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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.
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 articleSubject
Cell NucleusHumans
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
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https://hdl.handle.net/10161/18034Published Version (Please cite this version)
10.18632/oncotarget.2623Publication 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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Show full item recordScholars@Duke
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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