Familial clustering of site-specific cancer risks associated with BRCA1 and BRCA2 mutations in the Ashkenazi Jewish population

doi:10.1073/pnas.0511301103

Familial clustering of site-specific cancer risks associated with BRCA1 and BRCA2 mutations in the Ashkenazi Jewish population

*Medical Genetics Unit, Shaare Zedek Medical Center, Hebrew University Medical School, Jerusalem 91031, Israel;
^‡Oncogenetics Unit and
^¶Institute of Oncology, Chaim Sheba Medical Center, Tel-Hashomer 52621, Israel;
^§Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel;
^‖Department of Human Genetics, Rambam Medical Center, Bruce Rapaport Faculty of Medicine, Haifa 31096, Israel;
**Genetics Institute, Tel Aviv Sourasky Medical Center, Tel Aviv 64239, Israel;
^††Department of Medical Genetics, Rabin Medical Center-Beilinson Campus, Petah Tikva 49100, Israel;
^‡‡Departments of Medicine and Genome Sciences, University of Washington, Seattle, WA 98195; and
^¶¶Department of Family Medicine, Hebrew University Medical School, Jerusalem 91120, Israel

Contributed by Mary-Claire King, December 30, 2005
↵ ^†S.S., E.F., and B.K. contributed equally to this work.

Abstract

Inherited mutations in BRCA1 and BRCA2 lead to significantly increased risks of breast and ovarian cancer. We used epidemiologic methods to evaluate the relative risks of breast cancer vs. ovarian cancer among women of Ashkenazi Jewish ancestry with inherited mutations in BRCA1 or BRCA2. The cancer of a family's index case (i.e., breast cancer vs. ovarian cancer) was significantly associated with site-specific risks of cancer in relatives known to carry mutations in BRCA1 or BRCA2. Specifically, breast cancer risks were higher among relatives of breast cancer index cases compared with relatives of ovarian cancer index cases [hazard ratio (HR) = 3.0, P < 0.001 for BRCA1 carriers and HR = 4.8, P = 0.017 for BRCA2 carriers], and ovarian cancer risks were higher among relatives of ovarian cancer index cases compared with relatives of breast cancer index cases (HR = 7.2, P = 0.001 for BRCA1 carriers and HR = 15.8, P = 0.018 for BRCA2 carriers). Breast and ovarian cancer risks also increased with more recent year of birth. For each later decade of birth, risk increased 1.2-fold (P = 0.03). Effects of cancer site of the index case and of birth cohort were independent. These results suggest that both genetic and nongenetic factors modify cancer risks among BRCA1 and BRCA2 mutation carriers, and that genetic modifiers and other familial factors may influence risk specifically for either breast or ovarian cancer.

Footnotes

^§§To whom correspondence may be addressed. E-mail: mcking{at}u.washington.edu or lahad{at}szmc.org.il
Author contributions: E.F., B.K., R.G.-B., R.C., M.-C.K., A.L., and E.L.-L. designed research; S.S., E.F., B.K., R.C., M.-C.K., and E.L.-L. performed research; E.F., B.K., R.G.-B., A.O.-U., I.K.-B., R.S.-S., E.D., S.T., M.S., R.C., M.-C.K., and E.L.-L. contributed new reagents/analytic tools; M.-C.K., A.L., and E.L.-L. analyzed data; and E.F., M.-C.K., and E.L.-L. wrote the paper.
Conflict of interest statement: No conflicts declared.
Abbreviations:

HR,

hazard ratio;

NYBCS,

New York Breast Cancer Study