ABRAXAS (FAM175A) and Breast Cancer Susceptibility: No Evidence of Association in the Breast Cancer Family Registry

PLoS One. 2016 Jun 7;11(6):e0156820. doi: 10.1371/journal.pone.0156820. eCollection 2016.


Approximately half of the familial aggregation of breast cancer remains unexplained. This proportion is less for early-onset disease where familial aggregation is greater, suggesting that other susceptibility genes remain to be discovered. The majority of known breast cancer susceptibility genes are involved in the DNA double-strand break repair pathway. ABRAXAS is involved in this pathway and mutations in this gene impair BRCA1 recruitment to DNA damage foci and increase cell sensitivity to ionizing radiation. Moreover, a recurrent germline mutation was reported in Finnish high-risk breast cancer families. To determine if ABRAXAS could be a breast cancer susceptibility gene in other populations, we conducted a population-based case-control mutation screening study of the coding exons and exon/intron boundaries of ABRAXAS in the Breast Cancer Family Registry. In addition to the common variant p.Asp373Asn, sixteen distinct rare variants were identified. Although no significant difference in allele frequencies between cases and controls was observed for the identified variants, two variants, p.Gly39Val and p.Thr141Ile, were shown to diminish phosphorylation of gamma-H2AX in MCF7 human breast adenocarcinoma cells, an important biomarker of DNA double-strand breaks. Overall, likely damaging or neutral variants were evenly represented among cases and controls suggesting that rare variants in ABRAXAS may explain only a small proportion of hereditary breast cancer.

MeSH terms

  • Age of Onset
  • Breast Neoplasms / genetics*
  • Carrier Proteins / genetics*
  • Case-Control Studies
  • Female
  • Gene Frequency
  • Genetic Association Studies / methods*
  • Genetic Predisposition to Disease
  • Germ-Line Mutation
  • Humans
  • MCF-7 Cells
  • Pedigree
  • Polymorphism, Single Nucleotide*
  • Quebec


  • Carrier Proteins
  • FAM175A protein, human

Supplementary concepts

  • Breast Cancer, Familial

Grant support

This work was supported by the Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program – grant # CRN-87521, the Ministry of Economic Development, Innovation and Export Trade – grant # PSR-SIIRI-701 and by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research (GPH-129344), the Ministère de l’Économie, de la Science et de l'Innovation du Québec through Genome Québec, the Quebec Breast Cancer Foundation for the PERSPECTIVE project, the National Cancer Institute (NCI) and the National Institute of Health (NIH) grant R01 CA121245. This work was also supported by grant UM1 CA164920 from the 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 US Government or the BCFR. J.S. is Chairholder of the Canada Research Chair in Oncogenetics. J-Y.M. is a FQRS chercheur national investigator and was supported by a Canadian Institutes of Health Research operating grant. I.L.A is the Anne and Max Tanenbaum Chair in Molecular Medicine at the University of Toronto. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.