Methylation of Breast Cancer Predisposition Genes in Early-Onset Breast Cancer: Australian Breast Cancer Family Registry

• Published in: PloS one Vol. 11; no. 11; p. e0165436
• Main Authors: Scott, Cameron M., Joo, JiHoon Eric, O’Callaghan, Neil, Buchanan, Daniel D., Clendenning, Mark, Giles, Graham G., Hopper, John L., Wong, Ee Ming, Southey, Melissa C.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 30.11.2016; Public Library of Science (PLoS)
• Subjects: Adult; Age; Age of Onset; Australia; Biology and life sciences; Biomarkers, Tumor - genetics; BRCA1 protein; BRCA1 Protein - genetics; BRCA2 protein; BRCA2 Protein - genetics; Breast cancer; Breast Neoplasms - genetics; Cancer; Cancer genetics; Computer and Information Sciences; Deoxyribonucleic acid; Development and progression; Disease susceptibility; DNA; DNA Methylation; DNA, Neoplasm - genetics; E-cadherin; Female; Gene mutation; Gene silencing; Genes; Genetic aspects; Genetic Predisposition to Disease; Genetic screening; Germ-Line Mutation - genetics; Health risks; Humans; INK4a protein; Medicine and Health Sciences; Methylation; Microsatellite instability; Microsatellites; MLH1 protein; MSH2 protein; MSH6 protein; Mutation; Ovarian cancer; p16 Protein; p53 Protein; Promoter Regions, Genetic - genetics; Registries - statistics & numerical data; Research and analysis methods; Stability; Studies; Tumor proteins; Tumors; Womens health; Australia; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0165436

DNA methylation can mimic the effects of both germline and somatic mutations for cancer predisposition genes such as BRCA1 and p16INK4a. Constitutional DNA methylation of the BRCA1 promoter has been well described and is associated with an increased risk of early-onset breast cancers that have BRCA1-mutation associated histological features. The role of methylation in the context of other breast cancer predisposition genes has been less well studied and often with conflicting or ambiguous outcomes. We examined the role of methylation in known breast cancer susceptibility genes in breast cancer predisposition and tumor development. We applied the Infinium HumanMethylation450 Beadchip (HM450K) array to blood and tumor-derived DNA from 43 women diagnosed with breast cancer before the age of 40 years and measured the methylation profiles across promoter regions of BRCA1, BRCA2, ATM, PALB2, CDH1, TP53, FANCM, CHEK2, MLH1, MSH2, MSH6 and PMS2. Prior genetic testing had demonstrated that these women did not carry a germline mutation in BRCA1, ATM, CHEK2, PALB2, TP53, BRCA2, CDH1 or FANCM. In addition to the BRCA1 promoter region, this work identified regions with variable methylation at multiple breast cancer susceptibility genes including PALB2 and MLH1. Methylation at the region of MLH1 in these breast cancers was not associated with microsatellite instability. This work informs future studies of the role of methylation in breast cancer susceptibility gene silencing.