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.

2023-06-03

Joo, Jihoon E

Mahmood, Khalid

Walker, Romy

Georgeson, Peter

Candiloro, Ida

Clendenning, Mark

Como, Julia

Joseland, Sharelle

Preston, Susan

Graversen, Lise

Wilding, Mathilda

Field, Michael

Lemon, Michelle

Wakeling, Janette

Marfan, Helen

Susman, Rachel

Isbister, Joanne

Edwards, Emma

Bowman, Michelle

Kirk, Judy

Ip, Emilia

McKay, Lynne

Antill, Yoland

Hopper, John L

Boussioutas, Alex

Macrae, Finlay A

Dobrovic, Alexander

Jenkins, Mark A

Rosty, Christophe

Winship, Ingrid M

Buchanan, Daniel D

Colorectal cancer

Genome wide DNA methylation

Lynch syndrome

MLH1 epimutation

MLH1 methylation

MMR deficiency

Journal Article

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10.1186/s13148-023-01511-y

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 (< 45 years) were compared with 38 reference CRCs. Methylation-sensitive droplet digital PCR (ddPCR) was used to detect mosaic MLH1 methylation in blood, normal mucosa and buccal DNA. Genome-wide methylation-based Consensus Clustering identified four clusters where the tumour methylation profiles of germline MLH1: c.-11C > 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. 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.

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Clinical Epigenetics 2023-06-03; 15(1)

Clinical Epigenetics

1868-7083