Research Papers:
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
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Abstract
Min He1,4, Xin Hu1, Li Chen1,4, A-Yong Cao1, Ke-Da Yu1, Ting-Yan Shi2, Xia-Ying Kuang1,4, Wen-Biao Shi1, Hong Ling1, Shan Li1, Feng Qiao1, Ling Yao1, Qingyi Wei3,5, Gen-Hong Di1,4 and Zhi-Ming Shao1,3,4
1 Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai, China
2 Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
3 Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China
4 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
5 Duke Cancer Institute, Duke University Medical Center, Durham, NC, United States of America
Correspondence:
Zhi-Ming Shao, email:
Xin Hu, email:
Keywords: XRCC4, homozygous variant, nuclear localization, susceptibility, breast cancer
Received: September 07, 2014 Accepted: October 22, 2014 Published: October 22, 2014
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.
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