Germ-Line BRCA1 Mutations in Jewish and Non-Jewish Women with Early-Onset Breast Cancer
Michael G. FitzGerald, B.A., Deborah J. MacDonald, R.N., M.S., Michael Krainer, M.D., Ingrid Hoover, B.A., Erin O'Neil, B.A., Hilal Unsal, M.D., Sandra Silva-Arrieto, B.A., Dianne M. Finkelstein, Ph.D., Peggy Beer-Romero, M.S., Christoph Englert, Ph.D., Dennis C. Sgroi, M.D., Barbara L. Smith, M.D., Ph.D., Jerry W. Younger, M.D., Judy E. Garber, M.D., Rosemary B. Duda, M.D., Kathleen A. Mayzel, M.D., Kurt J. Isselbacher, M.D., Stephen H. Friend, M.D., Ph.D., and Daniel A. Haber, M.D., Ph.D.
Background Mutations in a germ-line allele of the BRCA1 genecontribute to the familial breast cancer syndrome. However,the prevalence of these mutations is unknown in women with breastcancer who do not have the features of this familial syndrome.We sought BRCA1 mutations in women who were given a diagnosisof breast cancer at an early age, because early onset is characteristicof a genetic predisposition to cancer.
Methods Clinical information and peripheral-blood mononuclearcells were obtained from 418 women from the Boston metropolitanarea in whom breast cancer was diagnosed at or before the ageof 40. A comprehensive BRCA1 mutational analysis, involvingautomated nucleotide sequencing and a protein-truncation assay,was undertaken in 30 of these women, who had breast cancer beforethe age of 30. In addition, the BRCA1 mutation 185delAG, whichis prevalent in the Ashkenazi Jewish population, was soughtwith an allele-specific polymerase-chain-reaction assay in 39Jewish women among the 418 women who had breast cancer at orbefore the age of 40.
Results Among 30 women with breast cancer before the age of30, 4 (13 percent) had definite, chain-terminating mutationsand 1 had a missense mutation. Two of the four Jewish womenin this cohort had the 185delAG mutation. Among the 39 Jewishwomen with breast cancer at or before the age of 40, 8 (21 percent)carried the 185delAG mutation (95 percent confidence interval,9 to 36 percent).
Conclusions Germ-line BRCA1 mutations can be present in youngwomen with breast cancer who do not belong to families withmultiple affected members. The specific BRCA1 mutation knownas 185delAG is strongly associated with the onset of breastcancer in Jewish women before the age of 40.
Source Information
From the Center for Cancer Risk Analysis and the Massachusetts General Hospital Cancer Center, Charlestown, Mass. (M.G.F., D.J.M., M.K., I.H., E.O., H.U., S.S.-A., P.B.-R., C.E., K.J.I., S.H.F., D.A.H.); and the Departments of Pathology (D.C.S.) and Medical and Surgical Oncology (D.M.F., B.L.S., J.W.Y., D.A.H.), Massachusetts General Hospital; the Department of Biostatistics, Harvard School of Public Health (D.M.F.); Dana–Farber Cancer Institute (J.E.G.); Beth Israel Hospital (R.B.D.); and Faulkner Hospital (K.A.M.) — all in Boston.
Address reprint requests to Dr. Haber at MGH Cancer Center, CNY7, Bldg. 149, Charlestown, MA 02129.
Breast Cancer and BRCA1 Mutations
Offit K., Mathew C. G., Solomon E., Hodgson S. V., Ithier G., Girard M., Stoppa-Lyonnet D., Sher C., Sharabani-Gargir L., Shohat M., Haber D. A., Garber J. E., Finkelstein D. M., Langston A. A., Malone K. E., Ostrander E. A.
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N Engl J Med 1996;
334:1197-1200, May 2, 1996.
Correspondence
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