Abstract
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.
Highlights
DNA damage induced by endogenous and exogenous genotoxic agents can promote genomic instability and directly lead to various diseases, cancer
Despite technical progress and studies with greater statistical power, only approximately 35% of the familial relative risk of breast cancer is currently explained by the known high- and intermediate-risk genes, suggesting that other breast cancer susceptibility genes, possibly involved in the homologous recombination repair (HRR) pathway, remain to be discovered
In addition to the common missense substitution p.Asp373Asn, High Resolution Melting curve (HRM) screening revealed sixteen rare distinct sequence variants, including an in-frame deletion found in one case and one control, eight missense substitutions, four silent substitutions, two intronic variations and one variant located in the 5’UTR region (S1 Fig)
Summary
DNA damage induced by endogenous and exogenous genotoxic agents can promote genomic instability and directly lead to various diseases, cancer. Germline mutations in genes involved in homologous recombination DNA repair have been associated with breast cancer susceptibility. These include high-penetrance susceptibility genes such as BRCA1 [2,3], BRCA2 [4, 5] and TP53 [6] and the moderate penetrance genes CHEK2 [7, 8], ATM [9, 10], BRIP1 [11], PALB2 [12, 13] and MRE11A, RAD50 and NBN [14]. Despite technical progress and studies with greater statistical power, only approximately 35% of the familial relative risk of breast cancer is currently explained by the known high- and intermediate-risk genes, suggesting that other breast cancer susceptibility genes, possibly involved in the homologous recombination repair (HRR) pathway, remain to be discovered
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