Abstract
Deleterious and missense mutations of RAD51C have recently been suggested to modulate the individual susceptibility to hereditary breast and ovarian cancer and unselected ovarian cancer, but not unselected breast cancer (BrC). We enrolled 132 unselected BrC females and 189 cancer-free female subjects to investigate whether common single nucleotide polymorphisms (SNPs) in non-coding regions of RAD51C modulate the risk of BrC, and whether they affect the level of oxidative stress and the extent/characteristics of DNA damage. Neither SNPs nor reconstructed haplotypes were found to significantly affect the unselected BrC risk. Contrary to this, carriers of rs12946522, rs16943176, rs12946397 and rs17222691 rare-alleles were found to present significantly increased level of blood plasma TBARS compared to respective wild-type homozygotes (p<0.05). Furthermore, these carriers showed significantly decreased fraction of oxidatively generated DNA damage (34% of total damaged DNA) in favor of DNA strand breakage, with no effect on total DNA damage, unlike respective wild-types, among which more evenly distributed proportions between oxidatively damaged DNA (48% of total DNA damage) and DNA strand breakage was found (p<0.0005 for the difference). Such effects were found among both the BrC cases and healthy subjects, indicating that they cannot be assumed as causal factors contributing to BrC development.
Highlights
Breast cancer (BrC) is the most common malignancy among women, with nearly 1.4 million new BrC cases causing nearly 460,000 deaths per year worldwide [1]
As all RAD51 paralogs are generally considered conservative with the frequency of missense mutations being very low, we recently focused on single nucleotide polymorphisms (SNPs) occurring in promoter, 59 untranslated region (59UTR) of exon 1 and intron 1 of these genes and found that genetic variability of XRCC3 and RAD51 may be of relevance with respect to head and neck cancer (HNC) [29]
In further we show that even though the variability in noncoding regions of RAD51C may not alter the risk of unselected BrC, it may be involved in modulation of the oxidative stress and may determine the characteristics of resulting DNA damage
Summary
Breast cancer (BrC) is the most common malignancy among women, with nearly 1.4 million new BrC cases causing nearly 460,000 deaths per year worldwide [1]. Studies have shown that familial BrC is likely a polygenic disease caused by mutations in several high-, moderate- and low-penetrance susceptibility genes. Genes like BRCA1, BRCA2, TP53 and PTEN are well-known highpenetrance susceptibility genes, nowadays it is assumed, that they account for roughly some 20% of all hereditary breast cancer cases [3,4,5]. The ongoing quest to identify additional BrC-susceptibility genes resulted in identification of several moderate-penetrance BrC-susceptibilty genes, the majority of which are somewhat related to Brca1/Brca2-mediated pathways. These include CHEK2, ATM, BRIP1, PALB2 and recently RAD51C, all of which are involved in various steps of DNA recombination repair [5,6,7]. An approximately 2-fold relative risk increase among carriers of heterozygous mutations in these genes has been implied [8]
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