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Comprehensive Evaluation of the Association Between Prostate Cancer and Genotypes/Haplotypes in CYP17A1, CYP3A4, and SRD5A2

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Comprehensive Evaluation of the Association Between Prostate Cancer and Genotypes/Haplotypes in CYP17A1, CYP3A4, and SRD5A2 European Journal of Human Genetics (2004) 12, 321–332 & 2004 Nature Publishing Group All rights reserved 1018-4813/04 $25.00 www.nature.com/ejhg ARTICLE Comprehensive evaluation of the association between prostate cancer and genotypes/haplotypes in CYP17A1, CYP3A4, and SRD5A2 Anu Loukola1, Monica Chadha1, Sharron G Penn1, David Rank1, David V Conti2, Deborah Thompson3, Mine Cicek4, Brad Love1, Vesna Bivolarevic1, Qiner Yang1, Yalin Jiang1, David KHanzel1, Katherine Dains1,PamelaLParis4,GrahamCasey4 and John S Witte*,2,3 1Amersham Biosciences, Sunnyvale, CA 94085, USA; 2Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44106, USA; 3International Agency for Cancer Research, Lyon, France; 4Department of Cancer Biology, Cleveland Clinic Foundation, Cleveland, OH 44195, USA Genes involved in the testosterone biosynthetic pathway – such as CYP17A1, CYP3A4, and SRD5A2 – represent strong candidates for affecting prostate cancer. Previous work has detected associations between individual variants in these three genes and prostate cancer risk and aggressiveness. To more comprehensively evaluate CYP17A1, CYP3A4, and SRD5A2, we undertook a two-phase study of the relationship between their genotypes/haplotypes and prostate cancer. Phase I of the study first searched for single-nucleotide polymorphisms (SNPs) in these genes by resequencing 24 individuals from the Coriell Polymorphism Discovery Resource, 92–110 men from prostate cancer case–control sibships, and by leveraging public databases. In all, 87 SNPs were discovered and genotyped in 276 men from case–control sibships. Those SNPs exhibiting preliminary case–control allele frequency differences, or distinguishing (ie, ‘tagging’) common haplotypes across the genes, were identified for further study (24 SNPs in total). In Phase II of the study, the 24 SNPs were genotyped in an additional 841 men from case–control sibships. Finally, associations between genotypes/haplotypes in CYP17A1, CYP3A4, and SRD5A2 and prostate cancer were evaluated in the total case–control sample of 1117 brothers from 506 sibships. Family-based analyses detected associations between prostate cancer risk or aggressiveness and a number of CYP3A4 SNPs (P- values between 0.006 and 0.05), a CYP3A4 haplotype (P-values 0.05 and 0.009 in nonstratified and stratified analysis, respectively), and two SRD5A2 SNPs in strong linkage disequilibrium (P ¼ 0.02). Undertaking a two-phase study comprising SNP discovery, haplotype tagging, and association analyses allowed us to more fully decipher the relation between CYP17A1, CYP3A4, and SRD5A2 and prostate cancer. European Journal of Human Genetics (2004) 12, 321–332. doi:10.1038/sj.ejhg.5201101 Published online 15 October 2003 Keywords: prostate cancer; association; CYP17A1; CYP3A4; SRD5A2; haplotyping; genetic susceptibility Introduction Society, 1 89 000 US men were diagnosed with prostate Prostate cancer is the most common noncutaneous cancer in the year 2002, and approximately 30 000 US men neoplasm among men. According to the American Cancer died from this disease. A clear risk factor for prostate cancer is age, suggesting an important role of exposure to *Correspondence: Dr J Witte, Department of Epidemiology and Biosta- endogenous and/or exogenous factors (eg, hormones or tistics, University of California San Francisco, 500 Parnassus Ave, MU-420 environmental agents). Another known risk factor is West, San Francisco, CA 94143-0560, USA. Tel: þ 1 415 476 1374; ethnicity: prostate cancer is almost two times more Fax: þ 1 415 476 6014; E-mail: [email protected] Received 6 May 2003; revised 18 August 2003; accepted 11 September common in African Americans than in Caucasians, 1,2 2003 whereas Asians have the lowest risk. Finally, there is an Prostate cancer and the androgen pathway A Loukola et al 322 increased risk among men with a positive family history of contributed information for calculating allele frequencies, prostate cancer.3 These factors suggest that both genes and only the 440 cases and 480 controls (920 men total) from environment predispose men to this disease. discordant families were informative for the conditional Substantial evidence from linkage studies supports the logistic regression analysis of association. existence of genetic factors for prostate cancer develop- The study population was recruited between January ment and progression. A number of chromosomal regions 1998 and January 2001 from the major medical institu- have been linked to prostate cancer, including 1q24–q25, tions in the greater Cleveland area and from the Henry 1q42.2–q43, 1p36, 8p22–23, 16q23, 17p11, 19q, 20q13, Ford Health System in Detroit. The study was approved by and Xq27–28.4 On 17p11, ELAC2 was the first prostate the collaborating institution’s Review Boards, and in- cancer-susceptibility gene cloned.5 Common allelic var- formed consent was obtained from all participating men. iants of ELAC2 were shown associated with prostate cancer Characteristics of the study population have been de- in some studies,6,7 but not all.8–11 Another candidate scribed elsewhere.13 prostate cancer-susceptibility gene, RNASEL, was identified Men diagnosed with histologically confirmed prostate in the HPC1 locus on 1q24–25.12 Subsequent studies cancer at age 73 or younger were invited to join the study if support a role both for inactivating mutations and variants they had a living unaffected brother who was either older in RNASEL and prostate cancer risk.13 – 15 than the proband, or at most 8 years younger than the age Since prostate growth depends on active testosterone,16 at diagnosis of the proband. This age restriction was and testosterone administration leads to the development selected in an attempt to increase the potential for finding of prostate adenocarcinomas in rats,17 studies of genes a genetic association with disease and to substantiate that involved in androgen metabolism have provided further the controls were not unaffected simply due to being of a insight into the genetic basis of this disease. Three such younger age. To help confirm that the controls were not genes are CYP17A1, CYP3A4, and SRD5A2. CYP17A1 is diseased, we tested the prostate-specific antigen (PSA) involved with the biosynthesis of testosterone in the levels in their blood (see discussion). Information on the gonads and adrenals, and is involved with catalyzing cases’ Gleason score and tumor stage (TNM) was deter- steroid 17a-hydroxylase and 17,20-lyase activities at key mined from their medical records. The study population points in this process.18 CYP3A4 catalyzes the 6b-hydro- was comprised of 90% Caucasians (European Americans), xylation of testosterone, suggesting that it may be involved and the remainder primarily African American (9%). in the metabolism and oxidative deactivation of this steroid.19 The SRD5A2 gene product catalyzes the conver- SNP discovery sion of testosterone to dihydrotestosterone,20 a highly A complementary approach was used to identify SNPs active form of this androgen. within CYP17A1, CYP3A4, and SRD5A2. We performed SNP Numerous previous studies have detected associations discovery by sequencing individuals from two populations: between variants in CYP17A1, CYP3A4, and SRD5A2 and (1) the Coriell Polymorphism Discovery Resource (Collins prostate cancer.21 – 31 These studies have focused only on et al32; Coriell Cell Repositories, Camden, NJ, USA); and (2) specific individual variants in the candidate genes. How- prostate cancer case–control sibships. The Coriell popula- ever, fully deciphering the impact of these genes on tion includes 24 individuals: six European Americans, six prostate cancer may require the evaluation of multiple African Americans, three Hispanic Americans, three Native variants or haplotypes. Therefore, we present here a two- Americans, and six Asian Americans. The prostate cancer phase comprehensive analysis of the association between case–control sibships used for SNP discovery were two multiple single-nucleotide polymorphism (SNP) geno- randomly selected subsets of our entire study population, types/haplotypes in CYP17A1, CYP3A4, and SRD5A2 and and included 67 cases and 43 controls for CYP17A1 and prostate cancer. CYP3A4, and 51 cases and 41 controls for SRD5A2. There was no overlap between the two subgroups. Of the 110 individuals sequenced for CYP17A1 and CYP3A4, 106 were Materials and methods European American, two were Hispanic American, and two Study population were African American. Of the 92 individuals sequenced A total of 1117 men (637 cases and 480 controls) from 506 for SRD5A2, 84 were European American and eight were sibships were included in the study. In total, 92 sibships African American. were concordant (ie, where all included men were For sequencing, PCR primers amplifying most of the diagnosed with prostate cancer, and there was no control coding regions, splice sites, 50 and 30 regions, and parts of sibling) and contained altogether 197 men. The remaining introns of CYP17A1, CYP3A4, and SRD5A2 were designed 414 sibships were discordant (ie, at least one control using the Primer3 program (http://www.genome.wi.mit. sibling) and contained 440 cases and 480 controls. edu/cgi-bin/primer/primer3.cgi). PCR products were Altogether, 52 discordant sibships had more than one sequenced using energy DYEnamict ET Terminator Kit control sib. Hence, while all of the 1117 study subjects on the MegaBACEt DNA Analysis System (Amersham European Journal of Human Genetics Prostate cancer and the androgen pathway
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