Analysis of Recently Identified Prostate Cancer Susceptibility Loci in a Population-based Study: Associations with Family History and Clinical Features

Abstract

Purpose: Two recent genome-wide association studies have highlighted several single nucleotide polymorphisms (SNPs) purported to be associated with prostate cancer risk.We investigated the significance of these SNPs in a population-based study of Caucasian men, testing the effects of each SNP in relation to family history of prostate cancer and the clinicopathologic features of the disease. Experimental Design: We genotyped 13 SNPs in 1,308 prostate cancer patients and 1,267 unaffected controls frequency matched to cases by five-year age groups. The association of each SNP with disease risk stratified by family history of prostate cancer and clinicopathologic features of the disease was calculated with the use of logistic and polytomous regression. Results: These results confirm the importance of multiple, previously reported SNPs in relation to prostate cancer susceptibility; 11 of the 13 SNPs were significantly associated with risk of developing prostate cancer. However, none of the SNP associations were of comparable magnitude with that associated with having a first-degree family history of the disease. Risk estimates associated with SNPs rs4242382 and rs2735839 varied by family history, whereas risk estimates for rs10993994 and rs5945619 varied by Gleason score. Conclusions: Our results confirm that several recently identified SNPs are associated with prostate cancer risk; however, the variant alleles only confer a low to moderate relative risk of disease and are generally not associated with more aggressive disease features.Recent genome-wide association studies (GWAS) have identified multiple genetic variants associated with prostate cancer risk (1 -5). At least four separate regions at 8q24 have been identified and replicated in numerous studies of both Caucasian and African-American men (1, 4 -18). Evidence that prostate cancer loci exist on chromosomes 10q11, 17q12, and 17q24 has also been presented and replicated in GWAS (10q11, refs. 1,4,19; 17q12, refs. 1,3,4,20; 17q24, refs. 1,3). In particular, two recent GWAS (1, 4) have each highlighted seven SNPs associated with prostate cancer risk, two of which (one at 10q11.2 and one at 11q13.2) were identified in both studies.Eeles et al. (2008) conducted a two-stage GWAS that initially analyzed 1,854 cases and 1,894 controls for 541,129 SNPs (1). To increase statistical power, the cases and controls in the 1st stage of the study were selected according to specific criteria. The cases had been diagnosed as a result of clinical symptoms rather than by routine prostate-specific antigen (PSA) screening and were further enriched by only including men diagnosed at V60 years of age or who had a family history of prostate cancer. The controls were screened for serum PSA level and were only included if they were z50 years of age and had a PSA of <0.5 ng/mL. In stage 2 of the study, 11 SNPs were evaluated in a population-based series of 3,268 cases and 3,366 controls from the United Kingdom and Australia. Although no specific selection criteria were assign...

Inherited genetic variant predisposes to aggressive but not indolent prostate cancer

“…Although the associations for some SNPs, such as those at 8q24, were stronger among patients with aggressive PCa in some studies when each type of case is compared versus unaffected controls (35,36), these SNPs were not associated with PCa aggressiveness in any of the studies when patients with more or less aggressive PCa were directly compared. Indeed, three large studies that were published recently each concluded the null association of the PCa risk-associated SNPs with PCa aggressiveness (26)(27)(28).…”

“…Unfortunately, none of these PCa risk-associated SNPs consistently distinguish risk for more or less aggressive cancer (26)(27)(28), nor are they associated with prostate cancer-specific mortality (29). As a result, there has been much debate regarding the clinical utility of these SNPs as a risk stratification tool (30,31).…”

Impact of Genotyping on Outcome of Prostatic Biopsies: A Multicenter Prospective Study

“…However, few studies have been able to show a clear and replicated association between these genetic variants and prostate cancer aggressiveness (20). To our knowledge, only 8q24 SNPs (rs1447295 and rs6983267) have been exposed as markers of aggressiveness, mainly through Gleason score, in multiple studies (8)(9)(10)(11)(12).…”

Prostate Cancer and Hereditary Syndromes

“…Среди причин, которые могли быть причастны к раз-витию РПЖ, отмечали: географическое место прожива-ния [19], возраст [19], инфекционные воспалительные процессы [2], этнических фон [22], диету [29], половые гормоны [15], семейные [1,3,7,13,23,30] и наследствен-ные факторы [1,9,11,20,24]. Положительный семейный анамнез является одним из самых сильных эпидемиоло-гических факторов риска развития РПЖ [11,20,24], кото-рый увеличивает риск для родственников первой степени более чем два раза.…”

“…Положительный семейный анамнез является одним из самых сильных эпидемиоло-гических факторов риска развития РПЖ [11,20,24], кото-рый увеличивает риск для родственников первой степени более чем два раза. Вместе с тем, семейные и наслед-ственные факторы, вызывающие развитие РПЖ, не впол-не понятны.…”