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RESEARCH PRODUCT

Integrative Genome-Scale DNA Methylation Analysis of a Large and Unselected Cohort Reveals 5 Distinct Subtypes of Colorectal Adenocarcinomas

Lisa BowdlerCheng LiuJennifer BorowskyTroy DumenilYu ImamuraAnn-marie PatchIsabell HoffmannGrant W. MontgomeryLeesa F. WocknerGunter HartelVicki L. J. WhitehallRenfu ShaoLochlan FennellKerenaftali KleinSabine TejparBarbara A. LeggettDiane MckeonePratyaksha WirapatiJohn V. PearsonPaul LochheadShuji OginoCatherine BondStephen H. KazakoffNicola WaddellKatia Nones

subject

0301 basic medicineHepatologyCpG Island Methylator PhenotypeColorectal cancerGastroenterologyMethylationBiologymedicine.disease_causemedicine.diseasedigestive system diseases3. Good health03 medical and health sciences030104 developmental biology0302 clinical medicineDNA methylationCancer researchmedicinelcsh:Diseases of the digestive system. Gastroenterology030211 gastroenterology & hepatologyKRASEpigeneticslcsh:RC799-869neoplasmsGeneExome sequencing

description

BACKGROUND & 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 by DNA Methylation and RNA expression microarray in 216 unselected colorectal cancers, and findings were validated using The Cancer Genome Atlas 450K and RNA sequencing data. Mutations in epigenetic regulators were assessed using CIMP-subtyped Cancer Genome Atlas exomes. RESULTS: CIMP-high cancers dichotomized into CIMP-H1 and CIMP-H2 based on methylation profile. KRAS mutation was associated significantly 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 < .0001). CIMP-H1 predominantly comprised consensus molecular subtype 1 cancers (70%) whereas consensus molecular subtype 3 was over-represented in the CIMP-H2 subgroup (55%). Polycomb Repressive Complex-2 (PRC2)-marked loci were subjected to significant gene body methylation in CIMP cancers (P < 1.6 × 10-78). We identified oncogenes susceptible to gene body methylation and Wnt pathway antagonists resistant to gene body methylation. CIMP cluster-specific mutations were observed in chromatin remodeling genes, such as in the SWItch/Sucrose Non-Fermentable and Chromodomain Helicase DNA-Binding gene families. CONCLUSIONS: There are 5 clinically and molecularly distinct subgroups of colorectal cancer. We show a striking association between CIMP and age, sex, and tumor location, and identify a role for gene body methylation in the 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. ispartof: CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY vol:8 issue:2 pages:269-290 ispartof: location:United States status: published

yearjournalcountryeditionlanguage
2019-01-01Cellular and Molecular Gastroenterology and Hepatology
https://doi.org/10.1016/j.jcmgh.2019.04.002