title: Use of multivariate analysis to suggest a new molecular classification of colorectal cancer.
abstract: 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.
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, UK.
authors.forename: Enric
authors.initials: E
authors.lastname: Domingo
authors.forename: Rajarajan
authors.initials: R
authors.lastname: Ramamoorthy
authors.forename: Dahmane
authors.initials: D
authors.lastname: Oukrif
authors.forename: Daniel
authors.initials: D
authors.lastname: Rosmarin
authors.forename: Michal
authors.initials: M
authors.lastname: Presz
authors.forename: Haitao
authors.initials: H
authors.lastname: Wang
authors.forename: Hannah
authors.initials: H
authors.lastname: Pulker
authors.forename: Helen
authors.initials: H
authors.lastname: Lockstone
authors.forename: Tarjei
authors.initials: T
authors.lastname: Hveem
authors.forename: Treena
authors.initials: T
authors.lastname: Cranston
authors.forename: Havard
authors.initials: H
authors.lastname: Danielsen
authors.forename: Marco
authors.initials: M
authors.lastname: Novelli
authors.forename: Brian
authors.initials: B
authors.lastname: Davidson
authors.forename: Zheng-Zhou
authors.initials: ZZ
authors.lastname: Xu
authors.forename: Peter
authors.initials: P
authors.lastname: Molloy
authors.forename: Elaine
authors.initials: E
authors.lastname: Johnstone
authors.forename: Christopher
authors.initials: C
authors.lastname: Holmes
authors.forename: Rachel
authors.initials: R
authors.lastname: Midgley
authors.forename: David
authors.initials: D
authors.lastname: Kerr
authors.forename: Oliver
authors.initials: O
authors.lastname: Sieber
authors.forename: Ian
authors.initials: I
authors.lastname: Tomlinson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D043171:Chromosomal Instability; D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000145:classification* / Q000235:genetics* / Q000401:mortality; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D025202:Molecular Diagnostic Techniques / Q000379:methods*; D015999:Multivariate Analysis; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D009367:Neoplasm Staging; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D016032:Randomized Controlled Trials as Topic; D012737:Sex Factors; D013388:Succinimides; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C117307:KRAS protein, human; C110990:N-methylsuccinimide; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D013388:Succinimides; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins