학술논문
Identifying primary and secondary MLH1 epimutation carriers displaying low-level constitutional MLH1 methylation using droplet digital PCR and genome-wide DNA methylation profiling of colorectal cancers
Document Type
article
Author
Jihoon E. Joo; Khalid Mahmood; Romy Walker; Peter Georgeson; Ida Candiloro; Mark Clendenning; Julia Como; Sharelle Joseland; Susan Preston; Lise Graversen; Mathilda Wilding; Michael Field; Michelle Lemon; Janette Wakeling; Helen Marfan; Rachel Susman; Joanne Isbister; Emma Edwards; Michelle Bowman; Judy Kirk; Emilia Ip; Lynne McKay; Yoland Antill; John L. Hopper; Alex Boussioutas; Finlay A. Macrae; Alexander Dobrovic; Mark A. Jenkins; Christophe Rosty; Ingrid M. Winship; Daniel D. Buchanan
Source
Clinical Epigenetics, Vol 15, Iss 1, Pp 1-17 (2023)
Subject
Language
English
ISSN
1868-7083
Abstract
Abstract Background MLH1 epimutation is characterised by constitutional monoallelic MLH1 promoter hypermethylation, which can cause colorectal cancer (CRC). Tumour molecular profiles of MLH1 epimutation CRCs were used to classify germline MLH1 promoter variants of uncertain significance and MLH1 methylated early-onset CRCs (EOCRCs). Genome-wide DNA methylation and somatic mutational profiles of tumours from two germline MLH1: c.-11C > T and one MLH1: c.-[28A > G; 7C > T] carriers and three MLH1 methylated EOCRCs ( T carriers and MLH1 methylated EOCRCs clustered with the constitutional MLH1 epimutation CRCs but not with the sporadic MLH1 methylated CRCs. Furthermore, monoallelic MLH1 methylation and APC promoter hypermethylation in tumour were observed in both MLH1 epimutation and germline MLH1: c.-11C > T carriers and MLH1 methylated EOCRCs. Mosaic constitutional MLH1 methylation in MLH1: c.-11C > T carriers and 1 of 3 MLH1 methylated EOCRCs was identified by methylation-sensitive ddPCR. Conclusions Mosaic MLH1 epimutation underlies the CRC aetiology in MLH1: c.-11C > T germline carriers and a subset of MLH1 methylated EOCRCs. Tumour profiling and ultra-sensitive ddPCR methylation testing can be used to identify mosaic MLH1 epimutation carriers.