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Meta-Analysis of BRCA1 and BRCA2 Penetrance

Sining Chen, Giovanni Parmigiani

From the Departments of Environmental Health Sciences and Biostatistics, Johns Hopkins Bloomberg School of Public Health; and the Department of Oncology Biostatistics and Pathology, Johns Hopkins University, Baltimore, MD

Address reprint requests to Sining Chen, PhD, Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe St, W7041, Baltimore, MD 21205; e-mail: sichen{at}jhsph.edu

Purpose Genetic counseling is now routinely offered to individuals at high risk of carrying a BRCA1 or BRCA2 mutation. Risk prediction provided by the counselor requires reliable estimates of the mutation penetrance. Such penetrance has been investigated by studies worldwide. The reported estimates vary. To facilitate clinical management and counseling of the at-risk population, we address this issue through a meta-analysis.

Methods We conducted a literature search on PubMed and selected studies that had nonoverlapping patient data, contained genotyping information, used statistical methods that account for the ascertainment, and reported risks in a useable format. We subsequently combined the published estimates using the DerSimonian and Laird random effects modeling approach.

Results Ten studies were eligible under the selection criteria. Between-study heterogeneity was observed. Study population, mutation type, design, and estimation methods did not seem to be systematic sources of heterogeneity. Meta-analytic mean cumulative cancer risks for mutation carriers at age 70 years were as follows: breast cancer risk of 57% (95% CI, 47% to 66%) for BRCA1 and 49% (95% CI, 40% to 57%) for BRCA2 mutation carriers; and ovarian cancer risk of 40% (95% CI, 35% to 46%) for BRCA1 and 18% (95% CI, 13% to 23%) for BRCA2 mutation carriers. We also report the prospective risks of developing cancer for currently asymptomatic carriers.

Conclusion This article provides a set of risk estimates for BRCA1 and BRCA2 mutation carriers that can be used by counselors and clinicians who are interested in advising patients based on a comprehensive set of studies rather than one specific study.

Supported in part by Grants No. P50CA88843, P50CA62924-05, 5P30 CA06973-39, and R01CA105090 from the National Cancer Institute; Grant No. HL99-024 from the National Institutes of Health, and the Hecht Fund.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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