Use of multivariate analysis to suggest a new molecular classification of colorectal cancer
A partir de données portant sur 906 patients atteints d'un cancer colorectal de stade II/III, cette étude met en oeuvre des analyses multivariées pour identifier une nouvelle classification moléculaire des cancers colorectaux
Molecular classification of colorectal cancer (CRC) iscurrently based on microsatellite 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: CIN and TP53 mutation;MSI and BRAFmutation; and KRAS and PIK3CA mutations. Negative associations occurred between: MSI and CIN; MSI and 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 were mostly 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, but Group 3 showed neither of these associations, but were of higher stage. By comparison, CIN+ cancers have conventionally 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.
The Journal of Pathology , résumé, 2011