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DNA double-strand break repair genotype and phenotype and breast cancer risk within sisters from the New York site of the Breast Cancer Family Registry (BCFR)

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Abstract

Purpose

We previously observed that poor DNA repair phenotype is associated with increased breast cancer (BC) risk within families. Here, we examined whether genetic variation in double-strand break repair (DSBR) genes is associated with BC risk and if genotypes are related to phenotype in unaffected women.

Methods

Using data from the New York site of the Breast Cancer Family Registry, we investigated 25 single-nucleotide polymorphism (SNPs) involved in DSBR using biospecimens from 337 BC cases and 410 unaffected sister controls.

Results

Genotypes in XRCC4 were associated with BC risk, with ORs of 1.67 (95 % CI 1.01–2.76) for the combined GA/AA of rs1805377 and 1.69 (95 % CI 1.03–2.77) for rs1056503 TG/GG; these associations were no longer statistically significant in multivariable conditional logistic regression models. When examining the association of SNPs with phenotype, we found that genotypes of XRCC5 rs3834 and rs1051685, which were highly correlated with each other, were associated with end-joining (EJ) capacity; women with the XRCC5 rs3834 GA genotype had better DNA repair as measured by higher levels of EJ capacity (37.8 ± 14.1 % for GA vs. 27.9 ± 11.8 % for GG carriers p = 0.0006). Women with the AA genotype of BRCA1 rs799917 also had higher EJ capacity (35.1 ± 9.2 %) than those with GG (26.4 ± 10.1 %, p = 0.02).

Conclusions

Overall, we found that selected DSBR genotypes were associated with phenotype, although they were not associated with BC risk itself, suggesting that phenotypic measures are influenced by endogenous and exogenous factors across the life course and may be better markers than genotypic measures for ascertaining BC risk.

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Abbreviations

BC:

Breast cancer

BCFR:

Breast Cancer Family Registry

CI:

Confidence interval

DSB:

Double-strand break

DSBR:

Double-strand break repair

EJ:

End-joining

HWE:

Hardy–Weinberg equilibrium

HR:

Homologous recombination

NER:

Nucleotide excision repair

NHEJ:

Non-homologous end-joining

OR:

Odds ratio

SNP:

Single-nucleotide polymorphism

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Acknowledgments

This work was supported by an award from the Breast Cancer Research Foundation and NIH Grants U01 CA69398, P30 CA13696, P30 ES009089, and K07 CA131094. This work was also supported by the National Cancer Institute, National Institutes of Health under RFA # CA-06-503 and through cooperative agreements with members of the Breast Cancer Family Registry (BCFR) and Principal Investigators, including Columbia University (U01 CA69398). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the BCFR, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the BCFR.

Conflict of interest

There is no conflict of interest of financial disclosures.

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Authors and Affiliations

  1. Department of Epidemiology, Mailman School of Public Health of Columbia University, 722 West 168th St., 724A, New York, NY, 10032, USA

    Hui-Chen Wu & Mary Beth Terry

  2. Department of Environmental Health Sciences, Mailman School of Public Health of Columbia University, New York, NY, USA

    Hui-Chen Wu, Lissette Delgado-Cruzata, Nicola Machella, Qiao Wang & Regina M. Santella

  3. Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA

    Regina M. Santella & Mary Beth Terry

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  1. Hui-Chen Wu
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  2. Lissette Delgado-Cruzata
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  3. Nicola Machella
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  4. Qiao Wang
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  5. Regina M. Santella
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  6. Mary Beth Terry
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Correspondence to Mary Beth Terry.

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Wu, HC., Delgado-Cruzata, L., Machella, N. et al. DNA double-strand break repair genotype and phenotype and breast cancer risk within sisters from the New York site of the Breast Cancer Family Registry (BCFR). Cancer Causes Control 24, 2157–2168 (2013). https://doi.org/10.1007/s10552-013-0292-z

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