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Genetic variation in DNA repair pathway genes and premenopausal breast cancer risk

  • Epidemiology
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Purpose We comprehensively evaluated genetic variants in DNA repair genes with premenopausal breast cancer risk. Methods In this nested case–control study of 239 prospectively ascertained premenopausal breast cancer cases and 477 matched controls within the Nurses’ Health Study II, we evaluated 1,463 genetic variants in 60 candidate genes across five DNA repair pathways, along with DNA polymerases, Fanconi Anemia complementation groups, and other related genes. Results Four variants were associated with breast cancer risk with a significance level of <0.01; two in the XPF gene and two in the XRCC3 gene. An increased risk was found in those harboring a greater number of missense putative risk alleles (a priori defined in an independent study) in the non-homologous end-joining (NHEJ) repair pathway of double-strand breaks (odds ratio (OR) per risk allele, 1.37 (95% confidence interval (CI), 1.03–1.82), P trend, 0.03). Conclusions This study implicates variants of genes in the double-strand break repair pathway in the etiology of premenopausal breast cancer.

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Abbreviations

BER:

Base excision repair

CI:

Confidence interval

DSB:

Double strand break

ER:

Estrogen receptor

HR:

Homologous recombination

LD:

Linkage disequilibrium

MMR:

Mismatch repair

NER:

Nucleotide excision repair

NHEJ:

Non-homologous end-joining

OR:

Odds ratio

PR:

Progesterone receptor

SNP:

Single nucleotide polymorphism

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Acknowledgements

We thank Dr. Paul de Bakker at the Broad Institute of Harvard and MIT for selecting tagging SNPs. We thank Pati Soule for her laboratory assistance, Dr. Daniel B. Mirel at the Broad Institute Center for Genotyping and Analysis for his coordination, and Dr. Fredrick Schumacher for generating the LD plots. We also thank the participants in the Nurses’ Health Study for their dedication and commitment. The work is supported by NIH grants CA098233, CA118447, CA067262, and CA050385. The Broad Institute Center for Genotyping and Analysis is supported by grant U54 RR020278-01 from the National Center for Research Resources.

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Authors and Affiliations

  1. Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, 181 Longwood Ave., Boston, MA, 02115, USA

    Jiali Han, Qun Guo, Walter C. Willett, Susan E. Hankinson & David J. Hunter

  2. Channing Laboratory, Department of Medicine, Harvard Medical School, 181 Longwood Ave., Boston, MA, 02115, USA

    Jiali Han, Qun Guo, Walter C. Willett, Susan E. Hankinson & David J. Hunter

  3. Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, 665 Huntington Ave., Boston, MA, 02115, USA

    Jiali Han, Tianhua Niu, David G. Cox & David J. Hunter

  4. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90089, USA

    Christopher Haiman

  5. Department of Epidemiology, Harvard School of Public Health, 665 Huntington Ave., Boston, MA, 02115, USA

    Tianhua Niu, David G. Cox, Walter C. Willett, Susan E. Hankinson & David J. Hunter

  6. Department of Nutrition, Harvard School of Public Health, 665 Huntington Ave., Boston, MA, 02115, USA

    Walter C. Willett & David J. Hunter

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  1. Jiali Han
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Correspondence to Jiali Han.

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Han, J., Haiman, C., Niu, T. et al. Genetic variation in DNA repair pathway genes and premenopausal breast cancer risk. Breast Cancer Res Treat 115, 613–622 (2009). https://doi.org/10.1007/s10549-008-0089-z

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  • DOI: https://doi.org/10.1007/s10549-008-0089-z

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