Use of multivariate analysis to suggest a new molecular classification of colorectal cancer. Issue 3 (25th January 2013)

• Record Type: Journal Article
• 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
• Is Part Of: Journal of pathology. Volume 229:Issue 3(2013)
• Page Start: 441
• Page End: 448
• Publication Date: 2013-01-25
• Subjects: Pathology -- Periodicals; 616.07
• DOI: 10.1002/path.4139
• Languages: English
• ISSNs: 0022-3417

Abstract

<abstract abstract-type="main"> <title>Abstract</title> <p> <bold>Molecular classification of colorectal cancer (CRC) is currently based on microsatellite instability (MSI), <italic>KRAS</italic> or <italic>BRAF</italic> 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 <italic>TP53</italic> mutation; MSI and <italic>BRAF</italic> mutation; and <italic>KRAS</italic> and <italic>PIK3CA</italic> mutations. Negative associations occurred between: MSI and CIN; MSI and <italic>NRAS</italic> mutation; and <italic>KRAS</italic> mutation, and each of <italic>NRAS</italic>, <italic>TP53</italic> and <italic>BRAF</italic> mutations. Some complex relationships were elucidated: <italic>KRAS</italic> and <italic>TP53</italic> mutations had both a direct negative association and a weaker, confounding, positive association via <italic>TP53</italic>–CIN–MSI–<italic>BRAF–KRAS</italic>. Our results suggested a new molecular classification of CRCs: (1) MSI<sup>+</sup> and/or <italic>BRAF</italic>‐mutant; (2) CIN<sup>+</sup> and/or <italic>TP53<sup>–</sup></italic> mutant, with wild‐type <italic>KRAS</italic> and <italic>PIK3CA</italic>; (3) <italic>KRAS</italic>‐ and/or <italic>PIK3CA</italic>‐mutant, CIN<italic><sup>+</sup>, TP53</italic>‐wild‐type; (4) <italic>KRAS<sup>–</sup></italic> and/or <italic>PIK3CA</italic>‐mutant, CIN<italic><sup>–</sup></italic>, <italic>TP53</italic>‐wild‐type; (5) <italic>NRAS</italic>‐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<sup>+</sup> 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<sup>+</sup> cancers have conventionally been associated with all three of these variables, because they have been tested <italic>en masse</italic>. 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.</bold> </p> </abstract>