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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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Date
2014-12
Authors
He, Min
Hu, Xin
Chen, Li
Cao, A-Yong
Yu, Ke-Da
Shi, Ting-Yan
Kuang, Xia-Ying
Shi, Wen-Biao
Ling, Hong
Li, Shan
Qiao, Feng
Yao, Ling
Wei, Qingyi
Di, Gen-Hong
Shao, Zhi-Ming
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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.
Type
Journal article
Subject
Cell Nucleus
Humans
Breast Neoplasms
DNA Damage
Genetic Predisposition to Disease
DNA-Binding Proteins
RNA, Small Interfering
Fluorescent Antibody Technique
Blotting, Western
Comet Assay
Immunohistochemistry
Case-Control Studies
Polymerase Chain Reaction
Immunoprecipitation
Protein Transport
Genotype
Genes, BRCA1
Genes, BRCA2
Asian Continental Ancestry Group
Female
Permalink
https://hdl.handle.net/10161/18034
Published Version (Please cite this version)
10.18632/oncotarget.2623
Publication Info
He, Min; Hu, Xin; Chen, Li; Cao, A-Yong; Yu, Ke-Da; Shi, Ting-Yan; ... Shao, Zhi-Ming (2014). 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. Oncotarget, 5(23). pp. 12218-12232. 10.18632/oncotarget.2623. Retrieved from https://hdl.handle.net/10161/18034.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Scholars@Duke

Wei

Qingyi Wei

Professor in Population Health Sciences
Qingyi Wei, MD, PhD, Professor in the Department of Medicine, is Associate Director for Cancer Control and Population Sciences, Co-leader of CCPS and Co-leader of Epidemiology and Population Genomics (Focus Area 1). He is a professor of Medicine and an internationally recognized epidemiologist focused on the molecular and genetic epidemiology of head and neck cancers, lung cancer, and melanoma. His research focuses on biomarkers and genetic determinants for the DNA repair deficient phenotype and
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