Abstract 5065: Gene expression profiling of colon adenocarcinomas reveals six prototypic molecular subtypes with distinct clinical and molecular characteristics
Authors: Marisa Laetitia , Vescovo Laure , Reyniès Aurélien , Duval Alex , Etienne-Grimaldi Marie-Christine , Gaub Marie-Pierre , Guenot Dominique , Kirzin Sylvain , Milano Gérard , Olschwang Sylviane , Selves Janick , Laurent-Puig Pierre , Boige Valérie 
Published: August 2012

Abstract
Purpose: The purpose of our study was to build up a molecular classification of colon cancers (CC) and to further identify a molecular signature that correlated with disease outcome through a genome-wide DNA and mRNA expression analysis. Material: Fresh frozen tumor tissues from 750 patients with stage I to IV CC were analyzed for anatomo-clinical characteristics and common DNA alterations including KRAS, BRAF, TP53 mutations, MMR (Mismatch Repair system) and CIMP (CpG island methylator phenotype) status. Among the 750 tumors, 443 were screened for pangenomic alteration and expression profiles using Affymetrix U133P2 chips and CGH arrays. Results: A robust approach based on unsupervised hierarchical clusterings of the 443 tumors revealed six main prototypic molecular subtypes with distinct clinical/molecular correlations and outcomes. The first (C1), fifth (C5) and sixth (C6) subtypes were more frequently CIN+ (chromosomal instability assessed by CGHa), TP53 mutant and left-sided tumors, without any molecular or clinical annotation able to clearly discriminate these three subgroups except the low relapse rate observed in the C5 subgroup (21.6% versus 30.9% and 39.3% in C1 and C6 subgroups, respectively). C2 was enriched for patients with deficient MMR (80.7%), CIMP+ (62.5%), BRAF mutant (37.3%) and right-sided (71%) CC with low relapsing rate (19.7%). C3 was enriched for KRAS mutant (76.2%) and right-sided tumors (57.8%). C4 included more CIMP+ (35.4%), BRAF mutant (25%), right-sided (64.2%) and relapsing (47.2%) CC. Of those 6 subtypes, C4 and C2 (dMMR) appeared to be the most segregated subtypes, others being less distant to each other. Although not significant, there was a trend in favor of a prognostic value of the six-subgroup classification, with C1, C4 and C6 subgroups having a relative poor outcome, and C2 and C5 a relative good outcome (65%, 64%, 63%, 77% and 83% 5-year disease-free survival, respectively; p=0.12). Using the limited number of molecular features available from 6 public datasets, we validated the molecular and clinical characteristics of C2, as well as the higher rate of relapse observed in C4. The prognostic value of the six-subtype classification was significant when applied to one independent dataset of 304 CC (p=0.012), with a worse prognosis confirmed for C1 and C4, and a better prognosis for C2 and C5. Conclusion: Our results suggest that CC develop as distinct molecular entities evolving through multiple pathways on the basis of several molecular features that may not result in a single but in several prognostic signatures according to each molecular subtype.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5065. doi:1538-7445.AM2012-5065