Haplotype-Based Association Studies of IGFBP1 and IGFBP3 with Prostate and Breast Cancer Risk: The Multiethnic Cohort
- Iona Cheng1,
- Kathryn L. Penney2,3,4,6,
- Daniel O. Stram9,
- Loic Le Marchand10,
- Elena Giorgi9,
- Christopher A. Haiman9,
- Laurence N. Kolonel10,
- Malcolm Pike9,
- Joel Hirschhorn2,3,5,7,
- Brian E. Henderson9 and
- Matthew L. Freedman2,4,8
- 1Department of Epidemiology and Biostatistics and Center for Human Genetics, University of California-San Francisco, San Francisco, California; 2Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts; Departments of 3Genetics, 4Medicine, and 5Pediatrics, Harvard Medical School; 6Department of Molecular Biology, Massachusetts General Hospital; 7Division of Genetics and Endocrinology, Children's Hospital and Department of Pediatrics; 8Dana-Farber Cancer Institute, Boston, Massachusetts; 9Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California; and 10Cancer Epidemiology Program, Cancer Research Center of Hawaii, University of Hawaii, Honolulu, Hawaii
- Requests for reprints:
Matthew Freedman, Program in Medical and Population Genetics, Dana-Farber Cancer Institute, Boston, MA 02115. E-mail: freedman{at}broad.mit.edu
Abstract
Collective evidence suggests that the insulin-like growth factor (IGF) system plays a role in prostate and breast cancer risk. IGF-binding proteins (IGFBP) are the principal regulatory molecules that modulate IGF-I bioavailability in the circulation and tissues. To examine whether inherited differences in the IGFBP1 and IGFBP3 genes influence prostate and breast cancer susceptibility, we conducted two large population-based association studies of African Americans, Native Hawaiians, Japanese Americans, Latinos, and Whites. To thoroughly assess the genetic variation across the two loci, we (a) sequenced the IGFBP1 and IGFBP3 exons in 95 aggressive prostate and 95 advanced breast cancer cases to ensure that we had identified all common missense variants and (b) characterized the linkage disequilibrium patterns and common haplotypes by genotyping 36 single nucleotide polymorphisms (SNP) spanning 71 kb across the loci (∼20 kb upstream and ∼40 kb downstream, respectively) in a panel of 349 control subjects of the five racial/ethnic groups. No new missense SNPs were found. We identified three regions of strong linkage disequilibrium and selected a subset of 23 tagging SNPs that could accurately predict both the common IGFBP1 and IGFBP3 haplotypes and the remaining 13 SNPs. We tested the association between IGFBP1 and IGFBP3 genotypes and haplotypes for their associations with prostate and breast cancer risk in two large case-control studies nested within the Multiethnic Cohort [prostate cases/controls = 2,320/2,290; breast cases (largely postmenopausal)/controls = 1,615/1,962]. We observed no strong associations between IGFBP1 and IGFBP3 genotypes or haplotypes with either prostate or breast cancer risk. Our results suggest that common genetic variation in the IGFBP1 and IGFBP3 genes do not substantially influence prostate and breast cancer susceptibility. (Cancer Epidemiol Biomarkers Prev 2006;15(10):1993–7)
Footnotes
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Grant support: National Cancer Institute grants CA 63464 and CA 54281, Howard Hughes Medical Institute physician postdoctoral fellowship (M.L. Freedman), and Department of Defense Health Disparity Training-Prostate Scholar Award DAMD # 17-02-1-0246 (M.L. Freedman).
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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Note: Supplementary data for this article are available at Cancer Epidemiology Biomakers and Prevention Online (http://cebp.aacrjournals.org/).
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- Accepted August 2, 2006.
- Received June 10, 2006.
- Revision received July 13, 2006.
