Genome Scale Epigenetic Profiling Reveals Five Distinct Subtypes of Colorectal Cancer

Abstract

BACKGROUND:Colorectal cancer is an epigenetically heterogeneous disease, however the extent and spectrum of the CpG Island Methylator Phenotype (CIMP) is not clear.RESULTSAn unselected cohort of 216 colorectal cancers clustered into five clinically and molecularly distinct subgroups using Illumina 450K DNA methylation arrays. CIMP-High cancers were most frequent in the proximal colons of female patients. These dichotomised into CIMP-Hl and CIMP-H2 based on methylation profile which was supported by over representation of BRAF (74%, P<0.0001) or KRAS (55%, P<0.0001) mutation, respectively. Congruent with increasing methylation, there was a stepwise increase in patient age from 62 years in the CI MP-Negative subgroup to 75 years in the CIMP-Hl subgroup (P<0.0001). There was a striking association between PRC2-marked loci and those subjected to significant gene body methylation in CIMP-type cancers (P<1.6xl078). We identified oncogenes susceptible to gene body methylation and Wnt pathway antagonists resistant to gene body methylation. CIMP cluster specific mutations were observed for genes involved in chromatin remodelling, such as in the SWI/SNF and NuRD complexes, suggesting synthetic lethality.CONCLUSIONThere are five clinically and molecularly distinct subgroups of colorectal cancer based on genome wide epigenetic profiling. These analyses highlighted an unidentified role for gene body methylation in progression of serrated neoplasia. Subgroup-specific mutation of distinct epigenetic regulator genes revealed potentially druggable vulnerabilities for these cancers, which may provide novel precision medicine approaches.

How theBRAFV600E Mutation Defines a Distinct Subgroup of Colorectal Cancer: Molecular and Clinical Implications

“…This panel has been widely utilised and provides a readily available platform to indicate the methylation status of large numbers of samples. Recent studies that have utilised genome-wide methylation arrays have confirmed that those cancers with the most frequent and widespread methylation do significantly correspond with the BRAF mutation and MLH1 methylation [51, 52]. Methylation was observed to occur as a continuum at several sites; however, 4 and 5 distinct methylation-based clusters were identified [51, 52], and cancers with the most methylated genomes not only were BRAF mutant and MSI but also classified as CIMP-high using the more recent CIMP-denoting markers [50] which supports the utility of this panel.…”

In colon cancer cells, fascin1 functions as a mechanosensor that transforms adherens junction mechanotransduction

“…2,9 Despite the suggestion, serrated pathway CRCs lack methylation of Wnt pathway genes. 72 Therefore, the molecular mechanism regulating Wnt activation in BRAF V600E -driven carcinogenesis has remained unresolved. Fascin1 is upregulated early in SSLs and our data show fascin1's direct role in Wnt activation suggesting a role for fascin1 in the initiation of serrated pathway carcinogenesis.…”

RET Protein Expression in Colorectal Cancer; An Immunohistochemical Assessment

“…One in twenty has the risk of developing CRC during their lifetime (Bardhan et al, 2013). CRC is characterized by certain genetic and epigenetic changes that induce proliferative activity and inhibit apoptosis (Fennell et al, 2018). Activating proto-oncogenes or de-activating some tumor suppressor genes can lead to cancer (Munteanu et al, 2015).…”