A Strong Candidate for the Breast and Ovarian A Strong Candidate for the Breast and Ovarian Cancer Susceptibility

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  • A Strong Candidate for the Breast and Ovarian Cancer Susceptibility Gene BRCA1 Author(s): Yoshio Miki, Jeff Swensen, Donna Shattuck-Eidens, P. Andrew Futreal, Keith Harshman, Sean Tavtigian, Qingyun Liu, Charles Cochran, L. Michelle Bennett, Wei Ding, Russell Bell, Judith Rosenthal, Charles Hussey, Thanh Tran, Melody McClure, Cheryl Frye, Tom Hattier, Robert Phelps, Astrid Haugen-Strano, Harold Katcher, Kazuko Yakumo, Zahra Gholami, Daniel Shaffer, Steven Stone, Steven Bayer, Christian Wray, Robert Bogden, Pri ... Reviewed work(s): Source: Science, New Series, Vol. 266, No. 5182 (Oct. 7, 1994), pp. 66-71 Published by: American Association for the Advancement of Science Stable URL: http://www.jstor.org/stable/2884716 . Accessed: 03/12/2011 17:29

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    A Strong Candidate for the Breast and Ovarian Cancer Susceptibility Gene BRCA1

    Yoshio Miki, Jeff Swensen, Donna Shattuck-Eidens, P. Andrew Futreal, Keith Harshman, Sean Tavtigian, Qingyun Liu, Charles Cochran,

    L. Michelle Bennett, Wei Ding, Russell Bell, Judith Rosenthal, Charles Hussey, Thanh Tran, Melody McClure, Cheryl Frye, Tom Hattier, Robert Phelps, Astrid Haugen-Strano, Harold Katcher, Kazuko Yakumo,

    Zahra Gholami, Daniel Shaffer, Steven Stone, Steven Bayer, Christian Wray, Robert Bogden, Priya Dayananth, John Ward, Patricia Tonin, Steven Narod,

    Pam K. Bristow, Frank H. Norris, Leah Helvering, Paul Morrison, Paul Rosteck, Mei Lai, J. Carl Barrett, Cathryn Lewis, Susan Neuhausen, Lisa Cannon-Albright, David Goldgar, Roger Wiseman, Alexander Kamb,

    Mark H. Skolnick*

    A strong candidate for the 17q-linked BRCA1 gene, which influences susceptibility to breast and ovarian cancer, has been identified by positional cloning methods. Probable predisposing mutations have been detected in five of eight kindreds presumed to seg- regate BRCA1 susceptibility alleles. The mutations include an 1 1-base pair deletion, a 1-base pair insertion, a stop codon, a missense substitution, and an inferred regulatory mutation. The BRCA1 gene is expressed in numerous tissues, including breast and ovary, and encodes a predicted protein of 1863 amino acids. This protein contains a zinc finger domain in its amino-terminal region, but is otherwise unrelated to previously described proteins. Identification of BRCA1 should facilitate early diagnosis of breast and ovarian cancer susceptibility in some individuals as well as a better understanding of breast cancer biology.

    Breast cancer is one of the most common and important diseases affecting women. Current estimates indicate that one in eight American women who reach age 95 will develop breast cancer (1). Treatment of advanced breast cancer is often futile and disfiguring, making early detection a high priority in medical management of the dis- ease. Ovarian cancer, although less frequent than breast cancer, is often rapidly fatal and is the fourth most common cause of cancer mortality in American women.

    Y. Miki, J. Swensen, K. Yakumo, C. Lewis, S. Neu- hausen, and D. Goldgar are in the Department of Medical Informatics, University of Utah Medical Center, Salt Lake City, UT 84132, USA. D. Shattuck-Eidens, K. Harshman, S. Tavtigian, 0. Liu, W. Ding, R. Bell, J. Rosenthal, C. Hussey, T. Tran, M. McClure, C. Frye, T. Hattier, R. Phelps, H. Katcher, Z. Gholami, D. Shaffer, S. Stone, S. Bayer, C. Wray, R. Bogden, P. Dayananth, and A. Kamb are at Myriad Genetics, 421 Wakara Way, Salt Lake City, UT 84108, USA. P. A. Futreal, C. Cochran, L. M. Bennett, A. Huagen-Strano, J. C. Barrett, and R. Wiseman are at the Laboratory of Molecular Carcinogenesis, National In- stitute of Environmental Health Sciences, National Insti- tutes of Health, Research Triangle Park, NC 27709, USA. J. Ward and L. Cannon-Albright are in the Department of Internal Medicine, University of Utah Medical Center, Salt Lake City, UT 84132, USA. P. Tonin and S. Narod are in the Department of Medical Genetics, McGill University, Montreal, Quebec, H3G 1A4, Canada. P. K. Bristow, F. H. Norris, L. Helvering, P. Morrmson, P. Rosteck, and M. Lai are at Lilly Research Laboratories, Eli Lilly and Com- pany, Indianapolis, IN 46285, USA. M. H. Skolnick is in the Department of Medical Informatics, University of Utah Medical Center, and Myriad Genetics, Salt Lake City, UT 84108, USA.

    *To whom correspondence should be addressed.

    Genetic factors contribute to an ill-de- fined proportion of breast cancer incidence, estimated to be about 5% of all cases but approximately 25% of cases diagnosed be- fore age 30 (2). Breast cancer has been subdivided into two types, early-onset and late-onset, a division that is based on an inflection in the age-specific incidence curve around age 50. Mutation of one gene, BRCA1, is thought to account for approxi- mately 45% of families with significantly high breast cancer incidence and at least 80% of families with increased incidence of both early-onset breast cancer and ovarian cancer (3). Intense efforts to isolate the BRCA1 gene have proceeded since it was first mapped to chromosome arm 17q in 1990 (4, 5). A second locus, BRCA2, re- cently mapped to chromosome arm 13q (6), appears to account for a proportion of early- onset breast cancer roughly equal to that resulting from BRCA1. Unlike BRCA1, however, BRCA2 may not influence ovari- an cancer risk. The remaining susceptibility to early-onset breast cancer is likely attrib- utable to unmapped genes for familial can- cer and rare germline mutations in genes such as TP53, which encodes the tumor suppressor protein p53 (7). It has also been suggested that heterozygote carriers of de- fective forms of the gene predisposing to ataxia telangiectasia are at higher risk for breast cancer (8, 9). Late-onset breast can-

    cer is often familial in origin, although the risks in relatives are not as high as those for early-onset breast cancer (10, 11 ). The per- centage of such cases that are due to genetic susceptibility is unknown.

    Like many other genes involved in fa- milial cancer, BRCA1 appears to encode a tumor suppressor, a protein that acts as a negative regulator of tumor growth. Can- cer-predisposing alleles typically carry mu- tations that cause loss or reduction of gene function. Predisposition to cancer is inher- ited as a dominant genetic trait, whereas the predisposing allele generally behaves as a recessive allele in somatic cells. Thus, a single inherited copy of the mutant allele causes predisposition, and loss or inactiva- tion of the wild-type allele completes one of the steps in progression toward malignancy. When chromosome loss is observed in breast and ovarian tumors from patients who carry BRCA1 predisposing alleles, the wild-type copy of BRCA1 is invariably lost while the presumptive mutant allele is re- tained (12-14). This finding supports the hypothesis that BRCA1 is a tumor suppres- sor gene and suggests that the functional BRCA1 protein is present in normal breast and ovarian epithelium tissue and is altered, reduced, or absent in some breast and ovar- ian tumors.

    Genetic analysis of recombinant chromo- somes in members of large kindreds allowed localization of BRCA1 initially to a region of 1 to 2 megabases on chromosome 17q (15- 17) and, subsequently, to a region of about 600 kilobase pairs (kb) (18) between markers D17S1321 and D17S1325 (19). A physical map comprised of overlapping yeast artificial chromosomes (YACs), Pl, bacterial artificial chromosomes (BACs), and cosmid clones was generated for this region (18).

    Identification of a strong BRCA1 can- didate gene. Several strategies were used to develop a detailed map of transcripts for the 600-kb region of 17q2l between D17S1321 and DJ 7S1 325. Sixty-five candidate ex- pressed sequences (20) within this region were identified. Expressed sequences were characterized by DNA sequence, database comparison, transcript size, expression pat- tern, genomic structure and, most impor- tantly, DNA sequence analysis in individu- als from kindreds that segregate 17q-linked breast and ovarian cancer susceptibility. Three expressed sequences eventually were merged into a single transcription unit whose characteristics strongly suggest that it is BRCAI (21). This transcription unit is located in the center of the 600-kb region (Fig. 1) spanning D17S855 and will be re- ferred to herein as BRCAJ.

    A combination of sequences obtained from complementary DNA (cDNA) clones, hybrid-selected sequences, and amplified polymerase chain reaction (PCR) products

    66 SCIENCE * VOL. 266 * 7 OCTOBER 1994

  • allowed the construction of a composite, full-length BRCA1 cDNA. The cDNA clone extending farthest in the 3' direction contains a polyadenyl