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Breast Cancer Research
Published in: Breast Cancer Research 4/2011

Open Access 01-08-2011 | Research article

Rare variants in the ATMgene and risk of breast cancer

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

Published in: Breast Cancer Research | Issue 4/2011

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Abstract

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. 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.

Methods

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.

Results

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.

Conclusions

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.
Appendix
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Metadata
Title
Rare variants in the ATMgene and risk of breast cancer
Authors
David E Goldgar
Sue Healey
James G Dowty
Leonard Da Silva
Xiaoqing Chen
Amanda B Spurdle
Mary Beth Terry
Mary J Daly
Saundra M Buys
Melissa C Southey
Irene Andrulis
Esther M John
Kum Kum Khanna
John L Hopper
Peter J Oefner
Sunil Lakhani
Georgia Chenevix-Trench
BCFR
kConFab
Publication date
01-08-2011
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 4/2011
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/bcr2919

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