Rare variants in the ATMgene and risk of breast cancer

David E Goldgar,Saundra M Buys,Melissa C Southey,Kum Kum Khanna,Xiaoqing Chen,Esther M John,Mary Beth Terry,John L Hopper,Leonard Da Silva,Amanda B Spurdle,Irene Andrulis,James G Dowty,Sue Healey,Mary J Daly,Peter J Oefner,Georgia Chenevix-Trench,Sunil Lakhani

doi:10.1186/bcr2919

Abstract

IntroductionThe 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.MethodsTo 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.ResultsIn 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.ConclusionsThe 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.

Highlights

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
We found marginal evidence that protein-truncating (T) and splice-site junction (SJ) mutations confer on average a moderately increased risk of breast cancer (odds ratio (OR), 2.3; 95% confidence interval (CI), 1.1 to 4.8), but stronger evidence that a subset of rare, evolutionarily unlikely missense C65 substitutions conferred on average a higher risk of breast cancer (OR, 18; 95% CI, 3 to 120)
Subjects We studied Caucasian cases of breast cancer (n = 2,517 invasive and 53 ductal carcinoma in situ (DCIS)) and controls (n = 1,448) from three sources: (a) population-based case and control breast cancer families from the NCI-sponsored Breast Cancer Family Registry (BCFR) [17]; (b) a clinic-based resource of Australian and New Zealand multiple-case breast cancer families from the Kathleen Cuningham Foundation Consortium for Research on Familial Breast Cancer [18]; and (c) Australian female controls chosen from the Red Cross Blood Bank to be ethnically and frequency matched for age to the age at diagnosis of kConFab cases [19] (Table 1)

Summary

Introduction

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. The ataxia-telangiectasia mutated (ATM) gene (MIM ID 208900) encodes a protein kinase that plays a major role in activating cellular responses to DNA double-strand breaks through downstream phosphorylation of central players in the DNA damage-response pathways, including BRCA1, p53, and Chk2 [1]. This study did not distinguish between the effects of protein-truncating and missense mutations, Gatti et al [15] had hypothesised in 1999 that, compared with protein-truncating mutations, some missense variants in ATM might act as dominant negatives and confer a high risk of breast cancer when heterozygous, causing a milder form of AT when homozygous

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Discussion

Conclusion