Molecular And Clinicopathologic Evidence Of Heterogeneity In Kras-Mutant Colon Cancers

3575 Background: The activation of the MEK/ERK signaling cascade by KRAS or BRAF mutations has a high incidence in colorectal cancer (CRC). While these mutations are mutually exclusive, we have identified a highly conserved gene expression pattern, characteristic to BRAF mutants, that can also be observed in KRAS mutants (AACR 2011, JCO 2012), and which defines a distinct subpopulation. Its characterization is important as it may shed a light on the observed survival and treatment response variability of this group of CRCs. Methods: A set of 257 stage II and III KRAS mutant CRCs from the PETACC3 clinical trial and a subset of 150 CRCs from TCGA project were used for this study. Gene expression data was available for all samples and, additionally, CNV and methylation data was available for some of the samples. Due to the limited number of MSI samples, the analyses were focused on MSS subpopulation. Results: The cluster analysis on the genes from the BRAF signature clearly indicated a major split of the KRAS mutants into two subgroups, that were further compared in terms of clinico-pathological and survival parameters. The BRAF-mutant-like (BML) subgroup was clearly enriched in MSI-H (p<0.001), right-sided (p=0.038) and mucinous histology (p<0.001) tumors. The enrichment in mucinous tumors remained significant also in stratified analysis by MSI status. In MSS, the BML subpopulation of KRAS mutants had the worst prognosis for overall survival (p=0.05, HR=1.6) and survival after relapse (p=0.004, HR=2.1). Analysis of differentially expressed genes between BML and the rest of KRAS mutants identified genes responsible for colon crypt differentiation, Wnt pathway activation and, more intriguingly, 50 other genes, all located on chromosome 20q, that had significantly different activation levels in BML tumors. Among these genes, there are a number of important tumor suppressors, like PLAGL2, TP53RK and POFUT1. No differences in type of KRAS mutation nor in PIK3CA mutations were found between BML and the rest of KRAS mutants. Conclusions: We identified a subgroup of KRAS mutants formed of more aggressive, poorly differentiated tumors. All these results prove that KRAS mutant CRCs form a heterogeneous group tumors.