• Institution: Univ of North Texas Library
  • Research in the physical sciences including applied physical sciences; astronomy; earth, atmospheric, and planetary sciences; and physics.
  • Science Sessions: The PNAS Podcast Program

Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2

  1. Ephrat Levy-Lahada,b,2
  1. aMedical Genetics Institute, Shaare Zedek Medical Center, Jerusalem 91031, Israel;
  2. bFaculty of Medicine, Hebrew University Medical School, Jerusalem 91120, Israel;
  3. cDepartment of Family Medicine, Clalit Health Services, Jerusalem 91120, Israel;
  4. dInstitute of Oncology, Sheba Medical Center, Tel Hashomer 52621, Israel;
  5. eSusanne Levy Gertner Oncogenetics Unit, Sheba Medical Center, Tel Hashomer 52621, Israel;
  6. fSackler School of Medicine, Tel Aviv University, Tel-Aviv 69978, Israel;
  7. gInstitute of Medical Screening, Sheba Medical Center, Tel Hashomer 52621, Israel;
  8. hTerem Family Medical Center, Jerusalem 92345, Israel;
  9. iDepartments of Medicine and Genome Sciences, University of Washington, Seattle, WA 98195; and
  10. jDepartment of Obstetrics and Gynecology, Shaare Zedek Medical Center, Jerusalem 91031, Israel

  1. Contributed by Mary-Claire King, August 19, 2014 (sent for review July 17, 2014; reviewed by Anne M. Bowcock and Karl Skorecki)

Significance

Inherited mutations in the tumor suppressor genes BRCA1 and BRCA2 predispose to very high risks of breast and ovarian cancer. For carriers of these mutations, risk-reducing surgery significantly reduces morbidity and mortality. General population screening for BRCA1 and BRCA2 mutations in young adult women could be feasible if accurate estimates of cancer risk for mutation carriers could be obtained. We determined that risks of breast and ovarian cancer for BRCA1 and BRCA2 mutation carriers ascertained from the general population are as high as for mutation carriers ascertained through personal or family history of cancer. General screening of BRCA1 and BRCA2 would identify many carriers who are currently not evaluated and could serve as a model for population screening for genetic predisposition to cancer.

Abstract

In the Ashkenazi Jewish (AJ) population of Israel, 11% of breast cancer and 40% of ovarian cancer are due to three inherited founder mutations in the cancer predisposition genes BRCA1 and BRCA2. For carriers of these mutations, risk-reducing salpingo-oophorectomy significantly reduces morbidity and mortality. Population screening for these mutations among AJ women may be justifiable if accurate estimates of cancer risk for mutation carriers can be obtained. We therefore undertook to determine risks of breast and ovarian cancer for BRCA1 and BRCA2 mutation carriers ascertained irrespective of personal or family history of cancer. Families harboring mutations in BRCA1 or BRCA2 were ascertained by identifying mutation carriers among healthy AJ males recruited from health screening centers and outpatient clinics. Female relatives of the carriers were then enrolled and genotyped. Among the female relatives with BRCA1 or BRCA2 mutations, cumulative risk of developing either breast or ovarian cancer by age 60 and 80, respectively, were 0.60 (± 0.07) and 0.83 (± 0.07) for BRCA1 carriers and 0.33 (± 0.09) and 0.76 (± 0.13) for BRCA2 carriers. Risks were higher in recent vs. earlier birth cohorts (P = 0.006). High cancer risks in BRCA1 or BRCA2 mutation carriers identified through healthy males provide an evidence base for initiating a general screening program in the AJ population. General screening would identify many carriers who are not evaluated by genetic testing based on family history criteria. Such a program could serve as a model to investigate implementation and outcomes of population screening for genetic predisposition to cancer in other populations.

Footnotes

  • ↵1E.G.-K. and A.L. contributed equally to this work.

  • ↵2To whom correspondence may be addressed. Email: mcking{at}u.washington.edu or lahad{at}szmc.org.il.

  • Author contributions: E.G.-K., A.L., M.-C.K., and E.L.-L. designed research; E.G.-K., A.L., B.K., E.F., S.S., P.R., R.B., M.G., J.G.-C., K.D., J.B.M., U.B., R.C., M.-C.K., and E.L.-L. performed research; E.G.-K., A.L., P.R., M.K.L., M.-C.K., and E.L.-L. analyzed data; A.L., M.-C.K., and E.L.-L. wrote the paper; and B.K., E.F., S.S., K.D., and U.B. referred participants.

  • Reviewers: A.M.B., Imperial College London; and K.S., Technion – Israel Institute of Technology.

  • The authors declare no conflict of interest.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1415979111/-/DCSupplemental.

Online Impact