Comprehensive molecular characterization of human colon and rectal cancer

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Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health.<br/> Learn more: <a class="usa-link" data-ga-category="Link click" data-ga-action="Disclaimer" data-ga-label="New disclaimer box" href="/about/disclaimer/">PMC Disclaimer</a> | <a class="usa-link" data-ga-category="Link click" data-ga-action="PMC Copyright Notice" data-ga-label="New disclaimer box" href="/about/copyright/"> PMC Copyright Notice </a> </div> </div> </div> <div class="grid-row pmc-wm desktop:margin-left-neg-6">  <main id="main-content" class="usa-layout-docs__main usa-layout-docs grid-col-12 pmc-layout pmc-prose padding-0" > <section class="pmc-journal-banner text-center line-height-none" aria-label="Journal banner"><img src="https://cdn.ncbi.nlm.nih.gov/pmc/banners/logo-npgopen.png" alt="Nature Portfolio logo" usemap="#pmc-banner-imagemap" width="500" height="75"><map name="pmc-banner-imagemap"><area alt="Link to Nature Portfolio" title="Link to Nature Portfolio" shape="default" href="https://doi.org/10.1038/nature11252" target="_blank" rel="noopener noreferrer"></map></section><article lang="en"><section aria-label="Article citation and metadata"><section class="pmc-layout__citation font-secondary font-xs"><div> <div class="display-inline-block"><button type="button" class="cursor-pointer text-no-underline bg-transparent border-0 padding-0 text-left margin-0 text-normal text-primary" aria-controls="journal_context_menu">Nature</button></div>. 2012 Jul 18;487(7407):330–337. doi: <a href="https://doi.org/10.1038/nature11252" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">10.1038/nature11252</a> </div> <nav id="journal_context_menu" hidden="hidden"><ul class="menu-list font-family-ui" role="menu"> <li role="presentation"><a href="https://www.ncbi.nlm.nih.gov/pmc/?term=%22Nature%22%5Bjour%5D" class="usa-link" role="menuitem">Search in PMC</a></li> <li role="presentation"><a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Nature%22%5Bjour%5D" lang="en" class="usa-link" role="menuitem">Search in PubMed</a></li> <li role="presentation"><a href="https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Nature%22%5BTitle%20Abbreviation%5D" class="usa-link" role="menuitem">View in NLM Catalog</a></li> <li role="presentation"><a href="?term=%22Nature%22%5Bjour%5D" class="usa-link" role="menuitem" data-add-to-search="true">Add to search</a></li> </ul></nav></section><section class="front-matter"><div class="ameta p font-secondary font-xs"> <hgroup><h1>Comprehensive molecular characterization of human colon and rectal cancer</h1></hgroup><div class="cg p"><span class="collab">The Cancer Genome Atlas Network</span></div> <ul class="d-buttons inline-list"> <li><button class="d-button" aria-controls="aip_a" aria-expanded="false">Author information</button></li> <li><button class="d-button" aria-controls="anp_a" aria-expanded="false">Article notes</button></li> <li><button class="d-button" aria-controls="clp_a" aria-expanded="false">Copyright and License information</button></li> </ul> <div class="d-panels font-secondary-light"> <div id="aip_a" class="d-panel p" style="display: none"> <div class="p" id="Aff2"> <sup>2</sup>Human Genome Sequencing Center, Baylor College of Medicine, Houston, 77030 Texas USA </div> <div id="Aff3"> <sup>3</sup>Department of Biology and Biochemistry, University of Houston, Houston, 77204 Texas USA </div> <div id="Aff4"> <sup>4</sup>Dan L. Duncan Cancer Center, Human Genome Sequencing Center, Baylor College of Medicine, Houston, 77030 Texas USA </div> <div id="Aff5"> <sup>5</sup>The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, 02142 Massachusetts USA </div> <div id="Aff6"> <sup>6</sup>Medical Sequencing Analysis and Informatics, The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, 02142 Massachusetts USA </div> <div id="Aff7"> <sup>7</sup>Department of Biology, Massachusetts Institute of Technology, Cambridge, 02142 Massachusetts USA </div> <div id="Aff8"> <sup>8</sup>Department of Systems Biology, Harvard University, Boston, 02115 Massachusetts USA </div> <div id="Aff9"> <sup>9</sup>Genetic Analysis Platform, The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, 02142 Massachusetts USA </div> <div id="Aff10"> <sup>10</sup>The Genome Institute, Washington University School of Medicine, St Louis, Missouri 63108 USA., , </div> <div id="Aff11"> <sup>11</sup>Department of Genetics, Washington University School of Medicine, St Louis, 63108 Missouri USA </div> <div id="Aff12"> <sup>12</sup>Siteman Cancer Center, Washington University School of Medicine, St Louis, 63108 Missouri USA </div> <div id="Aff13"> <sup>13</sup>Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, V5Z 1L3 British Columbia Canada </div> <div id="Aff14"> <sup>14</sup>Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 02115 Massachusetts USA </div> <div id="Aff15"> <sup>15</sup>Department of Pathology, Harvard Medical School, Boston, 02115 Massachusetts USA </div> <div id="Aff16"> <sup>16</sup>Department of Medical Oncology, Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, 02115 Massachusetts USA </div> <div id="Aff17"> <sup>17</sup>Department of Genetics, Harvard Medical School, Boston, 02115 Massachusetts USA </div> <div id="Aff18"> <sup>18</sup>Division of Genetics, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA., , </div> <div id="Aff19"> <sup>19</sup>The Center for Biomedical Informatics, Harvard Medical School, Boston, 02115 Massachusetts USA </div> <div id="Aff20"> <sup>20</sup>Informatics Program, Children’s Hospital, Boston, 02115 Massachusetts USA </div> <div id="Aff21"> <sup>21</sup>Department of Dermatology, Harvard Medical School, Boston, 02115 Massachusetts USA </div> <div id="Aff22"> <sup>22</sup>Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, 27599 North Carolina USA </div> <div id="Aff23"> <sup>23</sup>Institute for Pharmacogenetics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, 27599 North Carolina USA </div> <div id="Aff24"> <sup>24</sup>Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, 27599 North Carolina USA </div> <div id="Aff25"> <sup>25</sup>Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, 27599 North Carolina USA </div> <div id="Aff26"> <sup>26</sup>Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, 27599 North Carolina USA </div> <div id="Aff27"> <sup>27</sup>Carolina Center for Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, 27599 North Carolina USA </div> <div id="Aff28"> <sup>28</sup>Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, 27599 North Carolina USA </div> <div id="Aff29"> <sup>29</sup>Department of Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, 27599 North Carolina USA </div> <div id="Aff30"> <sup>30</sup>Department of Internal Medicine, Division of Medical Oncology, University of North Carolina at Chapel Hill, Chapel Hill, 27599 North Carolina USA </div> <div id="Aff31"> <sup>31</sup>University of Southern California Epigenome Center, University of Southern California, Los Angeles, 90089 California USA </div> <div id="Aff32"> <sup>32</sup>Cancer Biology Division, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, 21231 Maryland USA </div> <div id="Aff33"> <sup>33</sup>Institute for Systems Biology, Seattle, 98109 Washington USA </div> <div id="Aff34"> <sup>34</sup>Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, 77030 Texas USA </div> <div id="Aff35"> <sup>35</sup>Computational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, 10065 New York USA </div> <div id="Aff36"> <sup>36</sup>Divisions of Experimental Therapy, Molecular Biology, Surgical Oncology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands </div> <div id="Aff37"> <sup>37</sup>Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, 10065 New York USA </div> <div id="Aff38"> <sup>38</sup>Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, 10065 New York USA </div> <div id="Aff39"> <sup>39</sup>Department of Pathology, Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, 10065 New York USA </div> <div id="Aff40"> <sup>40</sup>Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA., , </div> <div id="Aff41"> <sup>41</sup>Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, 77030 Texas USA </div> <div id="Aff42"> <sup>42</sup>Department of Biomolecular Engineering and Center for Biomolecular Science and Engineering, University of California Santa Cruz, Santa Cruz, 95064 California USA </div> <div id="Aff43"> <sup>43</sup>Howard Hughes Medical Institute, University of California Santa Cruz, Santa Cruz, 95064 California USA </div> <div id="Aff44"> <sup>44</sup>Buck Institute for Age Research, Novato, 94945 California USA </div> <div id="Aff45"> <sup>45</sup>Division of Hematology/Oncology, University of California San Francisco, San Francisco, 94143 California USA </div> <div id="Aff46"> <sup>46</sup>Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, 97239 Oregon USA </div> <div id="Aff47"> <sup>47</sup>International Genomics Consortium, Phoenix, 85004 Arizona USA </div> <div id="Aff48"> <sup>48</sup>Nationwide Children’s Hospital Biospecimen Core Resource, The Research Institute at Nationwide Children’s Hospital, Columbus, Ohio 43205, USA., , </div> <div id="Aff49"> <sup>49</sup>Department of Pathology, The Ohio State University College of Medicine, Columbus, 43205 Ohio USA </div> <div id="Aff50"> <sup>50</sup>Department of Pediatrics, The Ohio State University College of Medicine, Columbus, 43205 Ohio USA </div> <div id="Aff51"> <sup>51</sup>Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Brookline, 02115 Massachusetts USA </div> <div id="Aff52"> <sup>52</sup>Department of Pathology, Christiana Care Health Services, Newark, Delaware 19718, USA., , </div> <div id="Aff53"> <sup>53</sup>Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, 10065 New York USA </div> <div id="Aff54"> <sup>54</sup>Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Brookline, 02115 Massachusetts USA </div> <div id="Aff55"> <sup>55</sup>Department of Surgery, Helen F. Graham Cancer Center at Christiana Care, Newark, 19718 Delaware USA </div> <div id="Aff56"> <sup>56</sup>Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA., , </div> <div id="Aff57"> <sup>57</sup>Klinik für Chirurgie, Krankenhaus Alten Eichen, Hamburg, 22527 Germany </div> <div id="Aff58"> <sup>58</sup>Department of Medical Oncology, Dana-Farber Cancer Institute, Brookline, 02115 Massachusetts USA </div> <div id="Aff59"> <sup>59</sup>Department of Medicine, Brigham and Women’s Hospital, Brookline, 02115 Massachusetts USA </div> <div id="Aff60"> <sup>60</sup>Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, 10065 New York USA </div> <div id="Aff61"> <sup>61</sup>Indivumed Inc., Kensington, 20895 Maryland USA </div> <div id="Aff62"> <sup>62</sup>ILSbio, LLC, Chestertown, 21620 Maryland USA </div> <div id="Aff63"> <sup>63</sup>Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, 10065 New York USA </div> <div id="Aff64"> <sup>64</sup>Department of Surgery, Brigham and Women’s Hospital, Brookline, 02115 Massachusetts USA </div> <div id="Aff65"> <sup>65</sup>Tissue and Blood Repository, Brigham and Women’s Hospital, Brookline, 02115 Massachusetts USA </div> <div id="Aff66"> <sup>66</sup>Dept of Radiation Oncology, University of North Carolina School of Medicine, Chapel Hill, 27599 North Carolina USA </div> <div id="Aff67"> <sup>67</sup>Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, 10065 New York USA </div> <div id="Aff68"> <sup>68</sup>Department of Pathology, Case Medical Center, Cleveland, 44106 Ohio USA </div> <div id="Aff69"> <sup>69</sup>Chirugische Klinik, Israelitisches Krankenhaus, Hamburg, 22297 Germany </div> <div id="Aff70"> <sup>70</sup>SRA International, Fairfax, Virginia 22033 USA </div> <div id="Aff71"> <sup>71</sup>The Cancer Genome Atlas Program Office, National Cancer Institute, National Institutes of Health, Bethesda, 20892 Maryland USA </div> <div id="Aff72"> <sup>72</sup>Center for Biomedical Informatics and Information Technology (CBIIT), National Cancer Institute, National Institutes of Health, Rockville, 20852 Maryland USA </div> <div id="Aff73"> <sup>73</sup>Scimentis, LLC, Statham, 30666 Georgia USA </div> <div id="Aff74"> <sup>74</sup>MLF Consulting, Arlington, 02474 Massachusetts USA </div> <div id="Aff75"> <sup>75</sup>National Human Genome Research Institute, National Institutes of Health, Bethesda, 20892 Maryland USA </div> </div> <div id="anp_a" class="d-panel p" style="display: none"><div class="notes p"><section id="historyarticle-meta1" class="history"><p>Received 2011 Nov 15; Accepted 2012 May 22; Issue date 2012.</p></section></div></div> <div id="clp_a" class="d-panel p" style="display: none"> <div>© The Author(s) 2012</div> <p>This article is distributed under the terms of the Creative Commons Attribution-Non-Commercial-Share Alike licence (<a href="https://creativecommons.org/licenses/by-nc-sa/3.0/" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">http://creativecommons.org/licenses/by-nc-sa/3.0/</a>), which permits distribution, and reproduction in any medium, provided the original author and source are credited. This licence does not permit commercial exploitation, and derivative works must be licensed under the same or similar licence.</p> <div class="p"><a href="/about/copyright/" class="usa-link">PMC Copyright notice</a></div> </div> </div> <div>PMCID: PMC3401966 NIHMSID: <a href="/articles/mid/NIHMS379461/" class="usa-link">NIHMS379461</a> PMID: <a href="https://pubmed.ncbi.nlm.nih.gov/22810696/" class="usa-link">22810696</a> </div> </div></section></section><section aria-label="Article content"><section class="body main-article-body"><section class="abstract" id="Abs1"><h2>Abstract</h2> <p>To characterize somatic alterations in colorectal carcinoma, we conducted a genome-scale analysis of 276 samples, analysing exome sequence, DNA copy number, promoter methylation and messenger RNA and microRNA expression. A subset of these samples (97) underwent low-depth-of-coverage whole-genome sequencing. In total, 16% of colorectal carcinomas were found to be hypermutated: three-quarters of these had the expected high microsatellite instability, usually with hypermethylation and <em>MLH1</em> silencing, and one-quarter had somatic mismatch-repair gene and polymerase ε (<em>POLE</em>) mutations. Excluding the hypermutated cancers, colon and rectum cancers were found to have considerably similar patterns of genomic alteration. Twenty-four genes were significantly mutated, and in addition to the expected <em>APC</em>, <em>TP53</em>, <em>SMAD4</em>, <em>PIK3CA</em> and <em>KRAS</em> mutations, we found frequent mutations in <em>ARID1A</em>, <em>SOX9</em> and <em>FAM123B.</em> Recurrent copy-number alterations include potentially drug-targetable amplifications of <em>ERBB2</em> and newly discovered amplification of <em>IGF2</em>. Recurrent chromosomal translocations include the fusion of <em>NAV2</em> and WNT pathway member <em>TCF7L1</em>. Integrative analyses suggest new markers for aggressive colorectal carcinoma and an important role for <em>MYC</em>-directed transcriptional activation and repression.</p> <section id="sec1"><h3 class="pmc_sec_title">Supplementary information</h3> <p>The online version of this article (doi:10.1038/nature11252) contains supplementary material, which is available to authorized users.</p></section><section id="kwd-group1" class="kwd-group"><p><strong>Subject terms:</strong> Genomics, Chromosome abnormality, DNA sequencing, Colorectal cancer</p></section></section><section class="abstract" id="Abs2"><hr class="headless"> <p>The Cancer Genome Atlas consortium reports on their genome-wide characterization of somatic alterations in colorectal cancer; in addition to revealing a remarkably consistent pattern of genomic alteration, with 24 genes being significantly mutated, the study identifies new targets for therapeutic intervention and suggests an important role for MYC-directed transcriptional activation and repression.</p> <section id="sec2"><h3 class="pmc_sec_title">Supplementary information</h3> <p>The online version of this article (doi:10.1038/nature11252) contains supplementary material, which is available to authorized users.</p></section></section><section class="abstract" id="Abs3"><h2>Mutations associated with colorectal cancer</h2> <p>The Cancer Genome Atlas consortium reports on their genome-wide characterization of somatic alterations in colorectal carcinoma. Combined analysis of exome sequence data, DNA copy number, promoter methylation, messenger RNA and microRNA expression, as well as low-coverage whole-genome sequencing reveal that 16% of these carcinomas have hypermutation. Of these, three-quarters have the expected high microsatellite instability, but the rest have somatic mismatch repair gene mutations. The data reveal a remarkably consistent pattern of genomic alteration, with 24 genes being significantly mutated. As well as identifying new biomarkers for aggressive colorectal carcinoma, the data imply an important role for <em>MYC</em>-directed transcriptional activation and repression.</p> <section id="sec3"><h3 class="pmc_sec_title">Supplementary information</h3> <p>The online version of this article (doi:10.1038/nature11252) contains supplementary material, which is available to authorized users.</p></section></section><section id="Sec1"><h2 class="pmc_sec_title">Main</h2> <p>The Cancer Genome Atlas project plans to profile genomic changes in 20 different cancer types and has so far published results on two cancer types<sup><a href="#CR1" class="usa-link" aria-describedby="CR1">1</a>,<a href="#CR2" class="usa-link" aria-describedby="CR2">2</a></sup>. We now present results from multidimensional analyses of human colorectal carcinoma (CRC).</p> <p>CRC is an important contributor to cancer mortality and morbidity. The distinction between the colon and the rectum is largely anatomical, but it has both surgical and radiotherapeutic management implications and it may have an impact on prognosis. Most investigators divide CRC biologically into those with microsatellite instability (MSI; located primarily in the right colon and frequently associated with the CpG island methylator phenotype (CIMP) and hyper-mutation) and those that are microsatellite stable but chromosomally unstable.</p> <p>A rich history of investigations (for a review see ref. <a href="#CR3" class="usa-link" aria-describedby="CR3">3</a>) has uncovered several critical genes and pathways important in the initiation and progression of CRC (ref. <a href="#CR3" class="usa-link" aria-describedby="CR3">3</a>). These include the WNT, RAS−MAPK, PI3K, TGF-β, P53 and DNA mismatch-repair pathways. Large-scale sequencing analyses<sup><a href="#CR4" class="usa-link" aria-describedby="CR4">4</a>,<a href="#CR5" class="usa-link" aria-describedby="CR5">5</a>,<a href="#CR6" class="usa-link" aria-describedby="CR6">6</a></sup> have identified numerous recurrently mutated genes and a recurrent chromosomal translocation. Despite this background, we have not had a fully integrated view of the genetic and genomic changes and their significance for colorectal tumorigenesis. Further insight into these changes may enable deeper understanding of the pathophysiology of CRC and may identify potential therapeutic targets.</p></section><section id="Sec2"><h2 class="pmc_sec_title">Results</h2> <p>Tumour and normal pairs were analysed by different platforms. The specific numbers of samples analysed by each platform are shown in <a href="#MOESM69" class="usa-link">Supplementary Table 1</a>.</p> <section id="Sec3"><h3 class="pmc_sec_title">Exome-sequence analysis</h3> <p>To define the mutational spectrum, we performed exome capture DNA sequencing on 224 tumour and normal pairs (all mutations are listed in <a href="#MOESM69" class="usa-link">Supplementary Table 2</a>). Sequencing achieved >20-fold coverage of at least 80% of targeted exons. The somatic mutation rates varied considerably among the samples. Some had mutation rates of <1 per 10<sup>6</sup> bases, whereas a few had mutations rates of >100 per 10<sup>6</sup>. We separated cases (84%) with a mutation rate of <8.24 per 10<sup>6</sup> (median number of non-silent mutations, 58) and those with mutation rates of >12 per 10<sup>6</sup> (median number of total mutations, 728), which we designated as hypermutated (<a href="#Fig1" class="usa-link">Fig. 1</a>).</p> <figure class="fig xbox font-sm" id="Fig1"><h4 class="obj_head">Figure 1. <strong>Mutation frequencies in human CRC.</strong> </h4> <p class="img-box line-height-none margin-x-neg-2 tablet:margin-x-0 text-center"><img class="graphic" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e0c/8127819/d098e83d26ba/41586_2012_BFnature11252_Fig1_HTML.jpg" loading="lazy" id="d32e3594" height="691" width="630" alt="Figure 1"></p> <div class="p text-right font-secondary"><a href="figure/Fig1/" class="usa-link" target="_blank" rel="noopener noreferrer">Open in a new tab</a></div> <figcaption><p><strong>a</strong>, Mutation frequencies in each of the tumour samples from 224 patients. Note a clear separation of hypermutated and non-hypermutated samples. Red, MSI high, CIMP high or MLH1 silenced; light blue, MSI low, or CIMP low; black, rectum; white, colon; grey, no data. Inset, mutations in mismatch-repair genes and <em>POLE</em> among the hypermutated samples. The order of the samples is the same as in the main graph. <strong>b</strong>, Significantly mutated genes in hypermutated and non-hypermutated tumours. Blue bars represent genes identified by the MutSig algorithm and black bars represent genes identified by manual examination of sequence data.</p> <p> <a href="#MOESM64" class="usa-link">PowerPoint slide</a> </p></figcaption></figure><p>To assess the basis for the considerably different mutation rates, we evaluated MSI<sup><a href="#CR7" class="usa-link" aria-describedby="CR7">7</a></sup> and mutations in the DNA mismatch-repair pathway<sup><a href="#CR8" class="usa-link" aria-describedby="CR8">8</a>,<a href="#CR9" class="usa-link" aria-describedby="CR9">9</a>,<a href="#CR10" class="usa-link" aria-describedby="CR10">10</a></sup> genes <em>MLH1</em>, <em>MLH3</em>, <em>MSH2</em>, <em>MSH3</em>, <em>MSH6</em> and <em>PMS2</em>. Among the 30 hypermutated tumours with a complete data set, 23 (77%) had high levels of MSI (MSI-H). Included in this group were 19 tumours with <em>MLH1</em> methylation, 17 of which had CIMP. By comparison, the remaining seven hypermutated tumours, including the six with the highest mutation rates, lacked MSI-H, CIMP or MLH1 methylation but usually had somatic mutations in one or more mismatch-repair genes or <em>POLΕ</em> aberrations seen rarely in the non-hypermutated tumours (<a href="#Fig1" class="usa-link">Fig. 1</a>).</p></section><section id="Sec4"><h3 class="pmc_sec_title">Gene mutations</h3> <p>Overall, we identified 32 somatic recurrently mutated genes (defined by MutSig<sup><a href="#CR11" class="usa-link" aria-describedby="CR11">11</a></sup> and manual curation) in the hypermutated and non-hypermutated cancers (<a href="#Fig1" class="usa-link">Fig. 1b</a>). After removal of non-expressed genes, there were 15 and 17 in the hypermutated and non-hypermutated cancers, respectively (<a href="#Fig1" class="usa-link">Fig. 1b</a>; for a complete list see <a href="#MOESM69" class="usa-link">Supplementary Table 3</a>). Among the non-hypermutated tumours, the eight most frequently mutated genes were <em>APC</em>, <em>TP53</em>, <em>KRAS</em>, <em>PIK3CA</em>, <em>FBXW7</em>, <em>SMAD4</em>, <em>TCF7L2</em> and <em>NRAS</em>. As expected, the mutated <em>KRAS</em> and <em>NRAS</em> genes usually had oncogenic codon 12 and 13 or codon 61 mutations, whereas the remaining genes had inactivating mutations. <em>CTNNB1</em>, <em>SMAD2</em>, <em>FAM123B</em> (also known as <em>WTX</em>) and <em>SOX9</em> were also mutated frequently. <em>FAM123B</em> is an X-linked negative regulator of WNT signalling<sup><a href="#CR12" class="usa-link" aria-describedby="CR12">12</a></sup>, and virtually all of its mutations were loss of function. Mutations in <em>SOX9</em>, a gene important for cell differentiation in the intestinal stem cell niche<sup><a href="#CR13" class="usa-link" aria-describedby="CR13">13</a>,<a href="#CR14" class="usa-link" aria-describedby="CR14">14</a></sup>, have not been associated previously with human cancer, but all nine mutated alleles in the non-hypermutated CRCs were frameshift or nonsense mutations. Tumour-suppressor genes <em>ATM</em> and <em>ARID1A</em> also had a disproportionately high number of frameshift or nonsense mutations. <em>ARID1A</em> mutations have recently been reported in CRC and many other cancers<sup><a href="#CR15" class="usa-link" aria-describedby="CR15">15</a>,<a href="#CR16" class="usa-link" aria-describedby="CR16">16</a></sup>.</p> <p>In the hypermutated tumours, <em>ACVR2A</em>, <em>APC</em>, <em>TGFBR2</em>, <em>MSH3</em>, <em>MSH6</em>, <em>SLC9A9</em> and <em>TCF7L2</em> were frequent targets of mutation (<a href="#Fig1" class="usa-link">Fig. 1b</a>), along with mostly <em>BRAF(V600E)</em> mutations. However, two genes that were frequently mutated in the non-hypermutated cancers were significantly less frequently mutated in hypermutated tumours: <em>TP53</em> (60 versus 20%, <em>P</em> < 0.0001) and <em>APC</em> (81% versus 51%, <em>P</em> = 0.0023; both Fisher’s exact test). Other genes, including <em>TGFBR2</em>, were mutated recurrently in the hypermutated cancers, but not in the non-hypermutated samples. These findings indicate that hypermutated and non-hypermutated tumours progress through different sequences of genetic events.</p> <p>As expected, hypermutated tumours with MLH1 silencing and MSI-H showed additional differences in the mutational profile. When we specifically examined 28 genes with long mononucleotide repeats in their coding sequences, we found that the rate of frameshift mutation was 3.6-fold higher than the rate of such mutations in hypermutated tumours without MLH1 silencing and 50-fold higher than that in non-hypermethylated tumours (<a href="#MOESM69" class="usa-link">Supplementary Table 2</a>).</p></section><section id="Sec5"><h3 class="pmc_sec_title">Mutation rate and methylation patterns</h3> <p>As mentioned above, patients with colon and rectal tumours are managed differently<sup><a href="#CR17" class="usa-link" aria-describedby="CR17">17</a></sup>, and epidemiology also highlights differences between the two<sup><a href="#CR17" class="usa-link" aria-describedby="CR17">17</a></sup>. An initial integrative analysis of MSI status, somatic copy-number alterations (SCNAs), CIMP status and gene-expression profiles of 132 colonic and 62 rectal tumours enabled us to examine possible biological differences between tumours in the two locations. Among the non-hypermutated tumours, however, the overall patterns of changes in copy number, CIMP, mRNA and miRNA were indistinguishable between colon and rectal carcinomas (<a href="#Fig2" class="usa-link">Fig. 2</a>). On the basis of this result, we merged the two for all subsequent analyses.</p> <figure class="fig xbox font-sm" id="Fig2"><h4 class="obj_head">Figure 2. <strong>Integrative analysis of genomic changes in 195 CRCs.</strong> </h4> <p class="img-box line-height-none margin-x-neg-2 tablet:margin-x-0 text-center"><img class="graphic" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e0c/8127819/3bb113331012/41586_2012_BFnature11252_Fig2_HTML.jpg" loading="lazy" id="d32e3825" height="361" width="630" alt="Figure 2"></p> <div class="p text-right font-secondary"><a href="figure/Fig2/" class="usa-link" target="_blank" rel="noopener noreferrer">Open in a new tab</a></div> <figcaption><p>Hypermutated tumours have near-diploid genomes and are highly enriched for hypermethylation, CIMP expression phenotype and <em>BRAF(V600E)</em> mutations. Non-hypermutated tumours originating from different sites are virtually indistinguishable from each other on the basis of their copy-number alteration patterns, DNA methylation or gene-expression patterns. Copy-number changes of the 22 autosomes are shown in shades of red for copy-number gains and shades of blue for copy-number losses.</p> <p> <a href="#MOESM65" class="usa-link">PowerPoint slide</a> </p></figcaption></figure><p>Unsupervised clustering of the promoter DNA methylation profiles of 236 colorectal tumours identified four subgroups (<a href="#MOESM69" class="usa-link">Supplementary Fig. 1</a> and <a href="#MOESM69" class="usa-link">Supplementary Methods</a>). Two of the clusters contained tumours with elevated rates of methylation and were classified as CIMP high and CIMP low, as previously described<sup><a href="#CR18" class="usa-link" aria-describedby="CR18">18</a></sup>. The two non-CIMP clusters were predominantly from tumours that were non-hypermutated and derived from different anatomic locations. mRNA expression profiles separated the colorectal tumours into three distinct clusters (<a href="#MOESM69" class="usa-link">Supplementary Fig. 2</a>). One significantly overlapped with CIMP-high tumours (<em>P</em> = 3 × 10<sup>−12</sup>) and was enriched with hypermutated tumours, and the other two clusters did not correspond with any group in the methylation data. Analysis of miRNA expression by unsupervised clustering (<a href="#MOESM69" class="usa-link">Supplementary Fig. 3</a>) identified no clear distinctions between rectal cancers and non-hypermethylated colon cancers.</p></section><section id="Sec6"><h3 class="pmc_sec_title">Chromosomal and sub-chromosomal changes</h3> <p>In total, 257 tumours were profiled for SCNAs with Affymetrix SNP 6.0 arrays. Of these tumours, 97 were also analysed by low-depth-of-coverage (low-pass) whole-genome sequencing. As expected, the hypermutated tumours had far fewer SCNAs (<a href="#Fig2" class="usa-link">Fig. 2</a>). No difference was found between microsatellite-stable and -unstable hypermutated tumours (<a href="#MOESM69" class="usa-link">Supplementary Fig. 4</a>). We used the GISTIC algorithm<sup><a href="#CR19" class="usa-link" aria-describedby="CR19">19</a></sup> to identify probable gene targets of focal alterations. There were several previously well-defined arm-level changes, including gains of 1q, 7p and q, 8p and q, 12q, 13q, 19q, and 20p and q (ref. <a href="#CR6" class="usa-link" aria-describedby="CR6">6</a>). (<a href="#MOESM69" class="usa-link">Supplementary Fig. 4</a> and <a href="#MOESM69" class="usa-link">Supplementary Table 4</a>). Significantly deleted chromosome arms were 18p and q (including <em>SMAD4</em>) in 66% of the tumours and 17p and q (including <em>TP53</em>) in 56%. Other significantly deleted chromosome arms were 1p, 4q, 5q, 8p, 14q, 15q, 20p and 22q.</p> <p>We identified 28 recurrent deletion peaks (<a href="#MOESM69" class="usa-link">Supplementary Fig. 4</a> and <a href="#MOESM69" class="usa-link">Supplementary Table 4</a>), including the genes <em>FHIT</em>, RBFOX1 and <em>WWOX</em> with large genomic footprints located in potentially fragile sites of the genome, in near-diploid hypermutated tumours. Other focal deletions involved tumour-suppressor genes such as <em>SMAD4</em>, <em>APC</em>, <em>PTEN</em> and <em>SMAD3</em>. A significant focal deletion of 10p25.2 spanned four genes, including <em>TCF7L2</em>, which was also frequently mutated in our data set. A gene fusion between adjacent genes <em>VTI1A</em> and <em>TCF7L2</em> through an interstitial deletion was found in 3% of CRCs and is required for survival of CRC cells bearing the translocation<sup><a href="#CR4" class="usa-link" aria-describedby="CR4">4</a></sup>.</p> <p>There were 17 regions of significant focal amplification (<a href="#MOESM69" class="usa-link">Supplementary Table 4</a>). Some of these were superimposed on broad gains of chromosome arms, and included a peak at 13q12.13 near the peptidase-coding gene <em>USP12</em> and at ∼500 kb distal to the CRC candidate oncogene <em>CDK8</em>; an adjacent peak at 13q12; a peak containing <em>KLF5</em> at 13q22.1; and a peak at 20q13.12 adjacent to <em>HNF4A</em>. Peaks on chromosome 8 included 8p12 (which contains the histone methyl-transferase-coding gene <em>WHSC1L1</em>, adjacent to <em>FGFR1</em>) and 8q24 (which contains <em>MYC</em>). An amplicon at 17q21.1, found in 4% of the tumours, contains seven genes, including the tyrosine kinase <em>ERBB2</em>. <em>ERBB2</em> amplifications have been described in colon, breast and gastro–oesophageal tumours, and breast and gastric cancers bearing these amplifications have been treated effectively with the anti-ERBB2 antibody trastuzumab<sup><a href="#CR20" class="usa-link" aria-describedby="CR20">20</a>,<a href="#CR21" class="usa-link" aria-describedby="CR21">21</a>,<a href="#CR22" class="usa-link" aria-describedby="CR22">22</a></sup>.</p> <p>One of the most common focal amplifications, found in 7% of the tumours, is the gain of a 100–150-kb region of the chromosome arm 11p15.5. It contains genes encoding insulin (<em>INS</em>), insulin-like growth factor 2 (<em>IGF2</em>) and tyrosine hydroxylase (<em>TH</em>), as well as <em>miR-483</em>, which is embedded within <em>IGF2</em> (<a href="#Fig3" class="usa-link">Fig. 3a</a>). We found elevated expression of <em>IGF2</em> and <em>miR-483</em> but not of <em>INS</em> and <em>TH</em> (<a href="#Fig3" class="usa-link">Fig. 3b, c</a>). Immediately adjacent to the amplified region is <em>ASCL2</em>, a transcription factor active in specifying intestinal stem-cell fate<sup><a href="#CR23" class="usa-link" aria-describedby="CR23">23</a></sup>. Although <em>ASCL2</em> has been implicated as a target of amplification in CRC<sup><a href="#CR23" class="usa-link" aria-describedby="CR23">23</a>,<a href="#CR24" class="usa-link" aria-describedby="CR24">24</a>,<a href="#CR25" class="usa-link" aria-describedby="CR25">25</a></sup>, it was consistently outside the region of amplification and its expression was not correlated with copy-number changes. These observations suggest that <em>IGF2</em> and miR-483 are candidate functional targets of 11p15.5 amplification. <em>IGF2</em> overexpression through loss of imprinting has been implicated in the promotion of CRC<sup><a href="#CR26" class="usa-link" aria-describedby="CR26">26</a>,<a href="#CR27" class="usa-link" aria-describedby="CR27">27</a></sup>. MiR-483 may also have a role in CRC pathogenesis<sup><a href="#CR28" class="usa-link" aria-describedby="CR28">28</a></sup>.</p> <figure class="fig xbox font-sm" id="Fig3"><h4 class="obj_head">Figure 3. <strong>Copy-number changes and structural aberrations in CRC.</strong> </h4> <p class="img-box line-height-none margin-x-neg-2 tablet:margin-x-0 text-center"><img class="graphic" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e0c/8127819/34a2ab4a1a3b/41586_2012_BFnature11252_Fig3_HTML.jpg" loading="lazy" id="d32e4090" height="579" width="630" alt="Figure 3"></p> <div class="p text-right font-secondary"><a href="figure/Fig3/" class="usa-link" target="_blank" rel="noopener noreferrer">Open in a new tab</a></div> <figcaption><p><strong>a</strong>, Focal amplification of 11p15.5. Segmented DNA copy-number data from single-nucleotide polymorphism (SNP) arrays and low-pass whole-genome sequencing (WGS) are shown. Each row represents a patient; amplified regions are shown in red. <strong>b</strong>, Correlation of expression levels with copy-number changes for <em>IGF2</em> and <em>miR-483</em>. <strong>c</strong>, <em>IGF2</em> amplification and overexpression are mutually exclusive of alterations in PI3K signalling-related genes. <strong>d</strong>, Recurrent <em>NAV2</em>–<em>TCF7L2</em> fusions. The structure of the two genes, locations of the breakpoints leading to the translocation and circular representations of all rearrangements in tumours with a fusion are shown. Red line lines represent the <em>NAV2</em>–<em>TCF7L2</em> fusions and black lines represent other rearrangements. The inner ring represents copy-number changes (blue denotes loss, pink denotes gain).</p> <p> <a href="#MOESM66" class="usa-link">PowerPoint slide</a> </p></figcaption></figure><p>A subset of tumours without <em>IGF2</em> amplification (15%) also had considerably higher levels of <em>IGF2</em> gene expression (as much as a 100-fold increase), an effect not attributable to methylation changes at the <em>IGF2</em> promoter. To assess the context of <em>IGF2</em> amplification/overexpression, we systematically searched for mutually exclusive genomic events using the MEMo method<sup><a href="#CR29" class="usa-link" aria-describedby="CR29">29</a></sup>. We found a pattern of near exclusivity (corrected <em>P</em> < 0.01) of <em>IGF2</em> overexpression with genomic events known to activate the PI3K pathway (mutations of <em>PIK3CA</em> and <em>PIK3R1</em> or deletion/mutation of <em>PTEN</em>; <a href="#Fig3" class="usa-link">Fig. 3c</a> and <a href="#MOESM69" class="usa-link">Supplementary Table 5</a>). The <em>IRS2</em> gene, encoding a protein linking IGF1R (the receptor for IGF2) with PI3K, is on chromosome 13, which is frequently gained in CRC. The cases with the highest <em>IRS2</em> expression were mutually exclusive of the cases with <em>IGF2</em> overexpression (<em>P</em> = 0.04) and also lacked mutations in the PI3K pathway (<em>P</em> = 0.0001; <a href="#Fig3" class="usa-link">Fig. 3c</a>). These results strongly suggest that the IGF2–IGF1R–IRS2 axis signals to PI3K in CRC and imply that therapeutic targeting of the pathway could act to block PI3K activity in this subset of patients.</p></section><section id="Sec7"><h3 class="pmc_sec_title">Translocations</h3> <p>To identify new chromosomal translocations, we performed low-pass, paired-end, whole-genome sequencing on 97 tumours with matched normal samples. In each case we achieved sequence coverage of ∼3–4-fold and a corresponding physical coverage of 7.5–10-fold. Despite the low genome coverage, we detected 250 candidate interchromosomal translocation events (range, 0–10 per tumour). Among these events, 212 had one or both breakpoints in an intergenic region, whereas the remaining 38 juxtaposed coding regions of two genes in putative fusion events, of which 18 were predicted to code for in-frame events (<a href="#MOESM69" class="usa-link">Supplementary Table 6</a>). We found three separate cases in which the first two exons of the <em>NAV2</em> gene on chromosome 11 are joined with the 3′ coding portion of <em>TCF7L1</em> on chromosome 2 (<a href="#MOESM69" class="usa-link">Supplementary Fig. 5</a>). <em>TCF7L1</em> encodes TCF3, a member of the TCF/LEF class of transcription factors that heterodimerize with nuclear β-catenin to enable β-catenin-mediated transcriptional regulation. Intriguingly, in all three cases, the predicted structure of the NAV2–TCF7L1 fusion protein lacks the TCF3 β-catenin-binding domain. This translocation is similar to another recurrent translocation identified in CRC, a fusion in which the amino terminus of VTI1A is joined to TCF4, which is encoded by <em>TCF7L2</em>, a homologue of <em>TCF7L1</em> that is deleted or mutated in 12% of non-hypermutated tumours<sup><a href="#CR4" class="usa-link" aria-describedby="CR4">4</a></sup>. We also observed 21 cases of translocation involving <em>TTC28</em> located on chromosome 22 (<a href="#MOESM69" class="usa-link">Supplementary Table 6</a>). In all cases the fusions predict inactivation of <em>TTC28</em>, which has been identified as a target of P53 and an inhibitor of tumour cell growth<sup><a href="#CR30" class="usa-link" aria-describedby="CR30">30</a></sup>. Eleven of the 19 (58%) gene–gene translocations were validated by obtaining PCR products or, in some cases, sequencing the junction fragments (<a href="#MOESM69" class="usa-link">Supplementary Fig. 5</a>).</p></section><section id="Sec8"><h3 class="pmc_sec_title">Altered pathways in CRC</h3> <p>Integrated analysis of mutations, copy number and mRNA expression changes in 195 tumours with complete data enriched our understanding of how some well-defined pathways are deregulated. We grouped samples by hypermutation status and identified recurrent alterations in the WNT, MAPK, PI3K, TGF-β and p53 pathways (<a href="#Fig4" class="usa-link">Fig. 4</a>, <a href="#MOESM69" class="usa-link">Supplementary Fig. 6</a> and <a href="#MOESM69" class="usa-link">Supplementary Table 1</a>).</p> <figure class="fig xbox font-sm" id="Fig4"><h4 class="obj_head">Figure 4. <strong>Diversity and frequency of genetic changes leading to deregulation of signalling pathways in CRC.</strong> </h4> <p class="img-box line-height-none margin-x-neg-2 tablet:margin-x-0 text-center"><img class="graphic" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e0c/8127819/f64274fd17cb/41586_2012_BFnature11252_Fig4_HTML.jpg" loading="lazy" id="d32e4244" height="404" width="630" alt="Figure 4"></p> <div class="p text-right font-secondary"><a href="figure/Fig4/" class="usa-link" target="_blank" rel="noopener noreferrer">Open in a new tab</a></div> <figcaption><p>Non-hypermutated (nHM; <em>n</em> = 165) and hypermutated (HM; <em>n</em> = 30) samples with complete data were analysed separately. Alterations are defined by somatic mutations, homozygous deletions, high-level focal amplifications, and, in some cases, by significant up- or downregulation of gene expression (<em>IGF2</em>, <em>FZD10</em>, <em>SMAD4</em>). Alteration frequencies are expressed as a percentage of all cases. Red denotes activated genes and blue denotes inactivated genes. Bottom panel shows for each sample if at least one gene in each of the five pathways described in this figure is altered.</p> <p> <a href="#MOESM67" class="usa-link">PowerPoint slide</a> </p></figcaption></figure><p>We found that the WNT signalling pathway was altered in 93% of all tumours, including biallelic inactivation of <em>APC</em> (<a href="#MOESM69" class="usa-link">Supplementary Table 7</a>) or activating mutations of <em>CTNNB1</em> in ∼80% of cases. There were also mutations in <em>SOX9</em> and mutations and deletions in <em>TCF7L2</em>, as well as the DKK family members and <em>AXIN2</em>, <em>FBXW7</em> (<a href="#MOESM69" class="usa-link">Supplementary Fig. 7</a>), <em>ARID1A</em> and <em>FAM123B</em> (the latter is a negative regulator of WNT–β-catenin signalling<sup><a href="#CR12" class="usa-link" aria-describedby="CR12">12</a></sup> found mutated in Wilms’ tumour<sup><a href="#CR31" class="usa-link" aria-describedby="CR31">31</a></sup>). A few mutations in <em>FAM123B</em> have previously been described in CRC<sup><a href="#CR32" class="usa-link" aria-describedby="CR32">32</a></sup>. SOX9 has been suggested to have a role in cancer, but no mutations have previously been described. The WNT receptor frizzled (<em>FZD10</em>) was overexpressed in ∼17% of samples, in some instances at levels of 100× normal. Altogether, we found 16 different altered WNT pathway genes, confirming the importance of this pathway in CRC. Interestingly, many of these alterations were found in tumours that harbour <em>APC</em> mutations, suggesting that multiple lesions affecting the WNT signalling pathway confer selective advantage.</p> <p>Genetic alterations in the PI3K and RAS–MAPK pathways are common in CRC. In addition to <em>IGF2</em> and <em>IRS2</em> overexpression, we found mutually exclusive mutations in <em>PIK3R1</em> and <em>PIK3CA</em> as well as deletions in <em>PTEN</em> in 2%, 15% and 4% of non-hypermutated tumours, respectively. We found that 55% of non-hypermutated tumours have alterations in <em>KRAS</em>, <em>NRAS</em> or <em>BRAF</em>, with a significant pattern of mutual exclusivity (<a href="#MOESM69" class="usa-link">Supplementary Fig. 6</a> and <a href="#MOESM69" class="usa-link">Supplementary Table 1</a>). We also evaluated mutations in the erythroblastic leukemia viral oncogene homolog (ERBB) family of receptors because of the translational relevance of such mutations. Mutations or amplifications in one of the four ERBB family genes are present in 22 out of 165 (13%) non-hypermutated and 16 out of 30 (53%) hypermutated cases. Some of the mutations are listed in the COSMIC database<sup><a href="#CR33" class="usa-link" aria-describedby="CR33">33</a></sup>, suggesting a functional role. Intriguingly, recurrent <em>ERBB2(V842I)</em> and <em>ERBB3(V104M)</em> mutations were found in four and two non-hypermutated cases, respectively. Mutations and focal amplifications of <em>ERBB2</em> (<a href="#MOESM69" class="usa-link">Supplementary Fig. 6</a>) should be evaluated as predictors of response to agents that target those receptors. We observed co-occurrence of alterations involving the RAS and PI3K pathways in one-third of tumours (<a href="#Fig4" class="usa-link">Fig. 4</a>; <em>P</em> = 0.039, Fisher’s exact test). These results indicate that simultaneous inhibition of the RAS and PI3K pathways may be required to achieve therapeutic benefit.</p> <p>The TGF-β signalling pathway is known to be deregulated in CRC and other cancers<sup><a href="#CR34" class="usa-link" aria-describedby="CR34">34</a></sup>. We found genomic alterations in <em>TGFBR1</em>, <em>TGFBR2</em>, <em>ACVR2A</em>, <em>ACVR1B</em>, <em>SMAD2</em>, <em>SMAD3</em> and <em>SMAD4</em> in 27% of the non-hypermutated and 87% of the hypermutated tumours. We also evaluated the p53 pathway, finding alterations in <em>TP53</em> in 59% of non-hypermutated cases (mostly biallelic; <a href="#MOESM69" class="usa-link">Supplementary Table 8</a>) and alterations in ATM, a kinase that phosphorylates and activates P53 after DNA damage, in 7%. Alterations in these two genes showed a trend towards mutual exclusivity (<em>P</em> = 0.016) (<a href="#Fig4" class="usa-link">Fig. 4</a>, <a href="#MOESM69" class="usa-link">Supplementary Fig. 6</a> and <a href="#MOESM69" class="usa-link">Supplementary Table 1</a>).</p> <p>We integrated copy number, gene expression, methylation and pathway data using the PARADIGM software platform<sup><a href="#CR35" class="usa-link" aria-describedby="CR35">35</a></sup>. The analysis showed a number of new characteristics of CRC (<a href="#Fig5" class="usa-link">Fig. 5a</a>). For example, despite the diversity in anatomical origin or mutation levels, nearly 100% of these tumours have changes in MYC transcriptional targets, both those promoted by and those inhibited by MYC. These findings are consistent with patterns deduced from genetic alterations (<a href="#Fig4" class="usa-link">Fig. 4</a>) and suggest an important role for <em>MYC</em> in CRC. The analysis also identified several gene networks altered across all tumour samples and those with differential alterations in hypermutated versus non-hypermutated samples (<a href="#MOESM69" class="usa-link">Supplementary Table 7</a>, Supplementary Data on the Cancer Genome Atlas publication webpage).</p> <figure class="fig xbox font-sm" id="Fig5"><h4 class="obj_head">Figure 5. <strong>Integrative analyses of multiple data sets.</strong> </h4> <p class="img-box line-height-none margin-x-neg-2 tablet:margin-x-0 text-center"><img class="graphic" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e0c/8127819/7d2dd59b07a3/41586_2012_BFnature11252_Fig5_HTML.jpg" loading="lazy" id="d32e4474" height="367" width="630" alt="Figure 5"></p> <div class="p text-right font-secondary"><a href="figure/Fig5/" class="usa-link" target="_blank" rel="noopener noreferrer">Open in a new tab</a></div> <figcaption><p><strong>a</strong>, Clustering of genes and pathways affected in colon and rectum tumours deduced by PARADIGM analysis. Blue denotes under-expressed relative to normal and red denotes overexpressed relative to normal. Some of the pathways deduced by this method are shown on the right. NHEJ, non-homologous end joining. <strong>b</strong>, Gene-expression signatures and SCNAs associated with tumour aggression. Molecular signatures (rows) that show a statistically significant association with tumour aggressiveness according to selected clinical assays (columns) are shown in colour, with red indicating markers of tumour aggressiveness and blue indicating the markers of less-aggressive tumours. Significance is based on the combined <em>P</em> value from the weighted Fisher’s method, corrected for multiple testing. Colour intensity and score is in accordance with the strength of an individual clinical–molecular association, and is proportional to log<sub>10</sub>(<em>P</em>), where <em>P</em> is the <em>P</em> value for that association. To limit the vertical extent of the figure, gene-expression signatures are restricted to a combined <em>P</em> value of <em>P</em> < 10<sup>−9</sup> and SCNAs to <em>P</em> < 10<sup>−7</sup>, and features are shown only if they are also significant in the subset of non-MSI-H samples (the analysis was performed separately on the full data as well as on the MSI-H and non-MSI-H subgroups).</p> <p> <a href="#MOESM68" class="usa-link">PowerPoint slide</a> </p></figcaption></figure><p>Because most of the tumours used in this study were derived from a prospective collection, survival data are not available. However, the tumours can be classified as aggressive or non-aggressive on the basis of tumour stage, lymph node status, distant metastasis and vascular invasion at the time of surgery. We found numerous molecular signatures associated with tumour aggressiveness, a subset of which is shown in <a href="#Fig5" class="usa-link">Fig. 5b</a>. They include specific focal amplifications and deletions, and altered gene-expression levels, including those of <em>SCN5A</em> (ref. <a href="#CR36" class="usa-link" aria-describedby="CR36">36</a>), a reported regulator of colon cancer invasion (see <a href="#MOESM69" class="usa-link">Supplementary Tables 10 and 11</a> for a full list). Association with tumour aggressiveness is also observed in altered expression of miRNAs and specific somatic mutations (<em>APC</em>, <em>TP53</em>, <em>PIK3CA</em>, <em>BRAF</em> and <em>FBXW7</em>; <a href="#MOESM69" class="usa-link">Supplementary Fig. 8b</a>). Mutations in <em>FBXW7</em> (38 cases) and distant metastasis (32 cases) never co-occurred (<em>P</em> = 0.0019). Interestingly, a number of genomic regions have multiple molecular associations with tumour aggressiveness that manifest as clinically related genomic hotspots. Examples of this are the region 20q13.12, which includes a focal amplification and multiple genes correlating with tumour aggression, and the region 22q12.3, containing <em>APOL6</em> (ref. <a href="#CR37" class="usa-link" aria-describedby="CR37">37</a>) (<a href="#MOESM69" class="usa-link">Supplementary Figures 8 and 9</a>).</p></section></section><section id="Sec9"><h2 class="pmc_sec_title">Discussion</h2> <p>This comprehensive integrative analysis of 224 colorectal tumour and normal pairs provides a number of insights into the biology of CRC and identifies potential therapeutic targets. To identify possible biological differences in colon and rectum tumours, we found, in the non-hypermutated tumours irrespective of their anatomical origin, the same type of copy number, expression profile, DNA methylation and miRNA changes. Over 94% had a mutation in one or more members of the WNT signalling pathway, predominantly in <em>APC</em>. However, there were some differences between tumours from the right colon and all other sites. Hypermethylation was more common in the right colon, and three-quarters of hypermutated samples came from the same site, although not all of them had MSI (<a href="#Fig2" class="usa-link">Fig. 2</a>). Why most of the hypermutated samples came from the right colon and why there are two classes of tumours at this site is not known. The origins of the colon from embryonic midgut and hindgut may provide an explanation. As the survival rate of patients with high MSI-related cancers is better and these cancers are hypermutated, mutation rate may be a better prognostic indicator.</p> <p>Whole-exome sequencing and integrative analysis of genomic data provided further insights into the pathways that are dysregulated in CRC. We found that 93% of non-hypermutated and 97% of hypermutated cases had a deregulated WNT signalling pathway. New findings included recurrent mutations in <em>FAM123B</em>, <em>ARID1A</em> and <em>SOX9</em> and very high levels of overexpression of the WNT ligand receptor gene <em>FZD10</em>. To our knowledge, <em>SOX9</em> has not previously been described as frequently mutated in any human cancer. <em>SOX9</em> is transcriptionally repressed by WNT signalling, and the SOX9 protein has been shown to facilitate β-catenin degradation<sup><a href="#CR38" class="usa-link" aria-describedby="CR38">38</a></sup>. <em>ARID1A</em> is frequently mutated in gynaecological cancers and has been shown to suppress <em>MYC</em> transcription<sup><a href="#CR39" class="usa-link" aria-describedby="CR39">39</a></sup>. Activation of WNT signalling and inactivation of the TGF-β signalling pathway are known to result in activation of MYC. Our mutational and integrative analyses emphasize the critical role of MYC in CRC. We also compared our results with other large-scale analyses<sup><a href="#CR6" class="usa-link" aria-describedby="CR6">6</a></sup> and found many similarities and few differences in mutated genes (<a href="#MOESM69" class="usa-link">Supplementary Table 3</a>).</p> <p>Our integrated analysis revealed a diverse set of changes in TCF/LEF-encoding genes, suggesting additional roles for TCF/LEF factors in CRC beyond being passive partners for β-catenin.</p> <p>Our data suggest a number of therapeutic approaches to CRC. Included are WNT-signalling inhibitors and small-molecule β-catenin inhibitors, which are showing initial promise<sup><a href="#CR40" class="usa-link" aria-describedby="CR40">40</a>,<a href="#CR41" class="usa-link" aria-describedby="CR41">41</a>,<a href="#CR42" class="usa-link" aria-describedby="CR42">42</a></sup>. We find that several proteins in the RTK–RAS and PI3K pathways, including IGF2, IGFR, ERBB2, ERBB3, MEK, AKT and MTOR could be targets for inhibition.</p> <p>Our analyses show that non-hypermutated adenocarcinomas of the colon and rectum are not distinguishable at the genomic level. However, tumours from the right/ascending colon were more likely to be hypermethylated and to have elevated mutation rates than were other CRCs. As has been recognized previously, activation of the WNT signalling pathway and inactivation of the TGF-β signalling pathway, resulting in increased activity of MYC, are nearly ubiquitous events in CRC. Genomic aberrations frequently target the MAPK and PI3K pathways but less frequently target receptor tyrosine kinases. In conclusion, the data presented here provide a useful resource for understanding this deadly disease and identifying possibilities for treating it in a targeted way.</p></section><section id="Sec10"><h2 class="pmc_sec_title">Methods Summary</h2> <p>Tumour and normal samples were processed by either of two biospecimen core resources, and aliquots of purified nucleic acids were shipped to the genome characterization and sequencing centres (<a href="#MOESM69" class="usa-link">Supplementary Methods</a>). The biospecimen core resources provided sample sets in several different batches. To assess any batch effects we examined the mRNA expression, miRNA expression and DNA methylation data sets using a combination of cluster analysis, enhanced principal component analysis and analysis of variance (<a href="#MOESM69" class="usa-link">Supplementary Methods</a>). Although some differences among batches were detected, we did not correct them computationally because the differences were generally modest and because some of them may reflect biological phenomena (<a href="#MOESM69" class="usa-link">Supplementary Methods</a>).</p> <p>We used Affymetrix SNP 6.0 microarrays to detect copy-number alterations. A subset of samples was subjected to low-pass (2–5×) whole-genome sequencing (Illumina HiSeq), in part for detection of SCNA and chromosomal translocations<sup><a href="#CR43" class="usa-link" aria-describedby="CR43">43</a>,<a href="#CR44" class="usa-link" aria-describedby="CR44">44</a></sup>. Gene-expression profiles were generated using Agilent microarrays and RNA-Seq. DNA methylation data were obtained using Illumina Infinium (HumanMethylation27) arrays. DNA sequencing of coding regions was performed by exome capture followed by sequencing on the SOLiD or Illumina HiSeq platforms. Details of the analytical methods used are described in <a href="#MOESM69" class="usa-link">Supplementary Methods</a>.</p> <p>All of the primary sequence files are deposited in dbGap and all other data are deposited at the Data Coordinating Center (DCC) for public access (<a href="http://cancergenome.nih.gov/" class="usa-link" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">http://cancergenome.nih.gov/</a>). Data matrices and supporting data can be found at <a href="http://tcga-data.nci.nih.gov/docs/publications/coadread_2012/" class="usa-link" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">http://tcga-data.nci.nih.gov/docs/publications/coadread_2012/</a>. The data can also be explored through the ISB Regulome Explorer (<a href="http://explorer.cancerregulome.org/" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">http://explorer.cancerregulome.org/</a>), Next Generation Clustered Heat Maps (<a href="http://bioinformatics.mdanderson.org/main/TCGA/Supplements/NGCHM-CRC" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">http://bioinformatics.mdanderson.org/main/TCGA/Supplements/NGCHM-CRC</a>) and the cBio Cancer Genomics Portal (<a href="http://cbioportal.org" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">http://cbioportal.org</a>). Descriptions of the data can be found at <a href="https://wiki.nci.nih.gov/x/j5dXAg" class="usa-link" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">https://wiki.nci.nih.gov/x/j5dXAg</a> and in <a href="#MOESM69" class="usa-link">Supplementary Methods</a>.</p></section><section id="sec14"><h2 class="pmc_sec_title">Supplementary information</h2> <section id="Sec11"><section class="sm xbox font-sm" id="MOESM69"><div class="media p"><div class="caption"> <a href="/articles/instance/8127819/bin/41586_2012_BFnature11252_MOESM69_ESM.pdf" data-ga-action="click_feat_suppl" class="usa-link"><span>Supplementary Information</span></a><sup> (7.9MB, pdf) </sup><p>This file contains the legends for Supplementary Tables 1-12, Supplementary Tables 1-9 and Supplementary Data files 1-2, Supplementary Methods, which include 17 Figures and 2 Tables (see Contents for details) and Supplementary Figures 1-9. (PDF 8117 kb)</p> </div></div></section><section class="sm xbox font-sm" id="MOESM70"><div class="media p"><div class="caption"> <a href="/articles/instance/8127819/bin/41586_2012_BFnature11252_MOESM70_ESM.zip" data-ga-action="click_feat_suppl" class="usa-link"><span>Supplementary Data</span></a><sup> (24.9MB, zip) </sup><p>This file contains Supplementary Table 2. (ZIP 25458 kb)</p> </div></div></section><section class="sm xbox font-sm" id="MOESM71"><div class="media p"><div class="caption"> <a href="/articles/instance/8127819/bin/41586_2012_BFnature11252_MOESM71_ESM.zip" data-ga-action="click_feat_suppl" class="usa-link"><span>Supplementary Data</span></a><sup> (2.7MB, zip) </sup><p>This file contains Supplementary Tables 1 and 3-12 (ZIP 2809 kb)</p> </div></div></section></section></section><section id="ack1" class="ack"><h2 class="pmc_sec_title">Acknowledgements</h2> <p>This work was supported by the following grants from the National Institutes of Health: U24CA143799, U24CA143835, U24CA143840, U24CA143843, U24CA143845, U24CA143848, U24CA143858, U24CA143866, U24CA143867, U24CA143882, U24CA143883, U24CA144025, U54HG003067, U54HG003079 and U54HG003273.</p></section><section id="App1" class="app"><section id="Sec12"><h3 class="pmc_sec_title">PowerPoint slides</h3> <div class="media p" id="MOESM64"><div class="caption"> <a href="/articles/instance/8127819/bin/41586_2012_BFnature11252_MOESM64_ESM.ppt" data-ga-action="click_feat_suppl" class="usa-link">PowerPoint slide for Fig. 1</a><sup> (576KB, ppt) </sup> </div></div> <div class="media p" id="MOESM65"><div class="caption"> <a href="/articles/instance/8127819/bin/41586_2012_BFnature11252_MOESM65_ESM.ppt" data-ga-action="click_feat_suppl" class="usa-link">PowerPoint slide for Fig. 2</a><sup> (536KB, ppt) </sup> </div></div> <div class="media p" id="MOESM66"><div class="caption"> <a href="/articles/instance/8127819/bin/41586_2012_BFnature11252_MOESM66_ESM.ppt" data-ga-action="click_feat_suppl" class="usa-link">PowerPoint slide for Fig. 3</a><sup> (563.5KB, ppt) </sup> </div></div> <div class="media p" id="MOESM67"><div class="caption"> <a href="/articles/instance/8127819/bin/41586_2012_BFnature11252_MOESM67_ESM.ppt" data-ga-action="click_feat_suppl" class="usa-link">PowerPoint slide for Fig. 4</a><sup> (559KB, ppt) </sup> </div></div> <div class="media p" id="MOESM68"><div class="caption"> <a href="/articles/instance/8127819/bin/41586_2012_BFnature11252_MOESM68_ESM.ppt" data-ga-action="click_feat_suppl" class="usa-link">PowerPoint slide for Fig. 5</a><sup> (581.5KB, ppt) </sup> </div></div></section></section><section id="notes1"><h2 class="pmc_sec_title">Author Contributions</h2> <p>The Cancer Genome Atlas 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 centers, cancer genome-characterization centers and genome data analysis centers. All data were released through the Data Coordinating Center. Project activities were coordinated by the National Cancer Institute and National Human Genome Research Institute project teams. Project leaders were R.K. and D.A.W. Writing team, T.A., A.J.B., T.A.C., L.D., A.H., S.R.H., R.K., P.W.L., M.M., N.S., I.S., J.M.S., J.T., V.T. and D.A.W.; mutations, M.S.L., L.R.T., D.A.W. and G.G.; copy-number and structural aberrations, A.H.R., A.J.B., A.H. and P.-C.C.; DNA methylation, T.H.; expression, J.T.A.; miRNA, G.R., A.C.; pathways, C.J.C., L.D., T.G., S.N., J.D.R., C.S., N.S., J.M.S. and V.T.</p></section><section id="notes2"><h2 class="pmc_sec_title">Accession codes</h2> <section id="d32e4671"><h3 class="pmc_sec_title">Data deposits</h3> <p>dbGaP accession numbers have been provided in Supplementary Table 1.</p></section></section><section id="notes3"><h2 class="pmc_sec_title">Competing interests</h2> <p>The author declare no competing financial interests.</p></section><section id="fn-group1" class="fn-group"><h2 class="pmc_sec_title">Footnotes</h2> <div class="fn-group p font-secondary-light font-sm"><div class="fn p" id="fn1"><p>(Participants are arranged by area of contribution, below, and by institution, above.)</p></div></div></section><section id="_ci93_" lang="en" class="contrib-info"><h2 class="pmc_sec_title">Contributor Information</h2> <p>The Cancer Genome Atlas Network: </p> <p><a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Muzny%20DM%22%5BAuthor%5D" class="usa-link">Donna M. Muzny</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Bainbridge%20MN%22%5BAuthor%5D" class="usa-link">Matthew N. Bainbridge</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Chang%20K%22%5BAuthor%5D" class="usa-link">Kyle Chang</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Dinh%20HH%22%5BAuthor%5D" class="usa-link">Huyen H. Dinh</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Drummond%20JA%22%5BAuthor%5D" class="usa-link">Jennifer A. Drummond</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Fowler%20G%22%5BAuthor%5D" class="usa-link">Gerald Fowler</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Kovar%20CL%22%5BAuthor%5D" class="usa-link">Christie L. Kovar</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Lewis%20LR%22%5BAuthor%5D" class="usa-link">Lora R. Lewis</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Morgan%20MB%22%5BAuthor%5D" class="usa-link">Margaret B. Morgan</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Newsham%20IF%22%5BAuthor%5D" class="usa-link">Irene F. Newsham</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Reid%20JG%22%5BAuthor%5D" class="usa-link">Jeffrey G. Reid</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Santibanez%20J%22%5BAuthor%5D" class="usa-link">Jireh Santibanez</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Shinbrot%20E%22%5BAuthor%5D" class="usa-link">Eve Shinbrot</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Trevino%20LR%22%5BAuthor%5D" class="usa-link">Lisa R. Trevino</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Wu%20YQ%22%5BAuthor%5D" class="usa-link">Yuan-Qing Wu</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Wang%20M%22%5BAuthor%5D" class="usa-link">Min Wang</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Gunaratne%20P%22%5BAuthor%5D" class="usa-link">Preethi Gunaratne</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Donehower%20LA%22%5BAuthor%5D" class="usa-link">Lawrence A. Donehower</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Creighton%20CJ%22%5BAuthor%5D" class="usa-link">Chad J. Creighton</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Wheeler%20DA%22%5BAuthor%5D" class="usa-link">David A. Wheeler</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Gibbs%20RA%22%5BAuthor%5D" class="usa-link">Richard A. Gibbs</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Lawrence%20MS%22%5BAuthor%5D" class="usa-link">Michael S. Lawrence</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Voet%20D%22%5BAuthor%5D" class="usa-link">Douglas Voet</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Jing%20R%22%5BAuthor%5D" class="usa-link">Rui Jing</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Cibulskis%20K%22%5BAuthor%5D" class="usa-link">Kristian Cibulskis</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Sivachenko%20A%22%5BAuthor%5D" class="usa-link">Andrey Sivachenko</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Stojanov%20P%22%5BAuthor%5D" class="usa-link">Petar Stojanov</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22McKenna%20A%22%5BAuthor%5D" class="usa-link">Aaron McKenna</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Lander%20ES%22%5BAuthor%5D" class="usa-link">Eric S. Lander</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Gabriel%20S%22%5BAuthor%5D" class="usa-link">Stacey Gabriel</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Getz%20G%22%5BAuthor%5D" class="usa-link">Gad Getz</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Ding%20L%22%5BAuthor%5D" class="usa-link">Li Ding</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Fulton%20RS%22%5BAuthor%5D" class="usa-link">Robert S. Fulton</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Koboldt%20DC%22%5BAuthor%5D" class="usa-link">Daniel C. Koboldt</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Wylie%20T%22%5BAuthor%5D" class="usa-link">Todd Wylie</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Walker%20J%22%5BAuthor%5D" class="usa-link">Jason Walker</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Dooling%20DJ%22%5BAuthor%5D" class="usa-link">David J. Dooling</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Fulton%20L%22%5BAuthor%5D" class="usa-link">Lucinda Fulton</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Delehaunty%20KD%22%5BAuthor%5D" class="usa-link">Kim D. Delehaunty</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Fronick%20CC%22%5BAuthor%5D" class="usa-link">Catrina C. Fronick</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Demeter%20R%22%5BAuthor%5D" class="usa-link">Ryan Demeter</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Mardis%20ER%22%5BAuthor%5D" class="usa-link">Elaine R. Mardis</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Wilson%20RK%22%5BAuthor%5D" class="usa-link">Richard K. Wilson</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Chu%20A%22%5BAuthor%5D" class="usa-link">Andy Chu</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Chun%20HJE%22%5BAuthor%5D" class="usa-link">Hye-Jung E. Chun</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Mungall%20AJ%22%5BAuthor%5D" class="usa-link">Andrew J. Mungall</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Pleasance%20E%22%5BAuthor%5D" class="usa-link">Erin Pleasance</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Gordon%20Robertson%20A%22%5BAuthor%5D" class="usa-link">A. Gordon Robertson</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Stoll%20D%22%5BAuthor%5D" class="usa-link">Dominik Stoll</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Balasundaram%20M%22%5BAuthor%5D" class="usa-link">Miruna Balasundaram</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Birol%20I%22%5BAuthor%5D" class="usa-link">Inanc Birol</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Butterfield%20YSN%22%5BAuthor%5D" class="usa-link">Yaron S. N. Butterfield</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Chuah%20E%22%5BAuthor%5D" class="usa-link">Eric Chuah</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Coope%20RJN%22%5BAuthor%5D" class="usa-link">Robin J. N. Coope</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Dhalla%20N%22%5BAuthor%5D" class="usa-link">Noreen Dhalla</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Guin%20R%22%5BAuthor%5D" class="usa-link">Ranabir Guin</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Hirst%20C%22%5BAuthor%5D" class="usa-link">Carrie Hirst</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Hirst%20M%22%5BAuthor%5D" class="usa-link">Martin Hirst</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Holt%20RA%22%5BAuthor%5D" class="usa-link">Robert A. Holt</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Lee%20D%22%5BAuthor%5D" class="usa-link">Darlene Lee</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Li%20HI%22%5BAuthor%5D" class="usa-link">Haiyan I. Li</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Mayo%20M%22%5BAuthor%5D" class="usa-link">Michael Mayo</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Moore%20RA%22%5BAuthor%5D" class="usa-link">Richard A. Moore</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Schein%20JE%22%5BAuthor%5D" class="usa-link">Jacqueline E. Schein</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Slobodan%20JR%22%5BAuthor%5D" class="usa-link">Jared R. Slobodan</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Tam%20A%22%5BAuthor%5D" class="usa-link">Angela Tam</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Thiessen%20N%22%5BAuthor%5D" class="usa-link">Nina Thiessen</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Varhol%20R%22%5BAuthor%5D" class="usa-link">Richard Varhol</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Zeng%20T%22%5BAuthor%5D" class="usa-link">Thomas Zeng</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Zhao%20Y%22%5BAuthor%5D" class="usa-link">Yongjun Zhao</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Jones%20SJM%22%5BAuthor%5D" class="usa-link">Steven J. M. Jones</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Marra%20MA%22%5BAuthor%5D" class="usa-link">Marco A. Marra</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Bass%20AJ%22%5BAuthor%5D" class="usa-link">Adam J. Bass</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Ramos%20AH%22%5BAuthor%5D" class="usa-link">Alex H. Ramos</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Saksena%20G%22%5BAuthor%5D" class="usa-link">Gordon Saksena</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Cherniack%20AD%22%5BAuthor%5D" class="usa-link">Andrew D. Cherniack</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Schumacher%20SE%22%5BAuthor%5D" class="usa-link">Stephen E. Schumacher</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Tabak%20B%22%5BAuthor%5D" class="usa-link">Barbara Tabak</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Carter%20SL%22%5BAuthor%5D" class="usa-link">Scott L. Carter</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Pho%20NH%22%5BAuthor%5D" class="usa-link">Nam H. Pho</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Nguyen%20H%22%5BAuthor%5D" class="usa-link">Huy Nguyen</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Onofrio%20RC%22%5BAuthor%5D" class="usa-link">Robert C. Onofrio</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Crenshaw%20A%22%5BAuthor%5D" class="usa-link">Andrew Crenshaw</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Ardlie%20K%22%5BAuthor%5D" class="usa-link">Kristin Ardlie</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Beroukhim%20R%22%5BAuthor%5D" class="usa-link">Rameen Beroukhim</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Winckler%20W%22%5BAuthor%5D" class="usa-link">Wendy Winckler</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Getz%20G%22%5BAuthor%5D" class="usa-link">Gad Getz</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Meyerson%20M%22%5BAuthor%5D" class="usa-link">Matthew Meyerson</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Protopopov%20A%22%5BAuthor%5D" class="usa-link">Alexei Protopopov</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Zhang%20J%22%5BAuthor%5D" class="usa-link">Juinhua Zhang</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Hadjipanayis%20A%22%5BAuthor%5D" class="usa-link">Angela Hadjipanayis</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Lee%20E%22%5BAuthor%5D" class="usa-link">Eunjung Lee</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Xi%20R%22%5BAuthor%5D" class="usa-link">Ruibin Xi</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Yang%20L%22%5BAuthor%5D" class="usa-link">Lixing Yang</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Ren%20X%22%5BAuthor%5D" class="usa-link">Xiaojia Ren</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Zhang%20H%22%5BAuthor%5D" class="usa-link">Hailei Zhang</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Sathiamoorthy%20N%22%5BAuthor%5D" class="usa-link">Narayanan Sathiamoorthy</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Shukla%20S%22%5BAuthor%5D" class="usa-link">Sachet Shukla</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Chen%20PC%22%5BAuthor%5D" class="usa-link">Peng-Chieh Chen</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Haseley%20P%22%5BAuthor%5D" class="usa-link">Psalm Haseley</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Xiao%20Y%22%5BAuthor%5D" class="usa-link">Yonghong Xiao</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Lee%20S%22%5BAuthor%5D" class="usa-link">Semin Lee</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Seidman%20J%22%5BAuthor%5D" class="usa-link">Jonathan Seidman</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Chin%20L%22%5BAuthor%5D" class="usa-link">Lynda Chin</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Park%20PJ%22%5BAuthor%5D" class="usa-link">Peter J. Park</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Kucherlapati%20R%22%5BAuthor%5D" class="usa-link">Raju Kucherlapati</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Todd%20Auman%20J%22%5BAuthor%5D" class="usa-link">J. Todd Auman</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Hoadley%20KA%22%5BAuthor%5D" class="usa-link">Katherine A. Hoadley</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Du%20Y%22%5BAuthor%5D" class="usa-link">Ying Du</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Wilkerson%20MD%22%5BAuthor%5D" class="usa-link">Matthew D. Wilkerson</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Shi%20Y%22%5BAuthor%5D" class="usa-link">Yan Shi</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Liquori%20C%22%5BAuthor%5D" class="usa-link">Christina Liquori</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Meng%20S%22%5BAuthor%5D" class="usa-link">Shaowu Meng</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Li%20L%22%5BAuthor%5D" class="usa-link">Ling Li</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Turman%20YJ%22%5BAuthor%5D" class="usa-link">Yidi J. Turman</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Topal%20MD%22%5BAuthor%5D" class="usa-link">Michael D. Topal</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Tan%20D%22%5BAuthor%5D" class="usa-link">Donghui Tan</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Waring%20S%22%5BAuthor%5D" class="usa-link">Scot Waring</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Buda%20E%22%5BAuthor%5D" class="usa-link">Elizabeth Buda</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Walsh%20J%22%5BAuthor%5D" class="usa-link">Jesse Walsh</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Jones%20CD%22%5BAuthor%5D" class="usa-link">Corbin D. Jones</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Mieczkowski%20PA%22%5BAuthor%5D" class="usa-link">Piotr A. Mieczkowski</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Singh%20D%22%5BAuthor%5D" class="usa-link">Darshan Singh</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Wu%20J%22%5BAuthor%5D" class="usa-link">Junyuan Wu</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Gulabani%20A%22%5BAuthor%5D" class="usa-link">Anisha Gulabani</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Dolina%20P%22%5BAuthor%5D" class="usa-link">Peter Dolina</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Bodenheimer%20T%22%5BAuthor%5D" class="usa-link">Tom Bodenheimer</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Hoyle%20AP%22%5BAuthor%5D" class="usa-link">Alan P. Hoyle</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Simons%20JV%22%5BAuthor%5D" class="usa-link">Janae V. Simons</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Soloway%20M%22%5BAuthor%5D" class="usa-link">Matthew Soloway</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Mose%20LE%22%5BAuthor%5D" class="usa-link">Lisle E. Mose</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Jefferys%20SR%22%5BAuthor%5D" class="usa-link">Stuart R. Jefferys</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Balu%20S%22%5BAuthor%5D" class="usa-link">Saianand Balu</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22O%E2%80%99Connor%20BD%22%5BAuthor%5D" class="usa-link">Brian D. O’Connor</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Prins%20JF%22%5BAuthor%5D" class="usa-link">Jan F. Prins</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Chiang%20DY%22%5BAuthor%5D" class="usa-link">Derek Y. Chiang</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Neil%20Hayes%20D%22%5BAuthor%5D" class="usa-link">D. Neil Hayes</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Perou%20CM%22%5BAuthor%5D" class="usa-link">Charles M. Perou</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Hinoue%20T%22%5BAuthor%5D" class="usa-link">Toshinori Hinoue</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Weisenberger%20DJ%22%5BAuthor%5D" class="usa-link">Daniel J. Weisenberger</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Maglinte%20DT%22%5BAuthor%5D" class="usa-link">Dennis T. Maglinte</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Pan%20F%22%5BAuthor%5D" class="usa-link">Fei Pan</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Berman%20BP%22%5BAuthor%5D" class="usa-link">Benjamin P. Berman</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Van%20Den%20Berg%20DJ%22%5BAuthor%5D" class="usa-link">David J. Van Den Berg</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Shen%20H%22%5BAuthor%5D" class="usa-link">Hui Shen</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Triche%20Jr%20T%22%5BAuthor%5D" class="usa-link">Timothy Triche Jr</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Baylin%20SB%22%5BAuthor%5D" class="usa-link">Stephen B. Baylin</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Laird%20PW%22%5BAuthor%5D" class="usa-link">Peter W. Laird</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Getz%20G%22%5BAuthor%5D" class="usa-link">Gad Getz</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Noble%20M%22%5BAuthor%5D" class="usa-link">Michael Noble</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Voet%20D%22%5BAuthor%5D" class="usa-link">Doug Voet</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Saksena%20G%22%5BAuthor%5D" class="usa-link">Gordon Saksena</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Gehlenborg%20N%22%5BAuthor%5D" class="usa-link">Nils Gehlenborg</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22DiCara%20D%22%5BAuthor%5D" class="usa-link">Daniel DiCara</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Zhang%20J%22%5BAuthor%5D" class="usa-link">Juinhua Zhang</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Zhang%20H%22%5BAuthor%5D" class="usa-link">Hailei Zhang</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Wu%20CJ%22%5BAuthor%5D" class="usa-link">Chang-Jiun Wu</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Yingchun%20Liu%20S%22%5BAuthor%5D" class="usa-link">Spring Yingchun Liu</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Shukla%20S%22%5BAuthor%5D" class="usa-link">Sachet Shukla</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Lawrence%20MS%22%5BAuthor%5D" class="usa-link">Michael S. Lawrence</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Zhou%20L%22%5BAuthor%5D" class="usa-link">Lihua Zhou</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Sivachenko%20A%22%5BAuthor%5D" class="usa-link">Andrey Sivachenko</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Lin%20P%22%5BAuthor%5D" class="usa-link">Pei Lin</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Stojanov%20P%22%5BAuthor%5D" class="usa-link">Petar Stojanov</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Jing%20R%22%5BAuthor%5D" class="usa-link">Rui Jing</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Park%20RW%22%5BAuthor%5D" class="usa-link">Richard W. Park</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Nazaire%20MD%22%5BAuthor%5D" class="usa-link">Marc-Danie Nazaire</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Robinson%20J%22%5BAuthor%5D" class="usa-link">Jim Robinson</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Thorvaldsdottir%20H%22%5BAuthor%5D" class="usa-link">Helga Thorvaldsdottir</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Mesirov%20J%22%5BAuthor%5D" class="usa-link">Jill Mesirov</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Park%20PJ%22%5BAuthor%5D" class="usa-link">Peter J. Park</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Chin%20L%22%5BAuthor%5D" class="usa-link">Lynda Chin</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Thorsson%20V%22%5BAuthor%5D" class="usa-link">Vesteinn Thorsson</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Reynolds%20SM%22%5BAuthor%5D" class="usa-link">Sheila M. Reynolds</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Bernard%20B%22%5BAuthor%5D" class="usa-link">Brady Bernard</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Kreisberg%20R%22%5BAuthor%5D" class="usa-link">Richard Kreisberg</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Lin%20J%22%5BAuthor%5D" class="usa-link">Jake Lin</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Iype%20L%22%5BAuthor%5D" class="usa-link">Lisa Iype</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Bressler%20R%22%5BAuthor%5D" class="usa-link">Ryan Bressler</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Erkkil%C3%A4%20T%22%5BAuthor%5D" class="usa-link">Timo Erkkilä</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Gundapuneni%20M%22%5BAuthor%5D" class="usa-link">Madhumati Gundapuneni</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Liu%20Y%22%5BAuthor%5D" class="usa-link">Yuexin Liu</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Norberg%20A%22%5BAuthor%5D" class="usa-link">Adam Norberg</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Robinson%20T%22%5BAuthor%5D" class="usa-link">Tom Robinson</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Yang%20D%22%5BAuthor%5D" class="usa-link">Da Yang</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Zhang%20W%22%5BAuthor%5D" class="usa-link">Wei Zhang</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Shmulevich%20I%22%5BAuthor%5D" class="usa-link">Ilya Shmulevich</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22de%20Ronde%20JJ%22%5BAuthor%5D" class="usa-link">Jorma J. de Ronde</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Schultz%20N%22%5BAuthor%5D" class="usa-link">Nikolaus Schultz</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Cerami%20E%22%5BAuthor%5D" class="usa-link">Ethan Cerami</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Ciriello%20G%22%5BAuthor%5D" class="usa-link">Giovanni Ciriello</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Goldberg%20AP%22%5BAuthor%5D" class="usa-link">Arthur P. Goldberg</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Gross%20B%22%5BAuthor%5D" class="usa-link">Benjamin Gross</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Jacobsen%20A%22%5BAuthor%5D" class="usa-link">Anders Jacobsen</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Gao%20J%22%5BAuthor%5D" class="usa-link">Jianjiong Gao</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Kaczkowski%20B%22%5BAuthor%5D" class="usa-link">Bogumil Kaczkowski</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Sinha%20R%22%5BAuthor%5D" class="usa-link">Rileen Sinha</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Arman%20Aksoy%20B%22%5BAuthor%5D" class="usa-link">B. Arman Aksoy</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Antipin%20Y%22%5BAuthor%5D" class="usa-link">Yevgeniy Antipin</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Reva%20B%22%5BAuthor%5D" class="usa-link">Boris Reva</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Shen%20R%22%5BAuthor%5D" class="usa-link">Ronglai Shen</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Taylor%20BS%22%5BAuthor%5D" class="usa-link">Barry S. Taylor</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Chan%20TA%22%5BAuthor%5D" class="usa-link">Timothy A. Chan</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Ladanyi%20M%22%5BAuthor%5D" class="usa-link">Marc Ladanyi</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Sander%20C%22%5BAuthor%5D" class="usa-link">Chris Sander</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Akbani%20R%22%5BAuthor%5D" class="usa-link">Rehan Akbani</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Zhang%20N%22%5BAuthor%5D" class="usa-link">Nianxiang Zhang</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Broom%20BM%22%5BAuthor%5D" class="usa-link">Bradley M. Broom</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Casasent%20T%22%5BAuthor%5D" class="usa-link">Tod Casasent</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Unruh%20A%22%5BAuthor%5D" class="usa-link">Anna Unruh</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Wakefield%20C%22%5BAuthor%5D" class="usa-link">Chris Wakefield</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Hamilton%20SR%22%5BAuthor%5D" class="usa-link">Stanley R. Hamilton</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Craig%20Cason%20R%22%5BAuthor%5D" class="usa-link">R. Craig Cason</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Baggerly%20KA%22%5BAuthor%5D" class="usa-link">Keith A. Baggerly</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Weinstein%20JN%22%5BAuthor%5D" class="usa-link">John N. Weinstein</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Haussler%20D%22%5BAuthor%5D" class="usa-link">David Haussler</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Benz%20CC%22%5BAuthor%5D" class="usa-link">Christopher C. Benz</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Stuart%20JM%22%5BAuthor%5D" class="usa-link">Joshua M. Stuart</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Benz%20SC%22%5BAuthor%5D" class="usa-link">Stephen C. Benz</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Zachary%20Sanborn%20J%22%5BAuthor%5D" class="usa-link">J. Zachary Sanborn</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Vaske%20CJ%22%5BAuthor%5D" class="usa-link">Charles J. Vaske</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Zhu%20J%22%5BAuthor%5D" class="usa-link">Jingchun Zhu</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Szeto%20C%22%5BAuthor%5D" class="usa-link">Christopher Szeto</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Scott%20GK%22%5BAuthor%5D" class="usa-link">Gary K. Scott</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Yau%20C%22%5BAuthor%5D" class="usa-link">Christina Yau</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Ng%20S%22%5BAuthor%5D" class="usa-link">Sam Ng</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Goldstein%20T%22%5BAuthor%5D" class="usa-link">Ted Goldstein</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Ellrott%20K%22%5BAuthor%5D" class="usa-link">Kyle Ellrott</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Collisson%20E%22%5BAuthor%5D" class="usa-link">Eric Collisson</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Cozen%20AE%22%5BAuthor%5D" class="usa-link">Aaron E. Cozen</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Zerbino%20D%22%5BAuthor%5D" class="usa-link">Daniel Zerbino</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Wilks%20C%22%5BAuthor%5D" class="usa-link">Christopher Wilks</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Craft%20B%22%5BAuthor%5D" class="usa-link">Brian Craft</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Spellman%20P%22%5BAuthor%5D" class="usa-link">Paul Spellman</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Penny%20R%22%5BAuthor%5D" class="usa-link">Robert Penny</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Shelton%20T%22%5BAuthor%5D" class="usa-link">Troy Shelton</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Hatfield%20M%22%5BAuthor%5D" class="usa-link">Martha Hatfield</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Morris%20S%22%5BAuthor%5D" class="usa-link">Scott Morris</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Yena%20P%22%5BAuthor%5D" class="usa-link">Peggy Yena</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Shelton%20C%22%5BAuthor%5D" class="usa-link">Candace Shelton</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Sherman%20M%22%5BAuthor%5D" class="usa-link">Mark Sherman</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Paulauskis%20J%22%5BAuthor%5D" class="usa-link">Joseph Paulauskis</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Gastier-Foster%20JM%22%5BAuthor%5D" class="usa-link">Julie M. Gastier-Foster</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Bowen%20J%22%5BAuthor%5D" class="usa-link">Jay Bowen</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Ramirez%20NC%22%5BAuthor%5D" class="usa-link">Nilsa C. Ramirez</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Black%20A%22%5BAuthor%5D" class="usa-link">Aaron Black</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Pyatt%20R%22%5BAuthor%5D" class="usa-link">Robert Pyatt</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Wise%20L%22%5BAuthor%5D" class="usa-link">Lisa Wise</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22White%20P%22%5BAuthor%5D" class="usa-link">Peter White</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Bertagnolli%20M%22%5BAuthor%5D" class="usa-link">Monica Bertagnolli</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Brown%20J%22%5BAuthor%5D" class="usa-link">Jen Brown</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Chan%20TA%22%5BAuthor%5D" class="usa-link">Timothy A. Chan</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Chu%20GC%22%5BAuthor%5D" class="usa-link">Gerald C. Chu</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Czerwinski%20C%22%5BAuthor%5D" class="usa-link">Christine Czerwinski</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Denstman%20F%22%5BAuthor%5D" class="usa-link">Fred Denstman</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Dhir%20R%22%5BAuthor%5D" class="usa-link">Rajiv Dhir</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22D%C3%B6rner%20A%22%5BAuthor%5D" class="usa-link">Arnulf Dörner</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Fuchs%20CS%22%5BAuthor%5D" class="usa-link">Charles S. Fuchs</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Guillem%20JG%22%5BAuthor%5D" class="usa-link">Jose G. Guillem</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Iacocca%20M%22%5BAuthor%5D" class="usa-link">Mary Iacocca</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Juhl%20H%22%5BAuthor%5D" class="usa-link">Hartmut Juhl</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Kaufman%20A%22%5BAuthor%5D" class="usa-link">Andrew Kaufman</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Kohl%20III%20B%22%5BAuthor%5D" class="usa-link">Bernard Kohl III</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Van%20Le%20X%22%5BAuthor%5D" class="usa-link">Xuan Van Le</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Mariano%20MC%22%5BAuthor%5D" class="usa-link">Maria C. Mariano</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Medina%20EN%22%5BAuthor%5D" class="usa-link">Elizabeth N. Medina</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Meyers%20M%22%5BAuthor%5D" class="usa-link">Michael Meyers</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Nash%20GM%22%5BAuthor%5D" class="usa-link">Garrett M. Nash</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Paty%20PB%22%5BAuthor%5D" class="usa-link">Phillip B. Paty</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Petrelli%20N%22%5BAuthor%5D" class="usa-link">Nicholas Petrelli</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Rabeno%20B%22%5BAuthor%5D" class="usa-link">Brenda Rabeno</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Richards%20WG%22%5BAuthor%5D" class="usa-link">William G. Richards</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Solit%20D%22%5BAuthor%5D" class="usa-link">David Solit</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Swanson%20P%22%5BAuthor%5D" class="usa-link">Pat Swanson</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Temple%20L%22%5BAuthor%5D" class="usa-link">Larissa Temple</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Tepper%20JE%22%5BAuthor%5D" class="usa-link">Joel E. Tepper</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Thorp%20R%22%5BAuthor%5D" class="usa-link">Richard Thorp</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Vakiani%20E%22%5BAuthor%5D" class="usa-link">Efsevia Vakiani</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Weiser%20MR%22%5BAuthor%5D" class="usa-link">Martin R. Weiser</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Willis%20JE%22%5BAuthor%5D" class="usa-link">Joseph E. Willis</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Witkin%20G%22%5BAuthor%5D" class="usa-link">Gary Witkin</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Zeng%20Z%22%5BAuthor%5D" class="usa-link">Zhaoshi Zeng</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Zinner%20MJ%22%5BAuthor%5D" class="usa-link">Michael J. Zinner</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Zornig%20C%22%5BAuthor%5D" class="usa-link">Carsten Zornig</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Jensen%20MA%22%5BAuthor%5D" class="usa-link">Mark A. Jensen</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Sfeir%20R%22%5BAuthor%5D" class="usa-link">Robert Sfeir</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Kahn%20AB%22%5BAuthor%5D" class="usa-link">Ari B. Kahn</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Chu%20AL%22%5BAuthor%5D" class="usa-link">Anna L. Chu</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Kothiyal%20P%22%5BAuthor%5D" class="usa-link">Prachi Kothiyal</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Wang%20Z%22%5BAuthor%5D" class="usa-link">Zhining Wang</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Snyder%20EE%22%5BAuthor%5D" class="usa-link">Eric E. Snyder</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Pontius%20J%22%5BAuthor%5D" class="usa-link">Joan Pontius</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Pihl%20TD%22%5BAuthor%5D" class="usa-link">Todd D. Pihl</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Ayala%20B%22%5BAuthor%5D" class="usa-link">Brenda Ayala</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Backus%20M%22%5BAuthor%5D" class="usa-link">Mark Backus</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Walton%20J%22%5BAuthor%5D" class="usa-link">Jessica Walton</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Whitmore%20J%22%5BAuthor%5D" class="usa-link">Jon Whitmore</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Baboud%20J%22%5BAuthor%5D" class="usa-link">Julien Baboud</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Berton%20DL%22%5BAuthor%5D" class="usa-link">Dominique L. Berton</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Nicholls%20MC%22%5BAuthor%5D" class="usa-link">Matthew C. Nicholls</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Srinivasan%20D%22%5BAuthor%5D" class="usa-link">Deepak Srinivasan</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Raman%20R%22%5BAuthor%5D" class="usa-link">Rohini Raman</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Girshik%20S%22%5BAuthor%5D" class="usa-link">Stanley Girshik</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Kigonya%20PA%22%5BAuthor%5D" class="usa-link">Peter A. Kigonya</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Alonso%20S%22%5BAuthor%5D" class="usa-link">Shelley Alonso</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Sanbhadti%20RN%22%5BAuthor%5D" class="usa-link">Rashmi N. Sanbhadti</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Barletta%20SP%22%5BAuthor%5D" class="usa-link">Sean P. Barletta</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Greene%20JM%22%5BAuthor%5D" class="usa-link">John M. 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(ZIP 25458 kb)</p> </div></div></section><section class="sm xbox font-sm" id="db_ds_supplementary-material3_reqid_"><div class="media p"><div class="caption"> <a href="/articles/instance/8127819/bin/41586_2012_BFnature11252_MOESM71_ESM.zip" data-ga-action="click_feat_suppl" class="usa-link"><span>Supplementary Data</span></a><sup> (2.7MB, zip) </sup><p>This file contains Supplementary Tables 1 and 3-12 (ZIP 2809 kb)</p> </div></div></section></section><section id="_adda93_" lang="en" class="data-availability-statement"><h3 class="pmc_sec_title">Data Availability Statement</h3> <section id="db_da_sec17_reqid_"><h3 class="pmc_sec_title">Data deposits</h3> <p>dbGaP accession numbers have been provided in Supplementary Table 1.</p></section></section></section></section><footer class="p courtesy-note font-secondary font-sm text-center"><hr class="headless"> <p>Articles from Nature are provided here courtesy of <strong>Nature Publishing Group</strong></p></footer></section></article> 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Comprehensive molecular characterization of human colon and rectal cancer - PMC