Genetic variants in ATM, H2AFX and MRE11 genes and susceptibility to breast cancer in the polish population

Abstract

BackgroundDNA damage repair is a complex process, which can trigger the development of cancer if disturbed. In this study, we hypothesize a role of variants in the ATM, H2AFX and MRE11 genes in determining breast cancer (BC) susceptibility.MethodsWe examined the whole sequence of the ATM kinase domain and estimated the frequency of founder mutations in the ATM gene (c.5932G > T, c.6095G > A, and c.7630-2A > C) and single nucleotide polymorphisms (SNPs) in H2AFX (rs643788, rs8551, rs7759, and rs2509049) and MRE11 (rs1061956 and rs2155209) among 315 breast cancer patients and 515 controls. The analysis was performed using high-resolution melting for new variants and the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method for recurrent ATM mutations. H2AFX and MRE11 polymorphisms were analyzed using TaqMan assays. The cumulative genetic risk scores (CGRS) were calculated using unweighted and weighted approaches.ResultsWe identified four mutations (c.6067G > A, c.8314G > A, c.8187A > T, and c.6095G > A) in the ATM gene in three BC cases and two control subjects. We observed a statistically significant association of H2AFX variants with BC. Risk alleles (the G of rs7759 and the T of rs8551 and rs2509049) were observed more frequently in BC cases compared to the control group, with P values, odds ratios (OR) and 95% confidence intervals (CIs) of 0.0018, 1.47 (1.19 to 1.82); 0.018, 1.33 (1.09 to 1.64); and 0.024, 1.3 (1.06 to 1.59), respectively. Haplotype-based tests identified a significant association of the H2AFX CACT haplotype with BC (P < 0.0001, OR = 27.29, 95% CI 3.56 to 209.5). The risk of BC increased with the growing number of risk alleles. The OR (95% CI) for carriers of ≥ four risk alleles was 1.71 (1.11 to 2.62) for the CGRS.ConclusionsThis study confirms that H2AFX variants are associated with an increased risk of BC. The above-reported sequence variants of MRE11 genes may not constitute a risk factor of breast cancer in the Polish population. The contribution of mutations detected in the ATM gene to the development of breast cancer needs further detailed study.

Plasma-Derived Exosomal hsa-miR-4488 and hsa-miR-1228-5p: Novel Biomarkers for Dermatomyositis-Associated Interstitial Lung Disease with Anti-Melanoma Differentiation-Associated Protein 5 Antibody-Positive Subset

“…In the present study, hsa-miR-4488 was significantly upregulated in DM-ILD-MDA5 Ab(+) when compared to DM-nonILD-MSA16(-) and HC, suggesting that miR-4488 may contribute to systemic inflammation in DM-ILD-MDA5 Ab(+) by upregulating NF- κ B signaling through repression of DDX39B. For its part, DDX39B promotes global translation and cell proliferation through upregulating preribosomal RNA levels, thereby contributing to oncogenesis [ 33 ], similar to H2AFX as a protooncogene [ 34 ]. hsa-miR-1228-5p was upregulated in DM-ILD-MDA5 Ab(+) and was downregulated in DM-nonILD-MSA16(-) when compared to HC.…”

Homologous Recombination Deficiency: Cancer Predispositions and Treatment Implications

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MRE11-RAD50-NBS1 complex alterations and DNA damage response: implications for cancer treatment

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