A recessive variant of XRCC4 predisposes to non- BRCA1/2 breast cancer in chinese women and impairs the DNA damage response via dysregulated nuclear localization.

Abstract

XRCC4 plays a crucial role in the non-homologous end joining pathway that maintains genome stability. In this two-stage case-control study with 1,764 non-BRCA1/2 breast cancer patients and 1,623 cancer-free controls, we investigated the contribution of genetic variants of XRCC4 to breast cancer susceptibility in Chinese women. We identified a recessive missense variant, rs3734091 (c.739G>T, p.Ala247Ser), of XRCC4 that was significantly associated with an increased risk of breast cancer (odds ratio [OR] = 3.92, P = 0.007), particularly with the risk of developing triple-negative breast cancer (OR = 18.65, P < 0.0001). This p.Ala247Ser variant disturbed the nuclear localization of XRCC4 in cells homozygous for the rs3734091-T allele but not in heterozygous cells at both the cellular and tissue levels. In heterozygous cells, wild-type XRCC4 facilitated the nuclear localization of the XRCC4A247S mutant, thus compensating for the impaired localization of XRCC4A247S. This provided a biological mechanism by which rs3734091 conferred an increased susceptibility to non-BRCA1/2 breast cancer exclusively under a recessive model. Further functional analyses revealed that p.Ala247Ser impaired the DNA damage repair capacity and ultimately perturbed genomic stability. Taken together, our findings document the role of XRCC4 in non-BRCA1/2 breast cancer predisposition and reveal its underlying biological mechanism of action.

• Authors: Min He, Xin Hu, Li Chen, A-Yong Cao, Ke-Da Yu, Ting-Yan Shi, Xia-Ying Kuang, Wen-Biao Shi, Hong Ling, Shan Li, Feng Qiao, Ling Yao, Qingyi Wei, Gen-Hong Di, Zhi-Ming Shao
• Journal: Oncotarget (Oncotarget) Vol. 5 Issue 23 Pg. 12218-32 (Dec 15 2014) ISSN: 1949-2553 [Electronic] United States
• PMID: 25360583 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• RNA, Small Interfering
• XRCC4 protein, human

Topics

• Asian People (genetics)
• Blotting, Western
• Breast Neoplasms (genetics, metabolism)
• Case-Control Studies
• Cell Nucleus (metabolism)
• Comet Assay
• DNA Damage
• DNA-Binding Proteins (genetics, metabolism)
• Female
• Fluorescent Antibody Technique
• Genes, BRCA1
• Genes, BRCA2
• Genetic Predisposition to Disease (genetics)
• Genotype
• Humans
• Immunohistochemistry
• Immunoprecipitation
• Polymerase Chain Reaction
• Protein Transport
• RNA, Small Interfering