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.
| dc.contributor.author | He, Min | |
| dc.contributor.author | Hu, Xin | |
| dc.contributor.author | Chen, Li | |
| dc.contributor.author | Cao, A-Yong | |
| dc.contributor.author | Yu, Ke-Da | |
| dc.contributor.author | Shi, Ting-Yan | |
| dc.contributor.author | Kuang, Xia-Ying | |
| dc.contributor.author | Shi, Wen-Biao | |
| dc.contributor.author | Ling, Hong | |
| dc.contributor.author | Li, Shan | |
| dc.contributor.author | Qiao, Feng | |
| dc.contributor.author | Yao, Ling | |
| dc.contributor.author | Wei, Qingyi | |
| dc.contributor.author | Di, Gen-Hong | |
| dc.contributor.author | Shao, Zhi-Ming | |
| dc.date.accessioned | 2019-02-01T15:30:54Z | |
| dc.date.available | 2019-02-01T15:30:54Z | |
| dc.date.issued | 2014-12 | |
| dc.date.updated | 2019-02-01T15:30:47Z | |
| dc.description.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. | |
| dc.identifier | 2623 | |
| dc.identifier.issn | 1949-2553 | |
| dc.identifier.issn | 1949-2553 | |
| dc.identifier.uri | ||
| dc.language | eng | |
| dc.publisher | Impact Journals, LLC | |
| dc.relation.ispartof | Oncotarget | |
| dc.relation.isversionof | 10.18632/oncotarget.2623 | |
| dc.subject | Cell Nucleus | |
| dc.subject | Humans | |
| dc.subject | Breast Neoplasms | |
| dc.subject | DNA Damage | |
| dc.subject | Genetic Predisposition to Disease | |
| dc.subject | DNA-Binding Proteins | |
| dc.subject | RNA, Small Interfering | |
| dc.subject | Fluorescent Antibody Technique | |
| dc.subject | Blotting, Western | |
| dc.subject | Comet Assay | |
| dc.subject | Immunohistochemistry | |
| dc.subject | Case-Control Studies | |
| dc.subject | Polymerase Chain Reaction | |
| dc.subject | Immunoprecipitation | |
| dc.subject | Protein Transport | |
| dc.subject | Genotype | |
| dc.subject | Genes, BRCA1 | |
| dc.subject | Genes, BRCA2 | |
| dc.subject | Asian Continental Ancestry Group | |
| dc.subject | Female | |
| dc.title | 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. | |
| dc.type | Journal article | |
| duke.contributor.orcid | Wei, Qingyi|0000-0002-3845-9445 | |
| pubs.begin-page | 12218 | |
| pubs.end-page | 12232 | |
| pubs.issue | 23 | |
| pubs.organisational-group | School of Medicine | |
| pubs.organisational-group | Duke | |
| pubs.organisational-group | Duke Cancer Institute | |
| pubs.organisational-group | Institutes and Centers | |
| pubs.organisational-group | Population Health Sciences | |
| pubs.organisational-group | Basic Science Departments | |
| pubs.organisational-group | Medicine, Medical Oncology | |
| pubs.organisational-group | Medicine | |
| pubs.organisational-group | Clinical Science Departments | |
| pubs.publication-status | Published | |
| pubs.volume | 5 |
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