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).
OBJECTIVE
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.
Department of Epidemiology, Mailman School of Public Health of Columbia University, 722 West 168th St., 724A, New York, NY, 10032, USA.
Hui-Chen
HC
Wu
Lissette
L
Delgado-Cruzata
Nicola
N
Machella
Qiao
Q
Wang
Regina M
RM
Santella
Mary Beth
MB
Terry
D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D053903:DNA Breaks, Double-Stranded; D004265:DNA Helicases / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D056726:Genetic Association Studies; D006801:Humans; D000072200:Ku Autoantigen; D008875:Middle Aged; D009518:New York; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D012042:Registries; D012307:Risk Factors; D035781:Siblings
D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; C101467:XRCC4 protein, human; D004265:DNA Helicases; C106893:XRCC5 protein, human; D000072200:Ku Autoantigen