Rad51 paralogs and the risk of unselected breast cancer: A case-control study.

Peter Grešner,Jolanta Gromadzińska,Ewa Jabłońska,Alvaro Galli

doi:10.1371/journal.pone.0226976

Peter Grešner, Jolanta Gromadzińska + Show 2 more

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https://doi.org/10.1371/journal.pone.0226976

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Journal: PloS one	Publication Date: Jan 6, 2020
Citations: 8	License type: CC BY 4.0

Affiliation: Nofer Institute of Occupational Medicine

Abstract

A case-control study was conducted in which we evaluated the association between genetic variability of DNA repair proteins belonging to the Rad51 family and breast cancer (BrC) risk. In the study, 132 female BrC cases and 189 healthy control females were genotyped for a total of 14 common single nucleotide polymorphisms (SNPs) within Rad51 and Xrcc3. Moreover, our previously reported Rad51C genetic data were involved to explore the nonlinear interactions among SNPs within the three genes and effect of such interactions on BrC risk. The rare rs5030789 genotype (-4601AA) in Rad51 was found to significantly decrease the BrC risk (OR = 0.5, 95% CI: 0.3–1.0, p<0.05). An interaction between this SNP, rs2619679 and rs2928140 (both in Rad51), was found to result in a two three-locus genotypes -4719AA/-4601AA/2972CG and -4719AT/-4601GA/2972CC, both of which were found to increase the risk of BrC (OR = 8.4, 95% CI: 1.8–38.6, p<0.0001), instead. Furthermore, rare Rad51 rs1801320 (135CC) and heterozygous Xrcc3 rs3212057 (10343GA) genotypes were found to respectively increase (OR = 10.6, 95% CI: 1.9–198, p<0.02) and decrease (OR = 0.0, 95% CI: 0.0-NA, p<0.05) the risk of BrC. Associations between these SNPs and BrC risk were further supported by outcomes of employed machine learning analyses. In Xrcc3, the 4541A/9685A haplotype was found to be significantly associated with reduced BrC risk (OR = 0.5; 95% CI: 0.3–0.9; p<0.05). Concluding, our study indicates a complex role of SNPs within Rad51 (especially rs5030789) and Xrcc3 in BrC, although their significance with respect to the disease needs to be further clarified.

Highlights

Breast cancer (BrC) is known to be the most common malignancy among women, with nearly 1.7 million new cases and more than 520,000 deaths per year worldwide [1]
Effects of non-coding single nucleotide polymorphisms (SNPs) were predicted for several well-known transcription factors (TF) against the HOCOMOCO-11 [69] database and are provided as fold changes in respective TF binding affinity caused by given SNP, calculated as the ratio of probability of finding a better scoring TF binding motif by chance given the wild-type and variant SNP allele, respectively [43]
As long as the rs5030789 is concerned, the rare -4601AA genotype was found to be almost twice less common among BrC cases compared to controls (12.5% vs. 23.4%), it was associated with significantly decreased BrC risk under recessive genetic model (OR = 0.5, 95%CI: 0.3–1.0; p

Summary

Introduction

Breast cancer (BrC) is known to be the most common malignancy among women, with nearly 1.7 million new cases and more than 520,000 deaths per year worldwide [1]. In addition to major BrC susceptibility genes including BRCA1 and BRCA2, other high- (such as TP53 and PTEN) and moderate- (CHEK2, ATM, BRIP1, PALB2, and RAD51C) penetrance susceptibility genes were found to play role in the onset of BrC [3,4,5]. Both BRCA genes together with the above-mentioned moderate-penetrance BrC susceptibility genes play their roles in homologous recombination (HR) DNA repair pathway involved in repair of DNA double strand breaks (DSB) [5,6,7,8]. It has been proposed that compromised capacity of the HR DNA repair system leads to increased accumulation of DNA damage, mutations and, increased risk of malignancies [9,10,11]

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