title: Methylation of Breast Cancer Predisposition Genes in Early-Onset Breast Cancer: Australian Breast Cancer Family Registry.
abstract: 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.
authors.affiliation: Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, VIC, 3010, Australia.
authors.forename: Cameron M
authors.initials: CM
authors.lastname: Scott
authors.affiliation: Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, VIC, 3010, Australia.
authors.forename: JiHoon Eric
authors.initials: JE
authors.lastname: Joo
authors.affiliation: Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, VIC, 3010, Australia.
authors.forename: Neil
authors.initials: N
authors.lastname: O'Callaghan
authors.affiliation: Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, VIC, Australia.|Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC, Australia.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Buchanan
authors.affiliation: Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, VIC, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Clendenning
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC, Australia.|Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC, Australia.
authors.forename: Graham G
authors.initials: GG
authors.lastname: Giles
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC, Australia.
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.affiliation: Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, VIC, 3010, Australia.
authors.forename: Ee Ming
authors.initials: EM
authors.lastname: Wong
authors.affiliation: Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, VIC, 3010, Australia.
authors.forename: Melissa C
authors.identifier: http://orcid.org/0000-0002-6313-9005
authors.initials: MC
authors.lastname: Southey
mesh_terms: D000328:Adult; D017668:Age of Onset; D001315:Australia; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics*; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D011401:Promoter Regions, Genetic / Q000235:genetics; D012042:Registries / Q000706:statistics & numerical data*
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm