-institutional-author__author-name">, Julie M. Gastier-Foster</li><li class="c-article-author-institutional-author__author-name">, Thomas Grossman</li><li class="c-article-author-institutional-author__author-name">, Hollie A. Harper</li><li class="c-article-author-institutional-author__author-name">, Melissa Hart-Kothari</li><li class="c-article-author-institutional-author__author-name">, Carmen Helsel</li><li class="c-article-author-institutional-author__author-name">, Aaron Hobensack</li><li class="c-article-author-institutional-author__author-name">, Harkness Kuck</li><li class="c-article-author-institutional-author__author-name">, Kelley Kneile</li><li class="c-article-author-institutional-author__author-name">, Kristen M. Leraas</li><li class="c-article-author-institutional-author__author-name">, Tara M. Lichtenberg</li><li class="c-article-author-institutional-author__author-name">, Cynthia McAllister</li><li class="c-article-author-institutional-author__author-name">, Robert E. Pyatt</li><li class="c-article-author-institutional-author__author-name">, Nilsa C. Ramirez</li><li class="c-article-author-institutional-author__author-name">, Teresa R. Tabler</li><li class="c-article-author-institutional-author__author-name">, Nathan Vanhoose</li><li class="c-article-author-institutional-author__author-name">, Peter White</li><li class="c-article-author-institutional-author__author-name">, Lisa Wise</li><li class="c-article-author-institutional-author__author-name"> & Erik Zmuda</li></ul></li><li class="c-article-author-institutional-author__author-name"><h4 class="c-article-author-institutional-author__sub-division">Tissue source sites: Asterand</h4><ul class="c-article-author-institutional-author__author-list"><li class="c-article-author-institutional-author__author-name">Nandita Barnabas</li><li class="c-article-author-institutional-author__author-name">, Charlenia Berry-Green</li><li class="c-article-author-institutional-author__author-name">, Victoria Blanc</li><li class="c-article-author-institutional-author__author-name">, Lori Boice</li><li class="c-article-author-institutional-author__author-name">, Michael Button</li><li class="c-article-author-institutional-author__author-name">, Adam Farkas</li><li class="c-article-author-institutional-author__author-name">, Alex Green</li><li class="c-article-author-institutional-author__author-name">, Jean MacKenzie</li><li class="c-article-author-institutional-author__author-name"> & Dana Nicholson</li></ul></li><li class="c-article-author-institutional-author__author-name"><h4 class="c-article-author-institutional-author__sub-division">British Columbia Cancer Agency</h4><ul class="c-article-author-institutional-author__author-list"><li class="c-article-author-institutional-author__author-name">Steve E. Kalloger</li><li class="c-article-author-institutional-author__author-name"> & C. Blake Gilks</li></ul></li><li class="c-article-author-institutional-author__author-name"><h4 class="c-article-author-institutional-author__sub-division">Cedars-Sinai Medical Center</h4><ul class="c-article-author-institutional-author__author-list"><li class="c-article-author-institutional-author__author-name">Beth Y. Karlan</li><li class="c-article-author-institutional-author__author-name">, Jenny Lester</li><li class="c-article-author-institutional-author__author-name"> & Sandra Orsulic</li></ul></li><li class="c-article-author-institutional-author__author-name"><h4 class="c-article-author-institutional-author__sub-division">Christiana Care</h4><ul class="c-article-author-institutional-author__author-list"><li class="c-article-author-institutional-author__author-name">Mark Borowsky</li><li class="c-article-author-institutional-author__author-name">, Mark Cadungog</li><li class="c-article-author-institutional-author__author-name">, Christine Czerwinski</li><li class="c-article-author-institutional-author__author-name">, Lori Huelsenbeck-Dill</li><li class="c-article-author-institutional-author__author-name">, Mary Iacocca</li><li class="c-article-author-institutional-author__author-name">, Nicholas Petrelli</li><li class="c-article-author-institutional-author__author-name">, Brenda Rabeno</li><li class="c-article-author-institutional-author__author-name"> & Gary Witkin</li></ul></li><li class="c-article-author-institutional-author__author-name"><h4 class="c-article-author-institutional-author__sub-division">Cureline</h4><ul class="c-article-author-institutional-author__author-list"><li class="c-article-author-institutional-author__author-name">Elena Nemirovich-Danchenko</li><li class="c-article-author-institutional-author__author-name">, Olga Potapova</li><li class="c-article-author-institutional-author__author-name"> & Daniil Rotin</li></ul></li><li class="c-article-author-institutional-author__author-name"><h4 class="c-article-author-institutional-author__sub-division">Duke University</h4><ul class="c-article-author-institutional-author__author-list"><li class="c-article-author-institutional-author__author-name">Andrew Berchuck</li></ul></li><li class="c-article-author-institutional-author__author-name"><h4 class="c-article-author-institutional-author__sub-division">Gynecologic Oncology Group</h4><ul class="c-article-author-institutional-author__author-list"><li class="c-article-author-institutional-author__author-name">Michael Birrer</li><li class="c-article-author-institutional-author__author-name">, Phillip DiSaia</li><li class="c-article-author-institutional-author__author-name"> & Laura Monovich</li></ul></li><li class="c-article-author-institutional-author__author-name"><h4 class="c-article-author-institutional-author__sub-division">International Genomics Consortium</h4><ul class="c-article-author-institutional-author__author-list"><li class="c-article-author-institutional-author__author-name">Erin Curley</li><li class="c-article-author-institutional-author__author-name">, Johanna Gardner</li><li class="c-article-author-institutional-author__author-name">, David Mallery</li><li class="c-article-author-institutional-author__author-name"> & Robert Penny</li></ul></li><li class="c-article-author-institutional-author__author-name"><h4 class="c-article-author-institutional-author__sub-division">Mayo Clinic</h4><ul class="c-article-author-institutional-author__author-list"><li class="c-article-author-institutional-author__author-name">Sean C. Dowdy</li><li class="c-article-author-institutional-author__author-name">, Boris Winterhoff</li><li class="c-article-author-institutional-author__author-name">, Linda Dao</li><li class="c-article-author-institutional-author__author-name">, Bobbie Gostout</li><li class="c-article-author-institutional-author__author-name">, Alexandra Meuter</li><li class="c-article-author-institutional-author__author-name"> & Attila Teoman</li></ul></li><li class="c-article-author-institutional-author__author-name"><h4 class="c-article-author-institutional-author__sub-division">Memorial Sloan-Kettering Cancer Center</h4><ul class="c-article-author-institutional-author__author-list"><li class="c-article-author-institutional-author__author-name">Fanny Dao</li><li class="c-article-author-institutional-author__author-name">, Narciso Olvera</li><li class="c-article-author-institutional-author__author-name">, Faina Bogomolniy</li><li class="c-article-author-institutional-author__author-name">, Karuna Garg</li><li class="c-article-author-institutional-author__author-name">, Robert A. Soslow</li><li class="c-article-author-institutional-author__author-name"> & Douglas A. Levine</li></ul></li><li class="c-article-author-institutional-author__author-name"><h4 class="c-article-author-institutional-author__sub-division">N. N. Blokhin Russian Cancer Research Center</h4><ul class="c-article-author-institutional-author__author-list"><li class="c-article-author-institutional-author__author-name">Mikhail Abramov</li></ul></li><li class="c-article-author-institutional-author__author-name"><h4 class="c-article-author-institutional-author__sub-division">Ontario Tumour Bank</h4><ul class="c-article-author-institutional-author__author-list"><li class="c-article-author-institutional-author__author-name">John M. S. Bartlett</li><li class="c-article-author-institutional-author__author-name">, Sugy Kodeeswaran</li><li class="c-article-author-institutional-author__author-name"> & Jeremy Parfitt</li></ul></li><li class="c-article-author-institutional-author__author-name"><h4 class="c-article-author-institutional-author__sub-division">St Petersburg Academic University</h4><ul class="c-article-author-institutional-author__author-list"><li class="c-article-author-institutional-author__author-name">Fedor Moiseenko</li></ul></li><li class="c-article-author-institutional-author__author-name"><h4 class="c-article-author-institutional-author__sub-division">University Health Network</h4><ul class="c-article-author-institutional-author__author-list"><li class="c-article-author-institutional-author__author-name">Blaise A. Clarke</li></ul></li><li class="c-article-author-institutional-author__author-name"><h4 class="c-article-author-institutional-author__sub-division">University of Hawaii</h4><ul class="c-article-author-institutional-author__author-list"><li class="c-article-author-institutional-author__author-name">Marc T. Goodman</li><li class="c-article-author-institutional-author__author-name">, Michael E. Carney</li><li class="c-article-author-institutional-author__author-name"> & Rayna K. Matsuno</li></ul></li><li class="c-article-author-institutional-author__author-name"><h4 class="c-article-author-institutional-author__sub-division">University of North Carolina</h4><ul class="c-article-author-institutional-author__author-list"><li class="c-article-author-institutional-author__author-name">Jennifer Fisher</li><li class="c-article-author-institutional-author__author-name">, Mei Huang</li><li class="c-article-author-institutional-author__author-name">, W. Kimryn Rathmell</li><li class="c-article-author-institutional-author__author-name">, Leigh Thorne</li><li class="c-article-author-institutional-author__author-name"> & Linda Van Le</li></ul></li><li class="c-article-author-institutional-author__author-name"><h4 class="c-article-author-institutional-author__sub-division">University of Pittsburgh</h4><ul class="c-article-author-institutional-author__author-list"><li class="c-article-author-institutional-author__author-name">Rajiv Dhir</li><li class="c-article-author-institutional-author__author-name">, Robert Edwards</li><li class="c-article-author-institutional-author__author-name">, Esther Elishaev</li><li class="c-article-author-institutional-author__author-name"> & Kristin Zorn</li></ul></li><li class="c-article-author-institutional-author__author-name"><h4 class="c-article-author-institutional-author__sub-division">The University of Texas MD Anderson Cancer Center</h4><ul class="c-article-author-institutional-author__author-list"><li class="c-article-author-institutional-author__author-name">Russell Broaddus</li></ul></li><li class="c-article-author-institutional-author__author-name"><h4 class="c-article-author-institutional-author__sub-division">Washington University School of Medicine</h4><ul class="c-article-author-institutional-author__author-list"><li class="c-article-author-institutional-author__author-name">Paul J. Goodfellow</li><li class="c-article-author-institutional-author__author-name"> & David Mutch</li></ul></li><li class="c-article-author-institutional-author__author-name"><h4 class="c-article-author-institutional-author__sub-division">Disease analysis working group</h4><ul class="c-article-author-institutional-author__author-list"><li class="c-article-author-institutional-author__author-name">Nikolaus Schultz</li><li class="c-article-author-institutional-author__author-name">, Yuexin Liu</li><li class="c-article-author-institutional-author__author-name">, Rehan Akbani</li><li class="c-article-author-institutional-author__author-name">, Andrew D. Cherniack</li><li class="c-article-author-institutional-author__author-name">, Ethan Cerami</li><li class="c-article-author-institutional-author__author-name">, Nils Weinhold</li><li class="c-article-author-institutional-author__author-name">, Hui Shen</li><li class="c-article-author-institutional-author__author-name">, Katherine A. Hoadley</li><li class="c-article-author-institutional-author__author-name">, Ari B. Kahn</li><li class="c-article-author-institutional-author__author-name">, Daphne W. Bell</li><li class="c-article-author-institutional-author__author-name">, Pamela M. Pollock</li><li class="c-article-author-institutional-author__author-name">, Chen Wang</li><li class="c-article-author-institutional-author__author-name">, David A.Wheeler</li><li class="c-article-author-institutional-author__author-name">, Eve Shinbrot</li><li class="c-article-author-institutional-author__author-name">, Beth Y. Karlan</li><li class="c-article-author-institutional-author__author-name">, Andrew Berchuck</li><li class="c-article-author-institutional-author__author-name">, Sean C. Dowdy</li><li class="c-article-author-institutional-author__author-name">, Boris Winterhoff</li><li class="c-article-author-institutional-author__author-name">, Marc T. Goodman</li><li class="c-article-author-institutional-author__author-name">, A. Gordon Robertson</li><li class="c-article-author-institutional-author__author-name">, Rameen Beroukhim</li><li class="c-article-author-institutional-author__author-name">, Itai Pashtan</li><li class="c-article-author-institutional-author__author-name">, Helga B. Salvesen</li><li class="c-article-author-institutional-author__author-name">, Peter W. Laird</li><li class="c-article-author-institutional-author__author-name">, Michael Noble</li><li class="c-article-author-institutional-author__author-name">, Joshua Stuart</li><li class="c-article-author-institutional-author__author-name">, Li Ding</li><li class="c-article-author-institutional-author__author-name">, Cyriac Kandoth</li><li class="c-article-author-institutional-author__author-name">, C. Blake Gilks</li><li class="c-article-author-institutional-author__author-name">, Robert A. Soslow</li><li class="c-article-author-institutional-author__author-name">, Paul J. Goodfellow</li><li class="c-article-author-institutional-author__author-name">, David Mutch</li><li class="c-article-author-institutional-author__author-name">, Russell Broaddus</li><li class="c-article-author-institutional-author__author-name">, Wei Zhang</li><li class="c-article-author-institutional-author__author-name">, Gordon B. Mills</li><li class="c-article-author-institutional-author__author-name">, Raju Kucherlapati</li><li class="c-article-author-institutional-author__author-name">, Elaine R. Mardis</li><li class="c-article-author-institutional-author__author-name"> & Douglas A. Levine</li></ul></li><li class="c-article-author-institutional-author__author-name"><h4 class="c-article-author-institutional-author__sub-division">Data coordination centre</h4><ul class="c-article-author-institutional-author__author-list"><li class="c-article-author-institutional-author__author-name">Brenda Ayala</li><li class="c-article-author-institutional-author__author-name">, Anna L. Chu</li><li class="c-article-author-institutional-author__author-name">, Mark A. Jensen</li><li class="c-article-author-institutional-author__author-name">, Prachi Kothiyal</li><li class="c-article-author-institutional-author__author-name">, Todd D. Pihl</li><li class="c-article-author-institutional-author__author-name">, Joan Pontius</li><li class="c-article-author-institutional-author__author-name">, David A. Pot</li><li class="c-article-author-institutional-author__author-name">, Eric E. Snyder</li><li class="c-article-author-institutional-author__author-name">, Deepak Srinivasan</li><li class="c-article-author-institutional-author__author-name"> & Ari B. Kahn</li></ul></li><li class="c-article-author-institutional-author__author-name"><h4 class="c-article-author-institutional-author__sub-division">Project team: National Cancer Institute</h4><ul class="c-article-author-institutional-author__author-list"><li class="c-article-author-institutional-author__author-name">Kenna R. Mills Shaw</li><li class="c-article-author-institutional-author__author-name">, Margi Sheth</li><li class="c-article-author-institutional-author__author-name">, Tanja Davidsen</li><li class="c-article-author-institutional-author__author-name">, Greg Eley Martin L. Ferguson</li><li class="c-article-author-institutional-author__author-name">, John A. Demchok</li><li class="c-article-author-institutional-author__author-name"> & Liming Yang</li></ul></li><li class="c-article-author-institutional-author__author-name"><h4 class="c-article-author-institutional-author__sub-division">National Human Genome Research Institute</h4><ul class="c-article-author-institutional-author__author-list"><li class="c-article-author-institutional-author__author-name">Mark S. Guyer</li><li class="c-article-author-institutional-author__author-name">, Bradley A. Ozenberger</li><li class="c-article-author-institutional-author__author-name"> & Heidi J. Sofia</li></ul></li><li class="c-article-author-institutional-author__author-name"><h4 class="c-article-author-institutional-author__sub-division">Writing committee</h4><ul class="c-article-author-institutional-author__author-list"><li class="c-article-author-institutional-author__author-name">Cyriac Kandoth</li><li class="c-article-author-institutional-author__author-name">, Nikolaus Schultz</li><li class="c-article-author-institutional-author__author-name">, Andrew D. Cherniack</li><li class="c-article-author-institutional-author__author-name">, Rehan Akbani</li><li class="c-article-author-institutional-author__author-name">, Yuexin Liu</li><li class="c-article-author-institutional-author__author-name">, Hui Shen</li><li class="c-article-author-institutional-author__author-name">, A. Gordon Robertson</li><li class="c-article-author-institutional-author__author-name">, Itai Pashtan</li><li class="c-article-author-institutional-author__author-name">, Ronglai Shen</li><li class="c-article-author-institutional-author__author-name">, Christopher C. Benz</li><li class="c-article-author-institutional-author__author-name">, Christina Yau</li><li class="c-article-author-institutional-author__author-name">, Peter W. Laird</li><li class="c-article-author-institutional-author__author-name">, Li Ding</li><li class="c-article-author-institutional-author__author-name">, Wei Zhang</li><li class="c-article-author-institutional-author__author-name">, Gordon B. Mills</li><li class="c-article-author-institutional-author__author-name">, Raju Kucherlapati</li><li class="c-article-author-institutional-author__author-name">, Elaine R. Mardis</li><li class="c-article-author-institutional-author__author-name"> & Douglas A. Levine</li></ul></li></ul></div><h3 class="c-article__sub-heading" id="contributions">Contributions</h3><p>The TCGA Research Network contributed collectively to this study. Biospecimens were provided by the tissue source sites and processed by the biospecimen core resource. Data generation and analyses were performed by the genome sequencing centres, cancer genome characterization centres and genome data analysis centres. All data were released through the data coordinating centre. The National Cancer Institute and National Human Genome Research Institute project teams coordinated project activities. We also acknowledge the following TCGA investigators who made substantial contributions to the project: N.S. (manuscript coordinator); J. Gao (data coordinator); C.K. and L. Ding (DNA sequence analysis); W.Z. and Y.L. (mRNA sequence analysis); H.S. and P.W.L. (DNA methylation analysis); A.D.C. and I.P. (copy number analysis); S.L. and A. Hadjipanayis (translocations); N.S., N.W. G.C., C.C.B. and C.Y. (pathway analysis); Andy C. and A.G.R. (miRNA sequence analysis); R. Broaddus, P.J.G., G.B.M. and R.A.S. (pathology and clinical expertise); G.B.M., H.L. and R.A. (reverse phase protein arrays); P.J.G. and R.B. (disease experts); G.B.M. and R.K. (manuscript editing); D.A.L. and E.R.M. (project chairs).</p><h3 class="c-article__sub-heading" id="corresponding-author">Corresponding author</h3><p id="corresponding-author-list">Correspondence to <a id="corresp-c1" href="mailto:levine2@mskcc.org">Douglas A. Levine</a>.</p></div></div></section><section data-title="Ethics declarations"><div class="c-article-section" id="ethics-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="ethics">Ethics declarations</h2><div class="c-article-section__content" id="ethics-content"> <h3 class="c-article__sub-heading">Competing interests</h3> <p>The author declares no competing financial interests.</p> </div></div></section><section data-title="Additional information"><div class="c-article-section" id="additional-information-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="additional-information">Additional information</h2><div class="c-article-section__content" id="additional-information-content"><p>The primary and processed data used to generate the analyses presented here are deposited at the Data Coordinating Center (<a href="https://tcga-data.nci.nih.gov/tcga/tcgaDownload.jsp">https://tcga-data.nci.nih.gov/tcga/tcgaDownload.jsp</a>); all of the primary sequence files are deposited in CGHub (<a href="https://cghub.ucsc.edu/">https://cghub.ucsc.edu/</a>). Sample lists, data matrices and supporting data can be found at: (<a href="https://tcga-data.nci.nih.gov/docs/publications/ucec_2013/">https://tcga-data.nci.nih.gov/docs/publications/ucec_2013/</a>). The data can be explored via the cBio Cancer Genomics Portal (<a href="http://cbioportal.org">http://cbioportal.org</a>). Reprints and permissions information is available at <a href="http://www.nature.com/reprints">www.nature.com/reprints</a>. The authors declare no competing financial interests. Readers are welcome to comment on the online version of the paper. Correspondence and requests for materials should be addressed to D.A.L. (levine2@mskcc.org).</p><p>(Participants are arranged by area of contribution and then by institution.)</p></div></div></section><section data-title="Supplementary information"><div class="c-article-section" id="Sec11-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec11">Supplementary information</h2><div class="c-article-section__content" id="Sec11-content"><div data-test="supplementary-info"><div id="figshareContainer" class="c-article-figshare-container" data-test="figshare-container"></div><div class="c-article-supplementary__item" data-test="supp-item" id="MOESM88"><h3 class="c-article-supplementary__title u-h3"><a class="print-link" data-track="click" data-track-action="view supplementary info" data-test="supp-info-link" data-track-label="supplementary information" href="https://static-content.springer.com/esm/art%3A10.1038%2Fnature12113/MediaObjects/41586_2013_BFnature12113_MOESM88_ESM.pdf" data-supp-info-image="">Supplementary Information</a></h3><div class="c-article-supplementary__description" data-component="thumbnail-container"><p>This file contains Supplementary Methods 1-12, which includes Supplementary Figures and Tables and additional references (see pages 1 and 2 for details). (PDF 14394 kb)</p></div></div><div class="c-article-supplementary__item" data-test="supp-item" id="MOESM89"><h3 class="c-article-supplementary__title u-h3"><a class="print-link" data-track="click" data-track-action="view supplementary info" data-test="supp-info-link" data-track-label="supplementary data" href="https://static-content.springer.com/esm/art%3A10.1038%2Fnature12113/MediaObjects/41586_2013_BFnature12113_MOESM89_ESM.zip" data-supp-info-image="">Supplementary Data</a></h3><div class="c-article-supplementary__description" data-component="thumbnail-container"><p>This zipped file contains Supplementary Data files 1.1, 2.1, 3.1, 3.2 and 5.1 (see Supplementary Information document for details). (ZIP 698 kb)</p></div></div></div></div></div></section><section data-title="PowerPoint slides"><div class="c-article-section" id="Sec12-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec12">PowerPoint slides</h2><div class="c-article-section__content" id="Sec12-content"><div data-test="supplementary-info"><div class="c-article-supplementary__item" data-test="supp-item" id="MOESM83"><h3 class="c-article-supplementary__title u-h3"><a class="print-link" data-track="click" data-track-action="view supplementary info" data-test="supp-info-link" data-track-label="powerpoint slide for fig. 1" href="https://static-content.springer.com/esm/art%3A10.1038%2Fnature12113/MediaObjects/41586_2013_BFnature12113_MOESM83_ESM.ppt" data-supp-info-image="">PowerPoint slide for Fig. 1</a></h3></div><div class="c-article-supplementary__item" data-test="supp-item" id="MOESM84"><h3 class="c-article-supplementary__title u-h3"><a class="print-link" data-track="click" data-track-action="view supplementary info" data-test="supp-info-link" data-track-label="powerpoint slide for fig. 2" href="https://static-content.springer.com/esm/art%3A10.1038%2Fnature12113/MediaObjects/41586_2013_BFnature12113_MOESM84_ESM.ppt" data-supp-info-image="">PowerPoint slide for Fig. 2</a></h3></div><div class="c-article-supplementary__item" data-test="supp-item" id="MOESM85"><h3 class="c-article-supplementary__title u-h3"><a class="print-link" data-track="click" data-track-action="view supplementary info" data-test="supp-info-link" data-track-label="powerpoint slide for fig. 3" href="https://static-content.springer.com/esm/art%3A10.1038%2Fnature12113/MediaObjects/41586_2013_BFnature12113_MOESM85_ESM.ppt" data-supp-info-image="">PowerPoint slide for Fig. 3</a></h3></div><div class="c-article-supplementary__item" data-test="supp-item" id="MOESM86"><h3 class="c-article-supplementary__title u-h3"><a class="print-link" data-track="click" data-track-action="view supplementary info" data-test="supp-info-link" data-track-label="powerpoint slide for fig. 4" href="https://static-content.springer.com/esm/art%3A10.1038%2Fnature12113/MediaObjects/41586_2013_BFnature12113_MOESM86_ESM.ppt" data-supp-info-image="">PowerPoint slide for Fig. 4</a></h3></div><div class="c-article-supplementary__item" data-test="supp-item" id="MOESM87"><h3 class="c-article-supplementary__title u-h3"><a class="print-link" data-track="click" data-track-action="view supplementary info" data-test="supp-info-link" data-track-label="powerpoint slide for fig. 5" href="https://static-content.springer.com/esm/art%3A10.1038%2Fnature12113/MediaObjects/41586_2013_BFnature12113_MOESM87_ESM.ppt" data-supp-info-image="">PowerPoint slide for Fig. 5</a></h3></div></div></div></div></section><section data-title="Rights and permissions"><div class="c-article-section" id="rightslink-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="rightslink">Rights and permissions</h2><div class="c-article-section__content" id="rightslink-content"> <p>This work is licensed under a Creative Commons Attribution-Non-Commercial-ShareAlike 3.0 Unported licence. 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Integrated genomic characterization of endometrial carcinoma. <i>Nature</i> <b>497</b>, 67–73 (2013). https://doi.org/10.1038/nature12113</p><p class="c-bibliographic-information__download-citation u-hide-print"><a data-test="citation-link" data-track="click" data-track-action="download article citation" data-track-label="link" data-track-external="" rel="nofollow" href="https://citation-needed.springer.com/v2/references/10.1038/nature12113?format=refman&flavour=citation">Download citation<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-download-medium"></use></svg></a></p><ul class="c-bibliographic-information__list" data-test="publication-history"><li class="c-bibliographic-information__list-item"><p>Received<span class="u-hide">: </span><span class="c-bibliographic-information__value"><time datetime="2012-12-10">10 December 2012</time></span></p></li><li class="c-bibliographic-information__list-item"><p>Accepted<span class="u-hide">: </span><span class="c-bibliographic-information__value"><time datetime="2013-03-21">21 March 2013</time></span></p></li><li class="c-bibliographic-information__list-item"><p>Published<span class="u-hide">: </span><span class="c-bibliographic-information__value"><time datetime="2013-05-01">01 May 2013</time></span></p></li><li class="c-bibliographic-information__list-item"><p>Issue Date<span class="u-hide">: </span><span class="c-bibliographic-information__value"><time datetime="2013-05-02">02 May 2013</time></span></p></li><li class="c-bibliographic-information__list-item c-bibliographic-information__list-item--full-width"><p><abbr title="Digital Object Identifier">DOI</abbr><span class="u-hide">: </span><span class="c-bibliographic-information__value">https://doi.org/10.1038/nature12113</span></p></li></ul><div data-component="share-box"><div class="c-article-share-box u-display-none" hidden=""><h3 class="c-article__sub-heading">Share this article</h3><p class="c-article-share-box__description">Anyone you share the following link with will be able to read this content:</p><button class="js-get-share-url c-article-share-box__button" type="button" id="get-share-url" data-track="click" data-track-label="button" data-track-external="" data-track-action="get shareable link">Get shareable link</button><div class="js-no-share-url-container u-display-none" hidden=""><p class="js-c-article-share-box__no-sharelink-info c-article-share-box__no-sharelink-info">Sorry, a shareable link is not currently available for this article.</p></div><div class="js-share-url-container u-display-none" hidden=""><p class="js-share-url c-article-share-box__only-read-input" id="share-url" data-track="click" data-track-label="button" data-track-action="select share url"></p><button class="js-copy-share-url c-article-share-box__button--link-like" type="button" id="copy-share-url" data-track="click" data-track-label="button" data-track-action="copy share url" data-track-external="">Copy to clipboard</button></div><p class="js-c-article-share-box__additional-info c-article-share-box__additional-info"> Provided by the Springer Nature SharedIt content-sharing initiative </p></div></div><div data-component="article-info-list"></div></div></div></div></div></section> </div> <section> <div class="c-article-section js-article-section" id="further-reading-section" data-test="further-reading-section"> <h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="further-reading">This article is cited by</h2> <div class="c-article-section__content js-collapsible-section" id="further-reading-content"> <ul class="c-article-further-reading__list" id="further-reading-list"> <li class="c-article-further-reading__item js-ref-item"> <h3 class="c-article-further-reading__title" data-test="article-title"> <a class="print-link" data-track="click" data-track-action="view further reading article" data-track-label="link:Emerging roles of prominin-1 (CD133) in the dynamics of plasma membrane architecture and cell signaling pathways in health and disease" href="https://doi.org/10.1186/s11658-024-00554-0"> Emerging roles of prominin-1 (CD133) in the dynamics of plasma membrane architecture and cell signaling pathways in health and disease </a> </h3> <ul data-test="author-list" class="c-author-list c-author-list--compact c-author-list--truncated u-sans-serif u-mb-4 u-mt-auto"> <li>Petr Pleskač</li><li>Christine A. 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