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Prognostic epigenetic 12-genes signature in human metastatic colorectal carcinomas

ABSTRACT: 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

ORGANISM(S): Homo sapiens

PROVIDER: GSE148766 | GEO | 2021/04/15

REPOSITORIES: GEO

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Project description:Aberrant DNA methylation, one of the major epigenetic alterations in cancer, has been reported to accumulate in a subset of colorectal cancer (CRC), so-called CpG island methylator phenotype (CIMP), which was known to correlate with microsatellite instability (MSI)-high CRC. To select new methylation markers genome-widely and epigenotype CRC by DNA methylation comprehensively, we performed methylated DNA immunoprecipitation-on-chip analysis using MSI-high CRC cell line HCT116 and microsatellite-stable SW480, and re-expression array analysis by 5-aza-2-deoxycytidine/Trichostatin A. Methylation levels of 44 new markers selected and 16 previously reported markers were analyzed quantitatively in 149 clinical CRC samples using MALDI-TOF mass spectrometry. By unsupervised two-way hierarchical clustering, CRC was clustered into high-, intermediate-, and low-methylation epigenotypes. Methylation markers were clustered into two groups: Group-1 showing methylation in high-methylation epigenotype and including all the 11 CIMP-related markers except NEUROG1, and Group-2 showing methylation in high- and intermediate-methylation epigenotypes. Marker panel deciding methylation epigenotypes with the highest accuracy was developed: 1st-Panel consisting of Group-1 genes (CACNA1G, LOX, SLC30A10) to extract high-methylation epigenotype, and 2nd-Panel consisting of Group-2 genes (ELMO1, FBN2, THBD, HAND1) and SLC30A10 again to divide the remains into intermediate- and low-methylation epigenotypes. High-methylation epigenotype correlated significantly with BRAF mutation, MSI, proximal tumor location, and mucinous component, in concordance with reported CIMP. Intermediate- and low-methylation epigenotypes significantly correlated with KRAS-mutation(+) and KRAS-mutation(-), respectively. KRAS-mutation(+) intermediate-methylation epigenotype showed worse prognosis than KRAS-mutation(-) low-methylation epigenotype (p=0.030). These three epigenotypes with different genetic characteristics suggested different molecular CRC genesis, and the markers might be useful to predict prognosis.

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Prognostic epigenetic 12-genes signature in human metastatic colorectal carcinomas

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