The 8q24 locus harbors common susceptibility alleles for prostate cancer. Through fine-mapping of 8q24 in five racial-ethnic populations in the Multiethnic Cohort Study (MEC), we identified three regions that contain 7 independent risk variants for prostate cancer. Only some of these variants were found in studies conducted in European Whites, thus, emphasizing the power of fine-mapping in multiple racial-ethnic populations to reveal a more complete spectrum of variants associated with disease risk. Further highlighting the breakthrough nature of the discoveries at the 8q24 locus this region has even more recently been found to harbor common susceptibility alleles for breast cancer and colorectal cancer (CRC). Genome-wide association (GWA) studies of breast and CRC are underway among populations of European ancestry and a number of other risk loci have been identified and confirmed. In this application, we propose to fine-map the 8q24 locus and the genomic regions identified in these breast and CRC GWA studies in multiple racial-ethnic populations with diverse genetic backgrounds and environmental exposures, to more comprehensively enumerate and localize the risk variants in these regions and to assess genetic risk heterogeneity in the population. In all regions, we will evaluate SNPs selected to highly predict all common alleles as defined in the HapMap populations. We will also perform exon resequencing of genes in candidate regions identified in GWA studies to test common coding variants. This work will be conducted in large case-control studies comprised of African Americans, Japanese Americans, Native Hawaiians, Latinos, and European Americans from the MEC that include 2,650 breast cancer cases and 2,900 controls, and 1,800 colorectal cancer cases, and 4,500 controls. Heterogeneity of genetic effects within and across populations, resulting from differences in linkage disequilibrium as well as in genetic, environmental and lifestyle risk factors, will be assessed to better define the susceptible subgroups of the population. We expect this work to significantly advance knowledge of the etiology of breast and CRC across these racial-ethnic populations, and to reveal a more complete picture as to the contribution of germline variation in these regions to breast and CRC risk;work that we hope will guide the development of future preventive, early detection and prognostic strategies.

Public Health Relevance

The goal of this project is to identify common risk alleles for breast and colorectal cancer in African American, Japanese American, Native Hawaiian, Latino and European American populations in the prospective Multiethnic Cohort Study. More specifically, we propose to fine-map genetic variation at chromosome 8q24 as well as regions identified in genome-wide scans in European Whites, in multiethnic samples, to localize functional variants as well as reveal the full spectrum of common alleles that contribute to risk of breast and colorectal cancer in the general population. We will also incorporate environment and lifestyle risk factors in association testing to assist in resolving potential heterogeneous genetic effects across populations, and, better define the subgroups of the population at greatest risk of developing these common cancers. We expect findings from this work to guide the development of future preventive, early detection and prognostic strategies

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA132839-03
Application #
7764795
Study Section
Special Emphasis Panel (ZRG1-HOP-N (03))
Program Officer
Zanetti, Krista A
Project Start
2008-03-15
Project End
2012-02-28
Budget Start
2010-03-01
Budget End
2012-02-28
Support Year
3
Fiscal Year
2010
Total Cost
$637,181
Indirect Cost
Name
University of Southern California
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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Hoffman, Joshua D; Graff, Rebecca E; Emami, Nima C et al. (2017) Cis-eQTL-based trans-ethnic meta-analysis reveals novel genes associated with breast cancer risk. PLoS Genet 13:e1006690
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Ovarian Cancer Association Consortium, Breast Cancer Association Consortium, and Consortium of Modifiers of BRCA1 and BRCA2 (see original citation for additional authors) (2016) No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer. Gynecol Oncol 141:386-401
Shi, Jiajun; Zhang, Yanfeng; Zheng, Wei et al. (2016) Fine-scale mapping of 8q24 locus identifies multiple independent risk variants for breast cancer. Int J Cancer 139:1303-1317
Zhao, Zhiguo; Wen, Wanqing; Michailidou, Kyriaki et al. (2016) Association of genetic susceptibility variants for type 2 diabetes with breast cancer risk in women of European ancestry. Cancer Causes Control 27:679-93
Lei, Jieping; Rudolph, Anja; Moysich, Kirsten B et al. (2016) Genetic variation in the immunosuppression pathway genes and breast cancer susceptibility: a pooled analysis of 42,510 cases and 40,577 controls from the Breast Cancer Association Consortium. Hum Genet 135:137-54
Petridis, Christos; Brook, Mark N; Shah, Vandna et al. (2016) Genetic predisposition to ductal carcinoma in situ of the breast. Breast Cancer Res 18:22

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