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)

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 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 versus 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 lifecourse and may be better markers than genotypic measures for ascertaining BC risk.

The association between BRCA1 gene polymorphism and cancer risk: a meta-analysis

“…Based on the inclusion and exclusion criteria, 19 articles remained [ 14 – 32 ]. One article containing data regarding various types of cancer was treated as independent studies [ 14 ], and there were seven articles containing studies of various BRCA1 polymorphisms [ 14 , 16 , 17 , 21 , 22 , 24 , 27 ]. Altogether, 35 studies contained in 19 articles involving 28,094 cases and 50,657 controls were included in this meta-analysis.…”

Association between BRCA1 rs799917 polymorphism and breast cancer risk: A meta-analysis of 19,878 subjects

“…The rs799917 polymorphism encodes a substitution at codon 871 (Pro871Leu) in a highly conserved region of the protein [22,35]. Though no functional researches have been performed to date, it is credible to say that this amino acid substitution can alter protein function to some degree [21]. Since the discovery of the BRCA1 rs799917 polymorphism, besides breast cancer, it has been widely researched in ovarian cancer [36], cervical cancer [37], non-small cell lung cancer [38], esophageal squamous cell carcinoma [39] and even nonHodgkin lymphoma [40].…”

“…1). Finally, a total of 8 case-control articles met our inclusion criteria [15][16][17][18][19][20][21][22], including 19,878 subjects. And detailed characteristics of these studies were presented in Table 1.…”

Mismatch Repair Polymorphisms as Markers of Breast Cancer Prevalence in the Breast Cancer Family Registry

“…We selected participants enrolled in the New York site of the BCFR with available DNA (8–18). Enrollment eligibility for participants in the parent study included having to meet one of the following criteria: i) A female relative who had been diagnosed with either breast or ovarian cancer prior to the age of 45; ii) A female relative who has been diagnosed with breast and ovarian cancer at any age; iii) Two or more female relatives who had been diagnosed with breast or ovarian cancer after the age of 45; iv) A male relative diagnosed with breast cancer at any age; v) A known carrier of BRCA1 or 2 mutation.…”