Abstract

Single nucleotide polymorphisms (SNPs) in DNA glycosylase genes involved in the base excision repair (BER) pathway can modify breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We previously found that SNP rs34259 in the uracil‐DNA glycosylase gene (UNG) might decrease ovarian cancer risk in BRCA2 mutation carriers. In the present study, we validated this finding in a larger series of familial breast and ovarian cancer patients to gain insights into how this UNG variant exerts its protective effect. We found that rs34259 is associated with significant UNG downregulation and with lower levels of DNA damage at telomeres. In addition, we found that this SNP is associated with significantly lower oxidative stress susceptibility and lower uracil accumulation at telomeres in BRCA2 mutation carriers. Our findings help to explain the association of this variant with a lower cancer risk in BRCA2 mutation carriers and highlight the importance of genetic changes in BER pathway genes as modifiers of cancer susceptibility for BRCA1 and BRCA2 mutation carriers.

Highlights

  • Women carrying germline mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of developing breast, ovarian, and other cancers (Milne et al, 2008)

  • (n = 23 463) from the CIMBA consortium, we found that single nucleotide polymorphism (SNP) rs34259 showed the strongest association with ovarian cancer risk among all SNPs covering the uracil-DNA glycosylase gene (UNG) gene: hazard ratio (HR): 0.80, 95% CI: 0.69–0.94, P = 7.6 9 10À3 (Osorio et al, 2014)

  • Rs34259 has been identified as a trans expression quantitative trait locus SNP that decreased UNG gene expression in two independent eQTL studies (Ardlie et al, 2015; Westra et al, 2013) and we considered it the best candidate

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Summary

Introduction

Women carrying germline mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of developing breast, ovarian, and other cancers (Milne et al, 2008). BRCA proteins are involved in double-strand break (DSB) DNA repair through the homologous recombination pathway (O’Donovan and Livingston, 2010), and cells harboring mutations in these genes are dependent on other DNA repair mechanisms. In this regard, we have shown that single nucleotide polymorphisms (SNPs) in genes from the base excision repair (BER) pathway can modify breast or ovarian cancer susceptibility in BRCA1 and BRCA2 mutation carriers (Osorio et al, 2014).

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