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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

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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 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 Your use of the JSTOR archive indicates your acceptance of the Terms & Conditions of Use, available at . http://www.jstor.org/page/info/about/policies/terms.jsp JSTOR is a not-for-profit service that helps scholars, researchers, and students discover, use, and build upon a wide range of content in a trusted digital archive. We use information technology and tools to increase productivity and facilitate new forms of scholarship. For more information about JSTOR, please contact [email protected]. American Association for the Advancement of Science is collaborating with JSTOR to digitize, preserve and extend access to Science. http://www.jstor.org .................................. .... .........................-. ....... ... .... .... ..... RE S ... ....... .......... cer is often familialin origin, althoughthe A Strong Candidate for the risksin relativesare not as high as those for early-onsetbreast cancer (10, 11). The per- centageof such casesthat aredue to genetic Breast and Ovarian Cancer susceptibilityis unknown. Like many other genes involved in fa- Susceptibility Gene BRCA1 milial cancer, BRCA1 appearsto encode a tumor suppressor,a protein that acts as a Yoshio Miki, Jeff Swensen, Donna Shattuck-Eidens, P. Andrew Futreal, negative regulatorof tumor growth. Can- Keith Harshman, Sean Tavtigian, Qingyun Liu, Charles Cochran, cer-predisposingalleles typicallycarry mu- L. Michelle Bennett, Wei Ding, Russell Bell, Judith Rosenthal, tations that cause loss or reductionof gene Charles Hussey, Thanh Tran, Melody McClure, Cheryl Frye, Tom Hattier, function. Predispositionto cancer is inher- Robert Phelps, Astrid Haugen-Strano, Harold Katcher, Kazuko Yakumo, ited as a dominant genetic trait, whereas Zahra Gholami, Daniel Shaffer, Steven Stone, Steven Bayer, Christian Wray, the predisposingallele generallybehaves as Narod, Robert Bogden, Priya Dayananth, John Ward, Patricia Tonin, Steven a recessiveallele in somatic cells. Thus, a Pam K. Bristow, Frank H. Norris, Leah Helvering, Paul Morrison, mutant allele Neuhausen, single inherited copy of the Paul Rosteck, Mei Lai, J. Carl Barrett, Cathryn Lewis, Susan inactiva- Alexander Kamb, causes predisposition,and loss or Lisa Cannon-Albright, David Goldgar, Roger Wiseman, completesone of Mark H. Skolnick* tion of the wild-typeallele the steps in progressiontoward malignancy. A strong candidate for the 17q-linked BRCA1 gene, which influences susceptibility to When chromosome loss is observed in breast and ovarian cancer, has been identified by positional cloning methods. Probable breast and ovarian tumors from patients predisposing mutations have been detected in five of eight kindreds presumed to seg- who carryBRCA1 predisposing alleles, the regate BRCA1 susceptibility alleles. The mutations include an 1 1-base pair deletion, a wild-typecopy of BRCA1is invariablylost 1-base pair insertion, a stop codon, a missense substitution, and an inferred regulatory while the presumptivemutant allele is re- mutation. The BRCA1 gene is expressed in numerous tissues, including breast and ovary, tained (12-14). This finding supportsthe and encodes a predicted protein of 1863 amino acids. This protein contains a zinc finger hypothesisthat BRCA1is a tumorsuppres- domain in its amino-terminal region, but is otherwise unrelated to previously described sor gene and suggeststhat the functional proteins. Identification of BRCA1 should facilitate early diagnosis of breast and ovarian BRCA1 protein is presentin normalbreast cancer susceptibility in some individuals as well as a better understanding of breast and ovarianepithelium tissue and is altered, cancer biology. reduced,or absentin some breastand ovar- ian tumors. Genetic analysisof recombinantchromo- somes in membersof largekindreds allowed Breast cancer is one of the most common Genetic factorscontribute to an ill-de- localizationof BRCA1initially to a regionof and important diseases affecting women. fined proportionof breastcancer incidence, 1 to 2 megabaseson chromosome17q (15- Currentestimates indicate that one in eight estimatedto be about 5% of all cases but 17) and, subsequently,to a region of about American women who reach age 95 will approximately25% of cases diagnosedbe- 600 kilobasepairs (kb) (18) betweenmarkers develop breast cancer (1). Treatment of fore age 30 (2). Breast cancer has been D17S1321 and D17S1325 (19). A physical advancedbreast cancer is often futile and subdividedinto two types, early-onsetand mapcomprised of overlappingyeast artificial disfiguring,making early detection a high late-onset, a division that is based on an chromosomes(YACs), Pl, bacterialartificial priorityin medicalmanagement of the dis- inflection in the age-specific incidence chromosomes(BACs), and cosmid clones was ease.Ovarian cancer, although less frequent curvearound age 50. Mutationof one gene, generatedfor this region(18). than breastcancer, is often rapidlyfatal and BRCA1,is thought to accountfor approxi- Identificationof a strong BRCA1 can- is the fourthmost common cause of cancer mately 45% of families with significantly didate gene. Severalstrategies were used to mortalityin Americanwomen. high breast cancer incidence and at least developa detailedmap of transcriptsfor the 80%of familieswith increasedincidence of 600-kbregion of 17q2l betweenD17S1321 Y. Miki, J. Swensen, K. Yakumo, C. Lewis, S. Neu- both early-onsetbreast cancer and ovarian and DJ 7S1325. Sixty-five candidate ex- hausen, and D. Goldgar are in the Department of Medical Informatics,University of Utah Medical Center, Salt Lake cancer (3). Intense efforts to isolate the pressedsequences (20) within this region City, UT 84132, USA. D. Shattuck-Eidens, K. Harshman, BRCA1 gene have proceededsince it was were identified. Expressedsequences were S. Tavtigian, 0. Liu, W. Ding, R. Bell, J. Rosenthal, C. first mapped to chromosomearm 17q in characterizedby DNA sequence, database Hussey, T. Tran, M. McClure, C. Frye, T. Hattier, R. expressionpat- Phelps, H. Katcher, Z. Gholami, D. Shaffer, S. Stone, S. 1990 (4, 5). A second locus, BRCA2, re- comparison,transcript size, Bayer, C. Wray, R. Bogden, P. Dayananth, and A. Kamb cently mappedto chromosomearm 13q (6), tern, genomic structureand, most impor- are at MyriadGenetics, 421 Wakara Way, Salt Lake City, appearsto accountfor a proportionof early- tantly, DNA sequenceanalysis in individu- UT 84108, USA. P. A. Futreal,C. Cochran, L. M. Bennett, als fromkindreds that segregate17q-linked A. Huagen-Strano, J. C. Barrett, and R. Wiseman are at onset breast cancer roughly equal to that the Laboratoryof Molecular Carcinogenesis, National In- resulting from BRCA1. Unlike BRCA1, breast and ovarian cancer susceptibility. stitute of EnvironmentalHealth Sciences, National Insti- however,BRCA2 may not influenceovari- Three expressedsequences eventually were tutes of Health, Research TrianglePark, NC 27709, USA. susceptibility merged into a single transcriptionunit J. Ward and L. Cannon-Albrightare in the Department of an cancerrisk. The remaining InternalMedicine, Universityof Utah Medical Center, Salt to early-onsetbreast cancer is likely attrib- whose characteristicsstrongly suggest that Lake City, UT 84132, USA. P. Tonin and S. Narod are in utable to unmappedgenes for familialcan- it is BRCAI (21). This transcriptionunit is the Department of Medical Genetics, McGill University, rare germline mutations in genes located in the center of the 600-kb region Montreal, Quebec, H3G 1A4, Canada. P. K. Bristow, F. cer and H. Norris, L. Helvering, P. Morrmson,P. Rosteck, and M. such as TP53, which encodes the tumor (Fig. 1) spanningD17S855 and will be re- Lai are at LillyResearch Laboratories, Eli Lillyand Com- suppressorprotein p53 (7). It has also been ferredto herein as BRCAJ. pany, Indianapolis, IN 46285, USA. M. H. Skolnick is in suggestedthat heterozygotecarriers of de- A combination of sequences obtained the Department of Medical Informatics,University of Utah DNA (cDNA) clones, Medical Center, and MyriadGenetics, Salt Lake City, UT fective forms of the gene predisposingto from complementary 84108, USA. ataxia telangiectasiaare at higher risk for hybrid-selected sequences, and amplified *To whom correspondence should be addressed. breastcancer (8, 9). Late-onsetbreast can- polymerase chain reaction (PCR) products 66 SCIENCE * VOL. 266 * 7 OCTOBER 1994 allowed the constructionof a composite, ing is coordinatedwith alternativesplicing BRCAI is conservedin mammals. full-length BRCA1 cDNA. The cDNA farther downstream,and whether all the Germline BRCA1 mutations in 17q- clone extendingfarthest in the 3' direction splice variants produce proteins with an linked kindreds. Identificationof a candi- contains a polyadenylatetract precededby identicalNH2-terminus, are questionsthat date gene as BRCAJrequires a demonstra- a polyadenylationsignal.
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