The goal of this project is to identify additional genes for inherited predisposition to breast cancer by studying families and patients of Ashkenazi Jewish (A J) ancestry. Several groups of people will be evaluated: ~60 AJ families with high incidence of breast cancer, ~900 unselected AJ breast cancer patients, ~100 AJ control families, and >3000 AJ population controls. The families and patients are wildtype by multiple tests at all known genes for inherited breast cancer. The proposed experimental and analytic approach is based on the distinctive historical demography of this 3opulation and combines linkage within families, haplotype sharing across families, resequencing candidate genes, and comparison of variant allele frequencies in independently ascertained cases vs. controls. This approach was validated by the identification of a previously undetected allele of CHEK2 co-segregating with breast cancer in a subset of these AJ families, then the demonstration that this allele was significantly more frequent among the AJ breast cancer cases than among AJ controls. Functionally, whereas wildtype human CHEK2 complemented the lethality of a Rad53 deletion in yeast, the mutant allele failed to do so. Most familial breast cancer remains unexplained by inherited mutations in BRCA1 or BRCA2 or other susceptibility genes. Discovery of additional breast cancer genes of moderate penetrance in the AJ population will be important to women both in this population and generally.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
1R01ES013160-01
Application #
6810313
Study Section
Special Emphasis Panel (ZRG1-CG (01))
Program Officer
Gray, Kimberly A
Project Start
2004-08-01
Project End
2009-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
1
Fiscal Year
2004
Total Cost
$360,050
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Chisholm, Karen M; Aubert, Sarah D; Freese, Krister P et al. (2012) A genomewide screen for suppressors of Alu-mediated rearrangements reveals a role for PIF1. PLoS One 7:e30748
Casadei, Silvia; Norquist, Barbara M; Walsh, Tom et al. (2011) Contribution of inherited mutations in the BRCA2-interacting protein PALB2 to familial breast cancer. Cancer Res 71:2222-9
Chisholm, Karen M; Goff, Barbara A; Garcia, Rochelle et al. (2008) Genomic structure of chromosome 17 deletions in BRCA1-associated ovarian cancers. Cancer Genet Cytogenet 183:41-8
DelloRusso, Christiana; Welcsh, Piri L; Wang, Weixin et al. (2007) Functional characterization of a novel BRCA1-null ovarian cancer cell line in response to ionizing radiation. Mol Cancer Res 5:35-45
Walsh, Tom; Casadei, Silvia; Coats, Kathryn Hale et al. (2006) Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA 295:1379-88
Shaag, Avraham; Walsh, Tom; Renbaum, Paul et al. (2005) Functional and genomic approaches reveal an ancient CHEK2 allele associated with breast cancer in the Ashkenazi Jewish population. Hum Mol Genet 14:555-63