Use of multivariate analysis to suggest a new molecular classification of colorectal cancer

• Published in: The Journal of pathology Vol. 229; no. 3; pp. 441 - 448
• Main Authors: Domingo, Enric, Ramamoorthy, Rajarajan, Oukrif, Dahmane, Rosmarin, Daniel, Presz, Michal, Wang, Haitao, Pulker, Hannah, Lockstone, Helen, Hveem, Tarjei, Cranston, Treena, Danielsen, Havard, Novelli, Marco, Davidson, Brian, Xu, Zheng-Zhou, Molloy, Peter, Johnstone, Elaine, Holmes, Christopher, Midgley, Rachel, Kerr, David, Sieber, Oliver, Tomlinson, Ian
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01-02-2013; Wiley Subscription Services, Inc
• Subjects: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor - genetics; Chromosomal Instability; Class I Phosphatidylinositol 3-Kinases; clinico-pathological associations; colorectal cancer; Colorectal Neoplasms - classification; Colorectal Neoplasms - genetics; Colorectal Neoplasms - mortality; Disease-Free Survival; Female; genetic pathways; Humans; Male; Microsatellite Instability; Middle Aged; molecular classification; Molecular Diagnostic Techniques - methods; Multivariate Analysis; Mutation; Neoplasm Proteins - genetics; Neoplasm Staging; Original Paper; Phosphatidylinositol 3-Kinases - genetics; prognostic markers; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins p21(ras); Randomized Controlled Trials as Topic; ras Proteins - genetics; Sex Factors; somatic mutations; Succinimides; Tumor Suppressor Protein p53 - genetics
• ISSN: 0022-3417; 1096-9896
• DOI: 10.1002/path.4139

Molecular classification of colorectal cancer (CRC) is currently 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 subgroups. 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 BRAF mutation; and KRAS and PIK3CA mutations. Negative associations occurred between: MSI and CIN; MSI and NRAS mutation; and KRAS mutation, and each of NRAS, TP53 and BRAF mutations. Some complex relationships were elucidated: KRAS and TP53 mutations had both a direct negative association and a weaker, confounding, positive association via TP53–CIN–MSI–BRAF–KRAS. Our results suggested a new molecular classification of CRCs: (1) MSI+ and/or BRAF‐mutant; (2) CIN+ and/or TP53– mutant, with wild‐type KRAS and PIK3CA; (3) KRAS‐ and/or PIK3CA‐mutant, CIN+, TP53‐wild‐type; (4) KRAS– and/or PIK3CA‐mutant, CIN–, TP53‐wild‐type; (5) NRAS‐mutant; (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 CIN+ CRC 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. 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.