Penetrance of ATM Gene Mutations in Breast Cancer: A Meta-Analysis of Different Measures of Risk

Abstract

The gene responsible for ataxia-telangiectasia syndrome, ATM, is also an intermediate-risk breast cancer (BC) susceptibility gene. Numerous studies have been carried out to determine the contribution of ATM gene mutations to BC risk. Epidemiological cohorts, segregation analyses, and case-control studies reported BC risk in different forms, including penetrance, relative risk, standardized incidence ratio, and odds ratio. Because the reported estimates vary both qualitatively and quantitatively, we developed a general model allowing the integration of the different types of cancer risk available in the literature. We performed a comprehensive meta-analysis identifying 19 studies, and used our model to obtain a consensus estimate of BC penetrance. We estimated the cumulative risk of BC in heterozygous ATM mutation carriers to be 6.02% by 50 years of age (95% credible interval: 4.58-7.42%) and 32.83% by 80 years of age (95% credible interval: 24.55-40.43%). An accurate assessment of cancer penetrance is crucial to help mutation carriers make medical and lifestyle decisions that can reduce their chances of developing the disease.

Keywords: ataxia-telangiectasia mutated (ATM) gene; genetic predisposition; hereditary breast cancer; penetrance.

Figure 1.

(A) Solid line: cumulative risk of breast cancer in heterozygous ATM mutation carriers along with 95% credible intervals (Weibull parameters: κ = 3.00; λ = 88.37). Dashed line: cumulative risk of breast cancer in non-carriers (Weibull parameters derived from SEER data for the US population: κ₀ = 2.25; λ₀ = 159.71). (B) Dashed/dotted lines: penetrance curves obtained in the leave-one-study-out tests of sensitivity (the curve obtained after removal of Thompson et al., 2005 is indicated with the dotted line). Solid line: weighted average of dashed/dotted lines.