Aberrant DNA methylation patterns in microsatellite stable human colorectal cancers define a new marker panel for the CpG island methylator phenotype

Abstract

A distinct group of colorectal carcinomas (CRCs) referred to as the “CpG island methylator phenotype” (CIMP) shows an extremely high incidence of de novo DNA methylation and may share common pathological, clinical or molecular features. However, there is limited consensus about which CpG islands (CGIs) define a CIMP, particularly in microsatellite stable (MSS) carcinomas. To study this phenotype in a systematic manner, we analyzed genome‐wide CGI DNA methylation profiles of 19 MSS CRC using methyl‐CpG immunoprecipitation (MCIp) and hybridization on 244K CGI oligonucleotide microarrays, determined KRAS and BRAF mutation status and compared disease‐related DNA methylation changes to chromosomal instability as detected by microarray‐based comparative genomic hybridization. Results were validated using mass spectrometry analysis of bisulfite‐converted DNA at a subset of 76 individual CGIs in 120 CRC and 43 matched normal tissue samples. Both genome‐wide profiling and CpG methylation fine mapping segregated a group of CRC showing pronounced and frequent de novo DNA methylation of a distinct group of CGIs that only partially overlapped with previously established classifiers. The CIMP group defined in our study revealed significant association with colon localization, either KRAS or BRAF mutation, and mostly minor chromosomal losses but no association with known histopathological features. Our data provide a basis for defining novel marker panels that may enable a more reliable classification of CIMP in all CRCs, independently of the MS status.

Characterization of the CpG island methylator phenotype subclass in papillary thyroid carcinoma

“…Previous studies have outlined the genome-wide landscape of cancer-specific DNA methylation changes, which is characteristic of global hypomethylation and a regional hypermethylation in CpG islands (CGIs) ( 8 – 10 ). The former is considered to favour chromosomal instability and inappropriate activation of oncogenes, the latter may lead to the - silencing of tumor-suppressor genes ( 8 , 11 ). Changes in DNA methylation in cancer have been regarded as promising targets for the development of powerful diagnostic, prognostic, and predictive biomarkers ( 12 , 13 ).…”

Polygenic Risk Scores for Follow Up After Colonoscopy and Polypectomy: Another Tool for Risk Stratification and Planning Surveillance?

“…However, work by Guo et al 12 and others also suggests that there is an opportunity to leverage well-established biologic and quality factors, such as age, sex, and extent of examination, and emerging factors, such as information on genetic predisposition and colonoscopist ADR, to develop even better, more comprehensive models for risk stratification. Although questionnaire-based, clinical and PRSbased tools seem to be clinically useful, incorporating additional blood-based markers (eg, information from the blood epigenome) 32,33 may provide a novel path toward improving further CRC risk prediction. Innovations in strategies for risk stratification may enable a new era of precision surveillance that might ultimately allow some low-risk patients to be offered long intervals between colonoscopy or even the option of noninvasive surveillance, such as with a fecal immunochemical test, and high-risk patients to receive tailored recommendations for close interval colonoscopy surveillance.…”