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.
Highlights
DNA damage repair is a complex process, which can trigger the development of cancer if disturbed
We detected two mutations in the control group: c.6095G > A and c. 8314G > A.Deleterious consequences of all detected changes were scored using the following tools: SIFT, PolyPhen2 and MutationTaster Phylop. All these algorithms estimate the pathogenic effects of Single nucleotide polymorphism (SNP) on protein in different ways
We showed that the germline p.Ile171Val mutation in NBN, one of the Mre11/ Rad50/NBN (M/R/N) genes, may be considered a risk factor in the development of solid malignant tumors, including breast cancer, larynx and colorectal cancer or acute lymphoblastic leukemia (ALL) [14,15,16,17]
Summary
DNA damage repair is a complex process, which can trigger the development of cancer if disturbed. We hypothesize a role of variants in the ATM, H2AFX and MRE11 genes in determining breast cancer (BC) susceptibility. Cell-cycle checkpoints and DNA damage repair prevent genetic instability and mutagenesis. In response to DNA double-strand breaks, a signaling cascade is initiated: first, the M/R/N complex, consisting of three proteins, MRE11, RAD50 and NBN, acts as a sensor for DNA damage. M/R/N proteins recruit the key signal transducer of DNA damage response: ataxia-telangiectasia mutated (ATM) kinase [1]. Activation of ATM causes cell cycle arrest. ATM phosphorylates several substrates, including histone H2AFX. The phosphorylated form of H2AFX, γ-H2AFX, modulates DNA repair mechanisms by reorganizing chromatin and preventing the separation of broken DNA ends
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