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Haplotype-Based Association Studies of IGFBP1 and IGFBP3 with Prostate and Breast Cancer Risk: The Multiethnic Cohort

¹ Department of Epidemiology and Biostatistics and Center for Human Genetics, University of California-San Francisco, San Francisco, California; ² Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts; Departments of ³ Genetics, ⁴ Medicine, and ⁵ Pediatrics, Harvard Medical School; ⁶ Department of Molecular Biology, Massachusetts General Hospital; ⁷ Division of Genetics and Endocrinology, Children's Hospital and Department of Pediatrics; ⁸ Dana-Farber Cancer Institute, Boston, Massachusetts; ⁹ Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California; and ¹⁰ Cancer 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

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)

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