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

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Haplotype-Based Association Studies of IGFBP1 and IGFBP3 with Prostate and Breast Cancer Risk: the Multiethnic Cohort 1993 Short Communication Haplotype-Based Association Studies of IGFBP1 and IGFBP3 with Prostate and Breast Cancer Risk: The Multiethnic Cohort Iona Cheng,1 Kathryn L. Penney,2,3,4,6 Daniel O. Stram,9 Loic Le Marchand,10 Elena Giorgi,9 Christopher A. Haiman,9 Laurence N. Kolonel,10 Malcolm Pike,9 Joel Hirschhorn,2,3,5,7 Brian E. Henderson,9 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 Abstract Collective evidence suggests that the insulin-like growth a panel of 349 control subjects of the five racial/ethnic factor (IGF) system plays a role in prostate and breast cancer groups. No new missense SNPs were found. We identified risk. IGF-binding proteins (IGFBP) are the principal regula- three regions of strong linkage disequilibrium and selected a tory molecules that modulate IGF-I bioavailability in the subset of 23 tagging SNPs that could accurately predict both circulation and tissues. To examine whether inherited the common IGFBP1 and IGFBP3 haplotypes and the differences in the IGFBP1 and IGFBP3 genes influence remaining 13 SNPs. We tested the association between prostate and breast cancer susceptibility, we conducted two IGFBP1 and IGFBP3 genotypes and haplotypes for their large population-based association studies of African Amer- associations with prostate and breast cancer risk in two large icans, Native Hawaiians, Japanese Americans, Latinos, and case-control studies nested within the Multiethnic Cohort Whites. To thoroughly assess the genetic variation across the [prostate cases/controls = 2,320/2,290; breast cases (largely two loci, we (a) sequenced the IGFBP1 and IGFBP3 exons in postmenopausal)/controls = 1,615/1,962]. We observed no 95 aggressive prostate and 95 advanced breast cancer cases to strong associations between IGFBP1 and IGFBP3 genotypes ensure that we had identified all common missense variants or haplotypes with either prostate or breast cancer risk. Our and (b) characterized the linkage disequilibrium patterns results suggest that common genetic variation in the IGFBP1 and common haplotypes by genotyping 36 single nucleo- and IGFBP3 genes do not substantially influence prostate tide polymorphisms (SNP) spanning 71 kb across the loci and breast cancer susceptibility. (Cancer Epidemiol Bio- (f20kb upstream and f40kb downstream, respectively) in markers Prev 2006;15(10):1993–7) Introduction Experimental and epidemiologic studies provide strong within the Multiethnic Cohort suggests that common genetic support for the role of the insulin-like growth factor (IGF) variation in IGF1 is associated with prostate cancer risk but system in prostate and breast cancer tumorigenesis (1-3). IGF- not associated with risk of breast cancer (7, 8). Whether or not I is a mitogen that regulates cell proliferation and also common genetic variation in IGFBPs is related to prostate inhibits apoptosis (4). The bioavailability of IGF-I in the and breast cancer risk has not been thoroughly examined. circulation and tissues is tightly regulated by IGF-binding Prior studies have examined a small number of polymor- proteins (IGFBP) that bind IGF-I with high affinity and phisms with most focusing on the IGFBP3 (A-202C) poly- specificity (5). In the circulation, >90% of IGF-I is bound to morphism as the C allele has been associated with lower IGFBP3 (5). IGFBP1 is inversely regulated by insulin and circulating levels of IGFBP3 (9-16), aggressive prostate cancer acutely mediates IGF-I bioavailability (6). Previous work (17), and increased breast cancer risk (9). The majority of these studies were conducted in modest-sized populations (9, 11, 14, 17-19). To systematically follow-up these prior reports, we undertook the first comprehensive evaluation of the Received 6/10/06; revised 7/13/06; accepted 8/2/06. genetic diversity of both the IGFBP1 and IGFBP3 genes, Grant support: National Cancer Institute grants CA 63464 and CA 54281, Howard Hughes Medical Institute physician postdoctoral fellowship (M.L. Freedman), and Department of which are located only 19 kb apart on chromosome 7p13-p12, Defense Health Disparity Training-Prostate Scholar Award DAMD # 17-02-1-0246 and conducted two large association studies to test whether (M.L. Freedman). inherited differences in these genes influence prostate and 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. breast cancer susceptibility. Section 1734 solely to indicate this fact. Note: Supplementary data for this article are available at Cancer Epidemiology Biomakers and Prevention Online (http://cebp.aacrjournals.org/). Requests for reprints: Matthew Freedman, Program in Medical and Population Genetics, Materials and Methods Dana-Farber Cancer Institute, Boston, MA 02115. E-mail: [email protected] Copyright D 2006 American Association for Cancer Research. The Multiethnic Cohort is a large population-based cohort doi:10.1158/1055-9965.EPI-06-0361 study of >215,000 individuals from Hawaii and California. The Cancer Epidemiol Biomarkers Prev 2006;15(10). October 2006 Downloaded from cebp.aacrjournals.org on September 30, 2021. © 2006 American Association for Cancer Research. 1994 IGFBP1 and IGFBP3 and Prostate and Breast Cancer Risk cohort is comprised of predominantly African Americans, SNPs between blocks 2 and 3 (SNP 23, 24, and 25), we were Native Hawaiians, Japanese Americans, Latinos, and Whites, unable to design a genotype assay for SNP 25. For the 13 SNPs who were between the ages of 45 and 75 years when recruited that were not genotyped in the case-control study, which we (1993-1996). Further methodologic details of this cohort are refer herein as ‘‘unmeasured SNPs,’’ we estimated for each provided elsewhere (20). individual the allelic distribution of these unmeasured SNPs Our prostate case-control study consists of 2,320 cases and by using the 23 tSNPs and genotype data obtained from the 2,290 controls. The breast case-control study is comprised of multiethnic panel. Within each region of strong LD, we used 1,615 cases and 1,962controls, the majority of which are genotype data from an individual tSNP or a combination of postmenopausal (87% and 82%, respectively). Aggressive tSNPs to predict each individual’s genotype for the unmea- R2 prostate cancer was defined as regional and metastatic tumors sured SNPs by calculating the squared correlations ( s) or localized tumors with Gleason grade >8, and advanced between each SNP (s) and their estimates obtained from the breast cancer was defined as regional and metastatic tumors. expectation-maximization algorithm. In situ cases of breast cancer were excluded from the study. Genotyping in Prostate and Breast Cancer Case-Control Detailed information about these nested case-control studies Studies. The tSNPs were genotyped in patient samples using have been reported previously (7, 21). This study was the 5¶ nuclease Taqman allelic discrimination assay. All assays approved by the Institutional Review Boards at the University were undertaken by individuals blinded to case-control status. of Hawaii and the University of Southern California. For the prostate samples, the concordance rate for 228 Sequencing. To identify missense single nucleotide poly- replicate samples was 99.8%, and the average genotyping morphisms (SNP) not in the standard databases, we attempted success was 98.8%. For the breast samples, the concordance to sequence the four coding exons of IGFBP1 and IGFBP3, rate for 263 replicates was 99.7%, and the average genotyping respectively, in 95 aggressive prostate and 95 advanced breast success was 97.9%. All tSNPs were in Hardy-Weinberg cancer cases (n = 19 per ethnic group). Exon 1 of IGFBP1 and equilibrium (P > 0.01 among controls in at least four of the exon 4 of IGFBP3 did not meet our sequencing criteria defined five ethnic groups). as >80% of the samples with phred (base calling) scores >20 for Prostate and Breast Cancer Case-Control Analyses. First, to at least 80% of the target bases. Thus, we relied on only publicly investigate the hypothesis that genetic susceptibility to cancer available SNP information for these two exons. Further details risk is associated with single causal variants, we evaluated the on sequencing methods are described elsewhere (22). relationship between IGFBP1 and IGFBP3 genotypes and SNP Selection and Genotyping for Genetic Characteriza- disease risk. We also considered potential gene-gene interac- IGFBP1-IGF1 tion. We genotyped SNPs spanning 71 kb across the IGFBP1 tive effects on prostate cancer risk between and IGFBP3-IGF1 (5.3 kb) and IGBP3 (9.0 kb) loci in a multiethnic panel of 349 by examining the respective multiplicative IGFBP1 IGFBP3 controls (Supplementary Fig. S1). We evaluated 19.3 and 18.7 effects between and polymorphisms and IGF1 kb upstream of the first exons of IGFBP1 and IGFBP3, rs7965399, an polymorphism previously associated with P respectively, and 46.3 and 43.2kb downstream of the increased prostate cancer risk ( = 0.002) in the Multiethnic transcribed region for each gene, respectively. A total of 36 Cohort (7). Odds ratios (OR) and 95% confidence intervals common SNPs (minor allele frequency >5%) was used for (95% CI) were estimated by unconditional logistic regression genetic characterization with an average density of one SNP for the association between genotypes and risk of prostate and every 2.0 kb (Supplementary Table S1).
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