Variants in the ATM gene and breast cancer susceptibility.
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ABSTRACT:
SUBMITTER: Milne RL
PROVIDER: S-EPMC2651585 | biostudies-literature | 2009
REPOSITORIES: biostudies-literature
Publications
Variants in the ATM gene and breast cancer susceptibility.
Genome medicine 20090122 1
It has been established that heterozygous carriers of ataxia-telangiectasia-causing mutations in the ATM gene are at approximately two-fold higher risk of breast cancer. Several studies have attempted to assess the potential implication of the gene's more common variants in breast cancer susceptibility. Three large case-control studies have consistently found no evidence of association for variants with minor allele frequency greater than 5%. Other studies have evaluated associations for coding ...[more]
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Project description:The ataxia-telangiectasia mutated (ATM) gene (MIM ID 208900) encodes a protein kinase that plays a significant role in the activation of cellular responses to DNA double-strand breaks through subsequent phosphorylation of central players in the DNA damage-response pathway. Recent studies have confirmed that some specific variants in the ATM gene are associated with increased breast cancer (BC) risk. However, the magnitude of risk and the subset of variants that are pathogenic for breast cancer remain unresolved.To investigate the role of ATM in BC susceptibility, we studied 76 rare sequence variants in the ATM gene in a case-control family study of 2,570 cases of breast cancer and 1,448 controls. The variants were grouped into three categories based on their likely pathogenicity, as determined by in silico analysis and analyzed by conditional logistic regression. Likely pathogenic sequence variants were genotyped in 129 family members of 27 carrier probands (15 of which carried c.7271T > G), and modified segregation analysis was used to estimate the BC penetrance associated with these rare ATM variants.In the case-control analysis, we observed an odds ratio of 2.55 and 95% confidence interval (CI, 0.54 to 12.0) for the most likely deleterious variants. In the family-based analyses, the maximum-likelihood estimate of the increased risk associated with these variants was hazard ratio (HR) = 6.88 (95% CI, 2.33 to 20.3; P = 0.00008), corresponding to a 60% cumulative risk of BC by age 80 years. Analysis of loss of heterozygosity (LOH) in 18 breast tumors from women carrying likely pathogenic rare sequence variants revealed no consistent pattern of loss of the ATM variant.The risk estimates from this study suggest that women carrying the pathogenic variant, ATM c.7271T > G, or truncating mutations demonstrate a significantly increased risk of breast cancer with a penetrance that appears similar to that conferred by germline mutations in BRCA2.
| S-EPMC3236337 | biostudies-literature
Project description:Approximately 0.5%-1% of the general population has been estimated to be heterozygous for a germline mutation in the ATM gene. Mutations in the ATM gene are responsible for the autosomal recessive disorder ataxia-telangiectasia (A-T) (MIM 208900). The finding that ATM-heterozygotes have an increased relative risk for breast cancer was supported by some studies but not confirmed by others. In view of this discrepancy, we examined the frequency of ATM germline mutations in a selected group of Dutch patients with breast cancer. We have analyzed ATM germline mutations in normal blood lymphocytes, using the protein-truncation test followed by genomic-sequence analysis. A high percentage of ATM germline mutations was demonstrated among patients with sporadic breast cancer. The 82 patients included in this study had developed breast cancer at age <45 and had survived >/=5 years (mean 15 years), and in 33 (40%) of the patients a contralateral breast tumor had been diagnosed. Among these patients we identified seven (8.5%) ATM germline mutations, of which five are distinct. One splice-site mutation (IVS10-6T-->G) was detected three times in our series. Four heterozygous carriers were patients with bilateral breast cancer. Our results indicate that the mutations identified in this study are "A-T disease-causing" mutations that might be associated with an increased risk of breast cancer in heterozygotes. We conclude that ATM heterozygotes have an approximately ninefold-increased risk of developing a type of breast cancer characterized by frequent bilateral occurrence, early age at onset, and long-term survival. The specific characteristics of our population of patients may explain why such a high frequency was not found in other series.
| S-EPMC1288102 | biostudies-literature
Project description:BACKGROUND:DNA 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. METHODS:We 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. RESULTS:We 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. CONCLUSIONS:This 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.
| S-EPMC5910560 | biostudies-literature
Project description:IntroductionCertain rare, familial mutations in the ATM, BRCA1, BRCA2, CHEK2 or TP53 genes increase susceptibility to breast cancer but it has not, until now, been clear whether common polymorphic variants in the same genes also increase risk.MethodsWe have attempted a comprehensive, single nucleotide polymorphism (SNP)- and haplotype-tagging association study on each of these five genes in up to 4,474 breast cancer cases from the British, East Anglian SEARCH study and 4,560 controls from the EPIC-Norfolk study, using a two-stage study design. Nine tag SNPs were genotyped in ATM, together with five in BRCA1, sixteen in BRCA2, ten in CHEK2 and five in TP53, with the aim of tagging all other known, common variants. SNPs generating the common amino acid substitutions were specifically forced into the tagging set for each gene.ResultsNo significant breast cancer associations were detected with any individual or combination of tag SNPs.ConclusionIt is unlikely that there are any other common variants in these genes conferring measurably increased risks of breast cancer in our study population.
| S-EPMC1868915 | biostudies-literature
Project description:ATM gene mutations have been implicated in many human cancers. However, the role of ATM polymorphisms in lung carcinogenesis is largely unexplored. We conducted a case-control analysis of 556 Caucasian non-small-cell lung cancer (NSCLC) patients and 556 controls frequency-matched on age, gender and smoking status. We genotyped 11 single nucleotide polymorphisms of the ATM gene and found that compared with the wild-type allele-containing genotypes, the homozygous variant genotypes of ATM08 (rs227060) and ATM10 (rs170548) were associated with elevated NSCLC risk with ORs of 1.55 (95% CI: 1.02-2.35) and 1.51 (0.99-2.31), respectively. ATM haplotypes and diplotypes were inferred using the Expectation-Maximization algorithm. Haplotype H5 was significantly associated with reduced NSCLC risk in former smokers with an OR of 0.47 (0.25-0.96) compared with the common H1 haplotype. Compared with the H1-H2 diplotype, H2-H2 and H3-H4 diplotypes were associated with increased NSCLC risk with ORs of 1.58 (0.99-2.54) and 2.29 (1.05-5.00), respectively. We then evaluated genotype-phenotype correlation in the control group using the comet assay to determine DNA damage and DNA repair capacity. Compared with individuals with at least 1 wild-type allele, the homozygous variant carriers of either ATM08 or ATM10 exhibited significantly increased DNA damage as evidenced by a higher mean value of the radiation-induced olive tail moment (ATM08: 4.86 +/- 2.43 vs. 3.79 +/- 1.51, p = 0.04; ATM10: 5.14 +/- 2.37 vs. 3.79 +/- 1.54, p = 0.01). Our study presents the first epidemiologic evidence that ATM genetic variants may affect NSCLC predisposition, and that the risk-conferring variants might act through down-regulating the functions of ATM in DNA repair activity upon genetic insults such as ionizing radiation.
| S-EPMC3477817 | biostudies-literature
Project description:BACKGROUND: Individuals heterozygous for germline ATM mutations have been reported to have an increased risk for breast cancer but the role for ATM genetic variants for breast cancer risk has remained unclear. Recently, a common ATM variant, ATMivs38 -8T>C in cis with the ATMex39 5557G>A (D1853N) variant, was suggested to associate with bilateral breast cancer among familial breast cancer patients from Northern Finland. We have here evaluated the 5557G>A and ivs38-8T>C variants in an extensive case-control association analysis. We also aimed to investigate whether there are other ATM mutations or variants contributing to breast cancer risk in our population. METHODS: Two common ATM variants, 5557G>A and ivs38-8T>C, previously suggested to associate with bilateral breast cancer, were genotyped in an extensive set of 786 familial and 884 unselected breast cancer cases as well as 708 healthy controls. We also screened the entire coding region and exon-intron boundaries of the ATM gene in 47 familial breast cancer patients and constructed haplotypes of the patients. The identified variants were also evaluated for increased breast cancer risk among additional breast cancer cases and controls. RESULTS: Neither of the two common variants, 5557G>A and ivs38-8T>C, nor any haplotype containing them, was significantly associated with breast cancer risk, bilateral breast cancer or multiple primary cancers in any of the patient groups or subgoups. Three rare missense alterations and one intronic change were each found in only one patient of over 250 familial patients studied and not among controls. The fourth missense alteration studied further was found with closely similar frequencies in over 600 familial cases and controls. CONCLUSION: Altogether, our results suggest very minor effect, if any, of ATM genetic variants on familial breast cancer in Southern Finland. Our results do not support association of the 5557G>A or ivs38-8T>C variant with increased breast cancer risk or with bilateral breast cancer.
| S-EPMC1592307 | biostudies-literature
Project description:BackgroundTruncating mutations in ATM have been shown to increase the risk of breast cancer but the effect of missense variants remains contentious.MethodsWe have genotyped five polymorphic (minor allele frequency, 0.9-2.6%) missense single nucleotide polymorphisms (SNP) in ATM (S49C, S707P, F858L, P1054R, and L1420F) in 26,101 breast cancer cases and 29,842 controls from 23 studies in the Breast Cancer Association Consortium.ResultsCombining the data from all five SNPs, the odds ratio (OR) was 1.05 for being a heterozygote for any of the SNPs and 1.51 for being a rare homozygote for any of the SNPs with an overall trend OR of 1.06 (P(trend) = 0.04). The trend OR among bilateral and familial cases was 1.12 (95% confidence interval, 1.02-1.23; P(trend) = 0.02).ConclusionsIn this large combined analysis, these five missense ATM SNPs were associated with a small increased risk of breast cancer, explaining an estimated 0.03% of the excess familial risk of breast cancer.ImpactTesting the combined effects of rare missense variants in known breast cancer genes in large collaborative studies should clarify their overall contribution to breast cancer susceptibility.
| S-EPMC2938473 | biostudies-literature
Project description:BACKGROUND: Emerging evidence suggests that ataxia telangiectasia-mutated (ATM) is involved in numerous damage repair signaling pathways and cell-cycle checkpoints. Heterozygous carriers of ATM-mutations have an increased risk for the development of breast cancer. The purpose of this study is to evaluate the association between ATM exon39 5557G > A (D1853N, rs1801516) polymorphism and breast cancer susceptibility with the use of a meta-analysis. METHODS: By searching PubMed and Embase databases, a total of 9 epidemiological studies with 4,191 cases and 3,780 controls were identified. Crude odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) for ATM D1853N polymorphism and breast cancer risk were calculated using fixed- or random-effects model based on the degree of heterogeneity among studies. RESULTS: No significant association between the ATM D1853N polymorphism and breast cancer risk was observed in overall analysis (GA versus GG: OR = 1.18; 95% CI, 0.90-1.53; AA versus GG: OR = 0.77; 95% CI, 0.58-1.03; dominant model: OR = 1.16; 95% CI, 0.89-1.51; and recessive model: OR = 0.78; 95% CI, 0.59-1.04, respectively). CONCLUSION: Our results indicate that ATM D1853N polymorphism is not a risk factor for developing breast cancer.
| S-EPMC2936337 | biostudies-literature
Project description:BackgroundProtein truncating variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 are associated with increased breast cancer risk, but risks associated with missense variants in these genes are uncertain.MethodsWe analyzed data on 59,639 breast cancer cases and 53,165 controls from studies participating in the Breast Cancer Association Consortium BRIDGES project. We sampled training (80%) and validation (20%) sets to analyze rare missense variants in ATM (1146 training variants), BRCA1 (644), BRCA2 (1425), CHEK2 (325), and PALB2 (472). We evaluated breast cancer risks according to five in silico prediction-of-deleteriousness algorithms, functional protein domain, and frequency, using logistic regression models and also mixture models in which a subset of variants was assumed to be risk-associated.ResultsThe most predictive in silico algorithms were Helix (BRCA1, BRCA2 and CHEK2) and CADD (ATM). Increased risks appeared restricted to functional protein domains for ATM (FAT and PIK domains) and BRCA1 (RING and BRCT domains). For ATM, BRCA1, and BRCA2, data were compatible with small subsets (approximately 7%, 2%, and 0.6%, respectively) of rare missense variants giving similar risk to those of protein truncating variants in the same gene. For CHEK2, data were more consistent with a large fraction (approximately 60%) of rare missense variants giving a lower risk (OR 1.75, 95% CI (1.47-2.08)) than CHEK2 protein truncating variants. There was little evidence for an association with risk for missense variants in PALB2. The best fitting models were well calibrated in the validation set.ConclusionsThese results will inform risk prediction models and the selection of candidate variants for functional assays and could contribute to the clinical reporting of gene panel testing for breast cancer susceptibility.
| S-EPMC9116026 | biostudies-literature
Project description:Heterozygous carriers of germ-line loss-of-function variants in the DNA repair gene PALB2 are at a highly increased lifetime risk for developing breast cancer. While truncating variants in PALB2 are known to increase cancer risk, the interpretation of missense variants of uncertain significance (VUS) is in its infancy. Here we describe the development of a relatively fast and easy cDNA-based system for the semi high-throughput functional analysis of 48 VUS in human PALB2. By assessing the ability of PALB2 VUS to rescue the DNA repair and checkpoint defects in Palb2 knockout mouse embryonic stem (mES) cells, we identify various VUS in PALB2 that impair its function. Three VUS in the coiled-coil domain of PALB2 abrogate the interaction with BRCA1, whereas several VUS in the WD40 domain dramatically reduce protein stability. Thus, our functional assays identify damaging VUS in PALB2 that may increase cancer risk.
| S-EPMC6876638 | biostudies-literature