{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:04:07Z","timestamp":1791331447236,"version":"4.3.1"},"reference-count":31,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2013,1,25]],"date-time":"2013-01-25T00:00:00Z","timestamp":1359072000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2013,2]]},"abstract":"Abstract<\/jats:title>\n \n \n Molecular classification of colorectal cancer (\n CRC<\/jats:styled-content>\n ) is currently based on microsatellite instability (\n MSI<\/jats:styled-content>\n ),\n \n KRAS<\/jats:styled-content>\n <\/jats:italic>\n or\n \n BRAF<\/jats:styled-content>\n <\/jats:italic>\n mutation and, occasionally, chromosomal instability (\n CIN<\/jats:styled-content>\n ). Whilst useful, these categories may not fully represent the underlying molecular subgroups. We screened 906 stage\n II<\/jats:styled-content>\n \/\n III CRCs<\/jats:styled-content>\n from the\n VICTOR<\/jats:styled-content>\n clinical trial for somatic mutations. Multivariate analyses (logistic regression, clustering, Bayesian networks) identified the primary molecular associations. Positive associations occurred between:\n CIN<\/jats:styled-content>\n and\n \n TP53<\/jats:styled-content>\n <\/jats:italic>\n mutation;\n MSI<\/jats:styled-content>\n and\n \n BRAF<\/jats:styled-content>\n <\/jats:italic>\n mutation; and\n \n KRAS<\/jats:styled-content>\n <\/jats:italic>\n and\n \n PIK3CA<\/jats:styled-content>\n <\/jats:italic>\n mutations. Negative associations occurred between:\n MSI<\/jats:styled-content>\n and\n CIN<\/jats:styled-content>\n ;\n MSI<\/jats:styled-content>\n and\n \n NRAS<\/jats:styled-content>\n <\/jats:italic>\n mutation; and\n \n KRAS<\/jats:styled-content>\n <\/jats:italic>\n mutation, and each of\n \n NRAS<\/jats:styled-content>\n <\/jats:italic>\n ,\n \n TP53<\/jats:styled-content>\n <\/jats:italic>\n and\n \n BRAF<\/jats:styled-content>\n <\/jats:italic>\n mutations. Some complex relationships were elucidated:\n \n KRAS<\/jats:styled-content>\n <\/jats:italic>\n and\n \n TP53<\/jats:styled-content>\n <\/jats:italic>\n mutations had both a direct negative association and a weaker, confounding, positive association via\n \n TP53<\/jats:styled-content>\n <\/jats:italic>\n \u2013\n CIN\u2013MSI<\/jats:styled-content>\n \u2013\n \n BRAF\u2013KRAS<\/jats:styled-content>\n <\/jats:italic>\n . Our results suggested a new molecular classification of\n CRCs<\/jats:styled-content>\n : (1)\n MSI<\/jats:styled-content>\n +<\/jats:sup>\n and\/or\n \n BRAF<\/jats:styled-content>\n <\/jats:italic>\n \u2010mutant; (2)\n CIN<\/jats:styled-content>\n +<\/jats:sup>\n and\/or\n \n TP53<\/jats:styled-content>\n \u2013<\/jats:sup>\n <\/jats:italic>\n mutant, with wild\u2010type\n \n KRAS<\/jats:styled-content>\n <\/jats:italic>\n and\n \n PIK3CA<\/jats:styled-content>\n <\/jats:italic>\n ; (3)\n \n KRAS<\/jats:styled-content>\n <\/jats:italic>\n \u2010 and\/or\n \n PIK3CA<\/jats:styled-content>\n <\/jats:italic>\n \u2010mutant,\n CIN<\/jats:styled-content>\n \n +<\/jats:sup>\n ,\n TP53<\/jats:styled-content>\n <\/jats:italic>\n \u2010wild\u2010type; (4)\n \n KRAS<\/jats:styled-content>\n \u2013<\/jats:sup>\n <\/jats:italic>\n and\/or\n \n PIK3CA<\/jats:styled-content>\n <\/jats:italic>\n \u2010mutant,\n CIN<\/jats:styled-content>\n \n \u2013<\/jats:sup>\n <\/jats:italic>\n ,\n \n TP53<\/jats:styled-content>\n <\/jats:italic>\n \u2010wild\u2010type; (5)\n \n NRAS<\/jats:styled-content>\n <\/jats:italic>\n \u2010mutant; (6) no mutations; (7) others. As expected, group 1 cancers were mostly proximal and poorly differentiated, usually occurring in women. Unexpectedly, two different types of\n CIN<\/jats:styled-content>\n +<\/jats:sup>\n CRC<\/jats:styled-content>\n were found: group 2 cancers were usually distal and occurred in men, whereas group 3 showed neither of these associations but were of higher stage.\n CIN<\/jats:styled-content>\n +<\/jats:sup>\n cancers have conventionally been associated with all three of these variables, because they have been tested\n en masse<\/jats:italic>\n . Our classification also showed potentially improved prognostic capabilities, with group 3, and possibly group 1, independently predicting disease\u2010free survival. Copyright \u00a9 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.\n <\/jats:bold>\n <\/jats:p>","DOI":"10.1002\/path.4139","type":"journal-article","created":{"date-parts":[[2012,11,20]],"date-time":"2012-11-20T04:47:37Z","timestamp":1353386857000},"page":"441-448","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":71,"title":["Use of multivariate analysis to suggest a new molecular classification of colorectal cancer"],"prefix":"10.1002","volume":"229","author":[{"given":"Enric","family":"Domingo","sequence":"first","affiliation":[{"name":"Molecular and Population Genetics Laboratory Wellcome Trust Centre for Human Genetics University of Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajarajan","family":"Ramamoorthy","sequence":"additional","affiliation":[{"name":"Molecular and Population Genetics Laboratory Wellcome Trust Centre for Human Genetics University of Oxford UK"},{"name":"Division of Surgery and Interventional Science 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Hospital Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Havard","family":"Danielsen","sequence":"additional","affiliation":[{"name":"Institute for Medical Informatics Oslo University Hospital Norway"},{"name":"Centre for Cancer Biomedicine University of Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Novelli","sequence":"additional","affiliation":[{"name":"Department of Pathology University College Hospital London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Davidson","sequence":"additional","affiliation":[{"name":"Division of Surgery and Interventional Science University College London, Royal Free Hospital London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng\u2010Zhou","family":"Xu","sequence":"additional","affiliation":[{"name":"CSIRO Preventative Health Flagship North Ryde NSW Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Molloy","sequence":"additional","affiliation":[{"name":"CSIRO Preventative Health Flagship North Ryde NSW Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaine","family":"Johnstone","sequence":"additional","affiliation":[{"name":"Department of Oncology University of Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Holmes","sequence":"additional","affiliation":[{"name":"Department of Statistics University of Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Midgley","sequence":"additional","affiliation":[{"name":"Department of Oncology University of Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Kerr","sequence":"additional","affiliation":[{"name":"Nuffield Department of Clinical Laboratory Sciences University of Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Sieber","sequence":"additional","affiliation":[{"name":"Ludwig Colon Cancer Initiative Laboratory Ludwig Institute for Cancer Research Melbourne Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Tomlinson","sequence":"additional","affiliation":[{"name":"Molecular and Population Genetics Laboratory Wellcome Trust Centre for Human Genetics University of Oxford 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