Rare variants in the ATM gene and risk of breast cancer

Goldgar, David E., Healey, Sue, Dowty, James G., Da Silva, Leonard, Chen, Xiaoqing, Spurdle, Amanda B., Terry, Mary B., Daly, Mary J., Buys, Saundra M., Southey, Melissa C., Andrulis, Irene, John, Esther M., Breast Cancer Family Registry, Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, Khanna, Kum K., Hopper, John L., Oefner, Peter J., Lakhani, Sunil and Chenevix-Trench, Georgia (2011) Rare variants in the ATM gene and risk of breast cancer. Breast Cancer Research, 13 4: R73-1-R73-9. doi:10.1186/bcr2919

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Author Goldgar, David E.
Healey, Sue
Dowty, James G.
Da Silva, Leonard
Chen, Xiaoqing
Spurdle, Amanda B.
Terry, Mary B.
Daly, Mary J.
Buys, Saundra M.
Southey, Melissa C.
Andrulis, Irene
John, Esther M.
Breast Cancer Family Registry
Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer
Khanna, Kum K.
Hopper, John L.
Oefner, Peter J.
Lakhani, Sunil
Chenevix-Trench, Georgia
Title Rare variants in the ATM gene and risk of breast cancer
Formatted title
Rare variants in the ATM gene and risk of breast cancer
Journal name Breast Cancer Research   Check publisher's open access policy
ISSN 1465-5411
Publication date 2011-07
Sub-type Article (original research)
DOI 10.1186/bcr2919
Open Access Status DOI
Volume 13
Issue 4
Start page R73-1
End page R73-9
Total pages 9
Place of publication London, England, U.K.
Publisher Current Medicine Group Ltd.
Collection year 2012
Language eng
Formatted 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.
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Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
School of Medicine Publications
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Created: Fri, 07 Oct 2011, 14:26:08 EST by Matthew Lamb on behalf of School of Medicine