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The Search for BRCA1¹

Department of Molecular and Cell Biology and School of Public Health, University of California, Berkeley, California 94720 [L. S. F., E. A. O., E. D. L., C. I. S., L. A. A., P. D., M. K. L., S. E. R., M.-C. K.], and Department of Obstetrics and Gynecology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 [J. B.]

BRCA1, a gene predisposing to breast and ovarian cancer, was mapped to chromosome 17q21 by linkage analysis. Loss of heterozygosity in breast and ovarian tumors from BRCA1-linked patients always involved loss of wild-type alleles from chromosome 17q21, suggesting that BRCA1 acts as a tumor suppressor gene. Meiotic recombination in linked families constrained the BRCA1 region to an estimated physical size of 650 kilobases. Twenty-two candidate genes were isolated by screening complementary DNA libraries with yeast artificial chromosomes and cosmids from the critical region. Of these, 8 were known human genes, 7 were homologues of genes identified in other species, and 7 encoded novel transcripts. Each gene was sequenced and analyzed for variation, revealing 44 variants, including two missense mutations in two genes which segregated with breast cancer and were not found in controls. However, no frame-shift, nonsense, or regulatory mutations were found.

¹ Based upon the Thirty-fourth G. H. A. Clowes Memorial Award Lecture presented at the 85th Annual Meeting of the American Association for Cancer Research, San Francisco, CA, April 10, 1994. This research was supported by grants from the National Cancer Institute (NIH R01 CA27632), the Breast Cancer Fund, and the Ensign and Lewis Foundation.

² Susan G. Komen Breast Cancer Foundation Fellow.

³ American Cancer Society Professor of Genetics and Epidemiology. To whom requests for reprints should be addressed.

Received 9/29/94. Accepted 11/14/94.

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