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Integrative genome-scale DNA Methylation analysis of a large and unselected cohort reveals five distinct subtypes of Colorectal Adenocarcinomas
Journal article   Open access   Peer reviewed

Integrative genome-scale DNA Methylation analysis of a large and unselected cohort reveals five distinct subtypes of Colorectal Adenocarcinomas

Lochlan Fennell, Troy Dumenil, Leesa Wockner, Gunter Hartel, Katia Nones, Catherine Bond, Jennifer Borowsky, Cheng Liu, Diane McKeone, Lisa Bowdler, …
Cellular and Molecular Gastroenterology and Hepatology, Vol.8(2), pp.269-290
2019
DOI: https://doi.org/10.1016/j.jcmgh.2019.04.002
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https://doi.org/10.1016/j.jcmgh.2019.04.002View
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Abstract

BACKGROUND AND AIMS: Colorectal cancer is an epigenetically heterogeneous disease, however the extent and spectrum of the CpG Island Methylator Phenotype (CIMP) is not clear. Methods: Genome scale methylation and transcript expression were measured using the Illumina HM450 DNA methylation and HT12 V3 expression microarrays in 216 unselected colorectal cancers, and findings validated using TCGA 450K and RNA-Seq data. Mutations in epigenetic regulators were assessed using CIMP subtyped Cancer Genome Atlas exomes. RESULTS: CIMP-High cancers dichotomised into CIMP-H1 and CIMP-H2 based on methylation profile. KRAS mutation was significantly associated with CIMP-H2 cancers, but not CIMP-H1 cancers. Congruent with increasing methylation, there was a stepwise increase in patient age from 62 years in the CIMP-Negative subgroup to 75 years in the CIMP-H1 subgroup (P<0.0001). CIMP-H1 were predominantly comprised of consensus molecular subtype 1 (CMS1) cancers (70%) whilst CMS3 was over-represented in the CIMP-H2 subgroup (55%). PRC2-marked loci were subjected to significant gene body methylation in CIMP cancers (P<1.6x10-78). We identified oncogenes susceptible to gene body methylation and Wnt pathway antagonists resistant to gene body methylation. CIMP cluster specific mutations were observed for in chromatin remodeling genes, such as in the SWI/SNF and CHD gene families. CONCLUSION: There are five clinically and molecularly distinct subgroups of colorectal cancer. We show a striking association between CIMP and age, gender and tumor location and identify an unidentified role for gene body methylation in progression of serrated neoplasia. These data support our recent findings that CIMP is uncommon in young patients and that BRAF mutant polyps in young patients may have limited potential for malignant progression.

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