Use of multivariate analysis to suggest a new molecular classification of colorectal cancer.
Molecular classification of colorectal cancer (CRC) iscurrently based onmicrosatellite instability (MSI), KRAS or BRAF mutation and, occasionally, chromosomal instability (CIN). Whilst useful, these categories may not fully represent the underlying molecular sub-groups. We screened 906 stage II/III CRCs from the VICTOR clinical trial for somatic mutations. Multivariate analyses (logistic regression, clustering, Bayesian networks) identified the primary molecular associations. Positive associations occurred between: CINand TP53mutation;MSIand BRAFmutation; andKRASand PIK3CAmutations. Negative associations occurred between: MSIand CIN; MSIand NRAS mutation; and KRASmutation and each of NRAS, TP53 and BRAF mutations.Some complex relationships were elucidated: KRASand TP53 mutations had both a direct negative association, and a weaker, confounding positive association via TP53-CIN-MSI-BRAF-KRAS. Our results suggesteda new molecular classification of CRCs: (1) MSI+ and/or BRAF-mutant; (2) CIN+ and/or TP53-mutant, with wildtypeKRAS and PIK3CA; (3) KRAS-and/or PIK3CA-mutant, CIN+,TP53-wildtype; (4) KRAS- and/or PIK3CA-mutant, CIN-, TP53-wildtype; (5) NRAS-mutant; (6) no mutations; (7) others.As expected, Group 1 cancers weremostly proximal and poorly-differentiated, usually occurring in women. Unexpectedly, different types of CIN+ CRC were found: Group 2 cancers were usually distal and occurred in men, butGroup 3showed neither of these associations, but were of higher stage.By comparison, CIN+ cancers haveconventionally been associated with all three of these variables, because they have been tested en masse. Our classification also showed potentially improved prognostic capabilities, with Group 3, and possibly Group 1, independently predicting disease-free survival. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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