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

PLoS One. 2016 Nov 30;11(11):e0165436. doi: 10.1371/journal.pone.0165436. eCollection 2016.

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.

MeSH terms

  • Adult
  • Age of Onset
  • Australia
  • BRCA1 Protein / genetics*
  • BRCA2 Protein / genetics*
  • Biomarkers, Tumor / genetics
  • Breast Neoplasms / genetics*
  • DNA Methylation*
  • DNA, Neoplasm / genetics
  • Female
  • Genetic Predisposition to Disease*
  • Germ-Line Mutation / genetics*
  • Humans
  • Promoter Regions, Genetic / genetics
  • Registries / statistics & numerical data*

Substances

  • BRCA1 Protein
  • BRCA1 protein, human
  • BRCA2 Protein
  • BRCA2 protein, human
  • Biomarkers, Tumor
  • DNA, Neoplasm

Supplementary concepts

  • Breast Cancer, Familial

Grant support

The Australia site of Breast Cancer Family Registry was supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia) and grant UM1 CA164920 from the USA National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. JLH is a Senior Principle Research Fellow and MCS is a Senior Research Fellow of the NHMRC. CMS is a recipient of a Genetic Epidemiology Laboratory Honors Scholarship, Department of Pathology, The University of Melbourne.