Prognostic epigenetic 12-genes signature in human metastatic colorectal carcinomas

Epigenetic remodeling is responsible for tumor progression and drug resistance in human colorectal carcinoma (CRC). This study addressed the hypothesis that DNA methylation profiling may identify metastatic CRC (mCRC) subtypes with defined clinical characters. Global differential methylation profile was comparatively analyzed between 24 first-line primary-resistant and 12 drug-sensitive mCRCs, two subgroups with significantly different outcome. Gene expression and methylation data from the TCGA mCRCs cohort were used to identify, among differentially methylated genes, a prognostic signature of functionally methylated genes. Twelve functionally methylated genes yielded a hierarchical clustering of patients in two well-defined subgroups with hypermethylated tumors characterized by a significantly worst relapse-free and overall survival compared to hypomethylated cancers. Interestingly, the poor prognosis cluster was enriched of CIMP-high and MSI-like cases. Furthermore, methylation events were enriched in genes located on arms q of chromosomes 13 and 20, this suggesting that epigenetic remodeling may involve selective genomic regions. Finally, the expression of the 12-genes signature and MSI-enriching genes was confirmed in two independent oxaliplatin- and irinotecan-resistant CRC cell lines. These data provide the proof of concept that the hypermethylation of specific sets of genes may provide prognostic informations being able to identify a subgroup of mCRCs with poor prognosis Bisulphite converted DNA from the 36 samples were hybridized to the Illumina Infinium 850K Human Methylation Beadchip v1.2