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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.

Publication ,  Journal Article
He, M; Hu, X; Chen, L; Cao, A-Y; Yu, K-D; Shi, T-Y; Kuang, X-Y; Shi, W-B; Ling, H; Li, S; Qiao, F; Yao, L; Wei, Q; Di, G-H; Shao, Z-M
Published in: Oncotarget
December 15, 2014

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.

Duke Scholars

Published In

Oncotarget

DOI

EISSN

1949-2553

Publication Date

December 15, 2014

Volume

5

Issue

23

Start / End Page

12218 / 12232

Location

United States

Related Subject Headings

  • RNA, Small Interfering
  • Protein Transport
  • Polymerase Chain Reaction
  • Immunoprecipitation
  • Immunohistochemistry
  • Humans
  • Genotype
  • Genetic Predisposition to Disease
  • Genes, BRCA2
  • Genes, BRCA1
 

Citation

APA
Chicago
ICMJE
MLA
NLM
He, M., Hu, X., Chen, L., Cao, A.-Y., Yu, K.-D., Shi, T.-Y., … Shao, Z.-M. (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), 12218–12232. https://doi.org/10.18632/oncotarget.2623
He, Min, Xin Hu, Li Chen, A-Yong Cao, Ke-Da Yu, Ting-Yan Shi, Xia-Ying Kuang, et al. “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, no. 23 (December 15, 2014): 12218–32. https://doi.org/10.18632/oncotarget.2623.
He, Min, et al. “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, vol. 5, no. 23, Dec. 2014, pp. 12218–32. Pubmed, doi:10.18632/oncotarget.2623.
He M, Hu X, Chen L, Cao A-Y, Yu K-D, Shi T-Y, Kuang X-Y, Shi W-B, Ling H, Li S, Qiao F, Yao L, Wei Q, Di G-H, Shao Z-M. 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. 2014 Dec 15;5(23):12218–12232.

Published In

Oncotarget

DOI

EISSN

1949-2553

Publication Date

December 15, 2014

Volume

5

Issue

23

Start / End Page

12218 / 12232

Location

United States

Related Subject Headings

  • RNA, Small Interfering
  • Protein Transport
  • Polymerase Chain Reaction
  • Immunoprecipitation
  • Immunohistochemistry
  • Humans
  • Genotype
  • Genetic Predisposition to Disease
  • Genes, BRCA2
  • Genes, BRCA1