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

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

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Genomics Center, Centre Hospitalier Universitaire de Québec Research Center and Laval University, Quebec, Canada.
INSERM, U900, Mines ParisTech, Institut Curie, Paris, France.
Genome Stability Laboratory, Centre Hospitalier Universitaire de Québec Research Center, HDQ Pavillon, Oncology Axis, Quebec, Canada.
Genetic Cancer Susceptibility group, International Agency for Research on Cancer, Lyon, France.
Center for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, Victoria, Australia.
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada.
Department of Molecular Genetics, University of Toronto, Toronto, Canada.
Genetic Epidemiology Laboratory, The University of Melbourne, Victoria, Australia.
Cancer Prevention Institute of California, Fremont, United States of America.
Stanford University School of Medicine and Stanford Cancer Institute, Stanford, United States of America.
Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University, Quebec, Canada.
Department of Oncological Sciences, University of Utah, Salt Lake City, United States of America.
Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America.


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.

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