Basic Biology of Aging at the University of Washington

Mary-Claire King

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My group studies the genetics of complex, common human conditions. Our primary areas of interest are breast and ovarian cancer and inherited deafness. Our approach is to apply human genetics and genomics to identification and characterization of critical genes in informative families and populations. Because these conditions are not purely genetic, we also study the interaction between genetic and environmental influences on human traits. Our lab also applies genomic sequencing to the identification of victims of human rights abuses. Other areas of interest include identification of genes associated with differences in the progression of AIDS and an analysis of mitochondrial DNA polymorphisms to trace the movement of human populations.

We have identified BRCA I as the principal gene responsible for inherited susceptibility to breast and/or ovarian cancer. Inherited mutations in BRCA1 and BRCA2 predispose individuals to breast and ovarian cancer, but the role of these genes in sporadic breast and ovarian cancer has been elusive. A major focus of our laboratory is to understand how BRCA1 inhibits breast and ovarian tumor growth. The wild-type BRCA1 gene inhibits growth of breast and ovarian cancer cell lines. We are also exploring growth inhibition by BRCA1 by characterizing the consequences of overexpression of BRCA1 and its mutants in breast and ovarian cells of different genetic backgrounds. We are evaluating penetrance and variable expressivity attributable to inherited mutations in BRCA1 and BRCA2 in four major epidemiologic series of breast cancer patients and their families. The possible efficacy of tamoxifen in prevention of breast cancer, specifically in women with inherited BRCA1 or BRCA2 mutations, is also under investigation.

Dr. King is American Cancer Society Professor of Medicine, Division of Medical Genetics, and Professor of Genome Science. She has served on multiple NIH study sections and on the President's Cancer Panel.

Selected Relevant Publications
Lynch ED, Lee MD, Morrow JE, Welcsh PL, Leon PL, King M-C. Non-syndromic deafness DFNAI associated with mutation of the human homolog HDIAI of the Drosophila diaphanous gene. Science 278:1315-1318, 1997.

Schubert EL, Lee MK, Mefford HC, Argonza RH, Morrow JE, Hull J, Dann JL, King MC. BRCA2 in American families with four or more cases of breast or ovarian cancer: recurrent and novel mutations, variable expression, penetrance, and the possibility of families whose cancer is not attributable to BRCA1 or BRCA2. Am J Hum Genet 60:1031-1040, 1997.

Brzovic PS, Meza J, King M-C, Klevit RE. The cancer-predisposing mutation C61G disrupts homodimer formation in the N-terminal BRCAI RING-finger domain. J Biol Chem 273:7795-7799, 1998.

Vahava O, Morell R, Lynch ED, Weiss S, Kagan ME, Ahituv N, Morrow JE, Lee MD, Skvorak AB, Morton CC, Blumenfeld A, Frydman M, Friedman TB, King M-C, Avraham KB. Mutation in transcription factor POU4F# associated with inherited progressive hearing loss in humans. Science 279:1950-1954, 1998.

Meza JE, Brzovic PS, King M-C, Klevit RE. Mapping the functional domains of BRCAI. Interaction of the ring finger domains of BRCA1 and BARD1. J Biol Chem 274:5659-5665, 1999.

Owens KM, King M-C. Genomic views of human history. Science 286:451-453, 1999.

Welcsh PL, Owens K, King M-C. Insights into the function of BRCA1 and BRCA2. Trends Genet 16:69-74, 2000.

Welcsh PL, King MC. BRCA1 and BRCA2 and the genetics of breast and ovarian cancer. Hum Mol Genet 10:705-713, 2001.

Brzovic PS, Rajagopal P, Hoyt DW, King MC, Klevit RE. Structure of a BRCA1-BARD1 heterodimeric ING-RING complex. Nature Struct Biol 8:833-837, 2001.