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

JE Joo; K Mahmood; R Walker; P Georgeson; I Candiloro; M Clendenning; J Como; S Joseland; S Preston; L Graversen; M Wilding; M Field; M Lemon; J Wakeling; H Marfan; R Susman; J Isbister; E Edwards; M Bowman; J Kirk; E Ip; L McKay; Y Antill; JL Hopper; A Boussioutas; FA Macrae; A Dobrovic; MA Jenkins; C Rosty; IM Winship; DD Buchanan

Journal article

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

JE Joo, K Mahmood, R Walker, P Georgeson, I Candiloro, M Clendenning, J Como, S Joseland, S Preston, L Graversen, M Wilding, M Field, M Lemon, J Wakeling, H Marfan, R Susman, J Isbister, E Edwards, M Bowman, J Kirk Show all

Clinical Epigenetics | Published : 2023

DOI: 10.1186/s13148-023-01511-y

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 ..

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University of Melbourne Researchers

Eric Joo Author

Khalid Mahmood Author

Romy Walker Author

Peter Georgeson Author

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Funding Acknowledgements

The design, analysis and interpretation of data for this study was supported by a National Health and Medical Research Council of Australia (NHMRC) project grant GNT1125269 (PI-Daniel Buchanan). In addition, this study was supported by the Australian Genome Research Facility's 2020 Summer Oncology Mini Grant Competition. DDB is supported by an NHMRC Investigator grant (GNT1194896) and University of Melbourne Dame Kate Campbell Fellowship. RW is supported by the Margaret and Irene Stewardson Fund Scholarship and by the Melbourne Research Scholarship. PG is supported by the University of Melbourne Research Scholarship. MAJ is supported by an NHMRC Investigator grant (GNT1195099). JLH is supported by the University of Melbourne Dame Kate Campbell Fellowship. Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number U01CA167551 and through a cooperative agreement with the Australasian Colorectal Cancer Family Registry (NCI/NIH U01 CA074778 and U01/U24 CA097735) and by the Victorian Cancer Registry, Australia. This research was performed under CCFR approved projects C-AU0818-01, C-AU-1014-01, C-AU-0312-01.