Prostate cancer and genetic susceptibility: a genome scan incorporating disease aggressiveness

BACKGROUND: Prostate cancer is a heterogeneous disease, both genetically and phenotypically. Linkage studies attempting to map genes for hereditary prostate cancer (HPC) have proved challenging, and one potential problem contributing to this challenge is the variability in disease phenotypes. METHODS: We collected clinical data on 784 affected men with prostate cancer from 248 HPC families for whom a genomic screen was performed. Disease characteristics (i.e., Gleason score, stage, prostate-specific antigen (PSA)) were used to classify affected men into categories of clinically insignificant, moderate, or aggressive prostate cancer. To potentially enrich for a genetic etiology, we restricted linkage analyses to only men with aggressive disease, although we used genotype information from all family members; linkage analyses used both dominant and recessive models. In addition, subset analyses considered age at diagnosis, number of affected men per family and other stratifications to try to increase genetic homogeneity. RESULTS: Several regions of interest (heterogeneity LOD score, HLOD>1.0) were identified in families (n=123) with >or=2 affecteds with aggressive prostate cancer. "Suggestive" linkage was observed at chromosome 22q11.1 (Dominant model HLOD=2.18) and the result was stronger (Dominant HLOD=2.75) in families with evidence of male-to-male transmission. A second region at 22q12.3-q13.1 was also highlighted (Recessive model HLOD=1.90) among men with aggressive disease, as was a region on chromosome 18. CONCLUSIONS: These analyses suggest that using clinically defined phenotypes may be a useful approach for simplifying the locus heterogeneity problems that confound the search for prostate cancer susceptibility genes.     

Genome-wide scan for linkage in finnish hereditary prostate cancer (HPC) families identifies novel susceptibility loci at 11q14 and 3p25-26

BACKGROUND: In order to identify predisposition loci to hereditary prostate cancer (HPC), we performed a genome-wide linkage analysis using samples from a genetically homogeneous population, with 13 Finnish multiplex prostate cancer families. METHODS: Altogether 87 DNA samples were genotyped from 13 families. Logarithm-of-odds (LOD) scores were calculated for all autosomes using FASTLINK and GENEHUNTER designating all unaffected men and all women as unknown. RESULTS: The highest LOD scores in the affected-only analyses were found at 11q14, where the two-point LOD score was 2.97 (theta = 0.0 at D11S901), GENEHUNTER heterogeneity LOD (HLOD) of 3.36, and a non-parametric-linkage (NPL) score of 2.67 (P = 0.008). A second positive site was at 3p25-26, with a two-point LOD score of 2.57 (theta = 0.01 at D3S1297), HLOD of 2.15, and NPL score of 2.27 (P = 0.02). CONCLUSIONS: The results suggest two HPC regions in the Finnish population, which have not been reported previously and warrant further study.     

Association of V89L SRD5A2 polymorphism with prostate cancer development in a Japanese population

PURPOSE: The SRD5A2 gene codes the steroid 5-reductase type II, a critical mediator of androgen action, and the V89L and A49T polymorphisms of this gene may be associated with a distinct enzyme activity. We explored the association among these polymorphisms and the risk of prostate cancer or benign prostatic hyperplasia (BPH) in a Japanese population. MATERIALS AND METHODS: This study included 302 patients with prostate cancer, 228 with BPH and 243 male controls. V89L and A49T polymorphisms were analyzed by the polymerase chain reaction restriction fragment length polymorphism method. Genotypes were evaluated by electrophoresis on agarose gel. RESULTS: For the V89L polymorphism there were no significant differences in genotype frequencies in patients with prostate cancer and controls (p = 0.071) or in patients with BPH and male controls (p = 0.219). However, males with the VV or VL genotype were at significantly increased risk for prostate cancer compared with those with the LL genotype (adjusted OR 1.69, 95% CI 1.07 to 2.65, p = 0.024). The risk of BPH in males with the VV or VL genotype was not significantly elevated in comparison with those with the LL genotype (adjusted OR 1.37, 95% CI 0.85 to 2.20, p = 0.194). The V89L variant was not associated with the grade or stage of prostate cancer, or with patient age. For the A49T polymorphism all subjects had the AA genotype. CONCLUSIONS: The V allele of the V89L polymorphism in the SRD5A2 gene may dominantly increase the risk of prostate cancer.     

SRD5A2 and HSD3B2 polymorphisms are associated with prostate cancer risk and aggressiveness

BACKGROUND: Dihydrotestosterone (DHT) is believed to play an important role in prostate carcinogenesis. Five alpha reductase type II (SRD5A2) and 3 beta-hydroxysteroid dehydrogenase type II (HSD3B2) are responsible for the biosynthesis and degradation of DHT in the prostate. Two polymorphisms, a valine (V) for leucine (L) substitution at the 89 codon of the SRD5A2 gene and a (TG)n,(TA)n,(CA)n repeat polymorphism within the third intron of the HSD3B2 gene were evaluated with regard to prostate cancer risk. METHODS: Blood samples were collected for 637 prostate cancer cases and 244 age and race frequency matched controls. In analysis, the SRD5A2 VL and LL genotypes were combined into one group and the HSD3B2 repeat polymorphism was dichotomized into short (<283) and long (> or =283) alleles. RESULTS: The SRD5A2 V89L polymorphism was not independently associated with prostate cancer risk. Carriage of at least one HSD3B2 intron 3 intron 3 short allele was associated with a significant increased risk for prostate cancer among all subjects (OR = 2.07, 95% CI = 1.08-3.95, P = 0.03) and Caucasians (OR = 2.80, CI = 2.80-7.43, P = 0.04), but not in African Americans (OR = 1.50, CI = 0.62-3.60, P = 0.37). Stratified analyses revealed that most of the prostate cancer risk associated with the intron 3 HSD3B2 short allele was confined to the SRD5A2 89L variant subgroup and indicated that in combination these polymorphisms may be associated with increased risk of aggressive (Gleason >7) disease (Gleason >7). CONCLUSIONS: In Caucasians, the HSD3B2 (TG)n,(TA)n,(CA)n intron 3 length polymorphism is associated with both prostate cancer risk and aggressiveness and the SRD5A2 V89L polymorphism may modify the risk conferred by this polymorphism.     

Associations between polymorphisms in the steroid 5-alpha reductase type II (SRD5A2) gene and benign prostatic hyperplasia and prostate cancer

The prostate gland is an androgen-dependent, and polymorphisms in androgen synthesis gene steroid 5-alpha reductase type II (SRD5A2) may be associated with benign prostatic hyperplasia (BPH) and prostate cancer. We evaluated the association between 3 polymorphisms in the SRD5A2 gene (2 single nucleotide polymorphism: alanine-49 to threonine [A49T] and valine-89 to leucine [V89L], and a (TA)n dinucleotide repeat in the 3' untranslated region), and BPH and prostate cancer within a multiethnic population. Men between 60 and 86 years of age were recruited from annual prostate cancer screening programs and from a large urology clinic. Unconditional logistic regression was used to compute odds ratios (OR) and 95% confidence intervals (95% CI). We genotyped 606 men (412 Hispanic, 98 Caucasian, 73 African-American, and 23 Asian), of whom 100 had prostate cancer, 393 had BPH (280 symptomatic and 113 asymptomatic), and 113 had normal prostates. Overall, the V89L variant was associated with prostate cancer; the OR for men with the leucine-leucine (LL) genotype compared to men with the valine-valine (VV) genotype was 4.47 (95% CI, 1.24-16.18). This association was stronger in Hispanics (OR=7.26; 95% CI: 1.49-35.47). Although V89L was nonsignificantly associated with BPH in overall population, BPH risk increased significantly with the number of L alleles in Hispanics (P for trend=0.03). Prostate cancer and BPH were not associated with the alanine-49 to threonine single nucleotide polymorphism and the (TA)n repeat. These results suggest that the SRD5A2 gene may play an important role in both BPH and prostate cancer.     

Genome linkage screen for prostate cancer susceptibility loci: results from the Mayo Clinic Familial Prostate Cancer Study

Prostate cancer is one of the most common cancers among men and has long been recognized to occur in familial clusters. Brothers and sons of affected men have a twofold to threefold increased risk of developing prostate cancer. However, identification of genetic susceptibility loci for prostate cancer has been extremely difficult. Several putative loci identified by genetic linkage have been reported to exist on chromosomes 1 (HPC1, PCAP, and CAPB), X (HPCX), 17 (HPC2), and 20 (HPC20), with genes RNASEL (HPC1) and ELAC2 (HPC2) tentatively defined. In this study, we report our genome linkage scan in 160 prostate cancer families, using the ABI Prism Linkage Mapping Set Version 2 with 402 microsatellite markers. The most significant linkage was found for chromosome 20, with a recessive model heterogeneity LOD score (HLOD) of 4.77, and a model-free LOD score (LOD - ZLR) of 3.46 for the entire group of pedigrees. Linkage for chromosome 20 was most prominent among families with a late age of diagnosis (average age at diagnosis >/= 66 years; maximum LOD - ZLR = 2.82), with <5 affected family members (LOD - ZLR = 3.02), with presence of hereditary prostate cancer (LOD - ZLR = 2.81), or with no male-to-male transmission of disease (LOD - ZLR = 3.84). No other chromosome showed significant evidence for linkage. However, chromosomes 6 and X showed suggestive results, with maximum LOD - ZLR values of 1.38 and 1.36, respectively. Subset analyses suggest additional chromosomal regions worth further follow-up.     

Suggestive genetic linkage to chromosome 11p11.2-q12.2 in hereditary prostate cancer families with primary kidney cancer

BACKGROUND: The Seattle-based PROGRESS study was started in 1995 to ascertain hereditary prostate cancer (HPC) families for studies of genetic susceptibility. Subsequent studies by several research groups, including our own, suggest that HPC is a genetically heterogeneous disease. To be successful in mapping loci for such a complex disease, one must consider ways of grouping families into subsets that likely share the same genetic origin. Towards that end, we analyzed a genome-wide scan of HPC families with primary kidney cancer. METHODS: An 8.1 cM genome-wide scan including 441 microsatellite markers was analyzed by both parametric and non-parametric linkage approaches in fifteen HPC families with the co-occurrence of kidney cancer. RESULTS: There was no evidence for significant linkage in the initial findings. However, two regions of suggestive linkage were observed at 11q12 and 4q21, with HLOD scores of 2.59 and 2.10, respectively. The primary result on chromosome 11 was strengthened after excluding two families with members who had rare transitional cell carcinoma (TCC). Specifically, we observed a non-parametric Kong and Cox P-value of 0.004 for marker D11S1290 at 11p11.2. The 8 cM region between 11p11.2 and 11q12.2 was refined by the addition of 16 new markers. The subset of HPC families with a median age of diagnosis >65 years demonstrated the strongest evidence for linkage, with an HLOD = 2.50. The P-values associated with non-parametric analysis ranged from 0.004 to 0.05 across five contiguous markers. CONCLUSIONS: Analysis of HPC families with members diagnosed with primary renal cell carcinoma demonstrates suggestive linkage to chromosome 11p11.2-q12.2.     

Association of prostate cancer risk and aggressiveness to androgen pathway genes: SRD5A2, CYP17, and the AR

BACKGROUND: The prostate is an androgen-regulated organ and polymorphisms in genes involved in testosterone synthesis, in particular, SRD5A2 (A49T and V89L variants), CYP17 (MspAI variant), and the AR (CAG, GGC repeats), represent candidate risk factors for prostate cancer incidence and aggressiveness. METHODS: We evaluated the relationship between these five polymorphisms and prostate cancer risk in a family-based case-control study (N = 920). Cases were diagnosed at major medical institutions in Cleveland Ohio, and Detroit Michigan, and their unaffected brothers were used as controls. Associations were investigated with regard to prostate cancer risk, and clinical characteristics at diagnosis (i.e., tumor stage/grade, age, family history). RESULTS: The SRD5A2 V89L variant was associated with an increased risk of prostate cancer (OR = 1.56, P = 0.02). This association was driven primarily by men diagnosed at an earlier age (OR = 2.35, P = 0.001), or with more aggressive disease (OR = 1.63, P = 0.06). None of the other variants exhibited noteworthy associations with disease. CONCLUSIONS: These findings suggest that the SRD5A2 V89L variant may influence risk of developing prostate cancer, especially among men with a younger age of diagnosis or more aggressive disease.     

Genomic scan of 254 hereditary prostate cancer families

Hereditary prostate cancer (HPC) is a genetically heterogeneous disease, complicating efforts to map and clone susceptibility loci. We have used stratification of a large dataset of 254 HPC families in an effort to improve power to detect HPC loci and to understand what types of family features may improve locus identification. The strongest result is that of a dominant locus at 6p22.3 (heterogeneity LOD (HLOD) = 2.51), the evidence for which is increased by consideration of the age of PC onset (HLOD = 3.43 in 214 families with median age-of-onset 56-72 years) and co-occurrence of primary brain cancer (HLOD = 2.34 in 21 families) in the families. Additional regions for which we observe modest evidence for linkage include chromosome 7q and 17p. Only weak evidence of several previously implicated HPC regions is detected. These analyses support the existence of multiple HPC loci, whose presence may be best identified by analyses of large, including pooled, datasets which consider locus heterogeneity.     

Association of polymorphisms within androgen receptor, 5alpha-reductase,and PSA genes with prostate volume,clinical parameters,and endocrine status in elderly men

BACKGROUND: The aim of this study was to assess the impact of polymorphisms of three genes within the androgen pathway on prostate volume, clinical parameters, and endocrine status. METHODS: Elderly men with lower urinary tract symptoms underwent clinical and endocrine work-up. In parallel, polymorphisms within the 5alpha-reductase gene (SRD5A2 V89L and A49T), the androgen receptor gene (AR; number of CAG repeats), and the prostate specific antigen (PSA) gene (A --> G substitution at position-158) were determined by polymerase chain reaction and restriction-length polymorphism analysis by using DNA from peripheral blood. RESULTS: A total of 190 men (66.5 +/- 9.2 yr) were analyzed. The number of CAG repeats within the AR and the PSA polymorphism revealed no associations to clinical and endocrine parameters. Individuals carrying the mutated SRD5A2 A49T allele (5.3% of the total population) had larger prostates (54.1 vs. 39.3 ml), higher PSA levels (12.2 vs. 4.3 ng/ml), and a 35% reduction in prostatic stroma/epithelial cell ratio. Men with the mutated SRD5A2 V89L gene had lower testosterone levels. CONCLUSIONS: In contrast to prostate cancer, polymorphisms within AR and PSA genes do not seem to be of importance for benign prostatic hyperplasia. Polymorphisms within the 5alpha-reductase gene are interesting biomarkers for the development of benign prostatic hyperplasia and benign prostatic enlargement.     

Association of hereditary prostate cancer gene polymorphic variants with sporadic aggressive prostate carcinoma

BACKGROUND: ELAC2, MSR1, and RNASEL are candidate genes for hereditary prostate carcinoma (HPC). While, studies have demonstrated that single nucleotide polymorphisms (SNPs) in these genes are associated with sporadic disease as well as HPC, these results are often not replicated in follow-up studies. Given that the majority of patients studied had localized disease and up to 50% of localized prostate cancer is clinically insignificant, the inability to replicate the initial findings may reflect that some subjects had indolent tumors. Herein, we examine patients with metastatic disease to determine if an association exists between HPC SNPs and unambiguously significant prostate cancer. METHODS: We examined polymorphisms within ELAC2 (S217L, A541T, E622V), MSR1 (P275A, R293X, aIVS5-59c), and RNASEL (E265X, R462Q, D541E) in 150 European-Americans with metastatic prostate cancer and 170 prostate cancer-free controls using pyrosequencing assays. RESULTS: Only ELAC2 217L (37% cases vs. 29% controls (P=0.034)) and RNASEL 541E (61% cases vs. 53% controls (P=0.045)) were over-represented. Analysis of genotypes revealed that presence of the leucine ELAC2 allele (OR 1.54: 95% CI=0.99-2.41, SS vs. SL, LL) and homozygosity for the glutamic acid RNASEL allele (OR 1.68: 95% CI=1.04-2.70, EE vs. DE, DD) were associated with increased risk. Patients with both genotypes were of particularly high-risk (OR 2.66: 95% CI=1.36-5.19). CONCLUSIONS: These results suggest that, in a European-American population, ELAC2 217L and RNASEL 541E are associated with metastatic sporadic disease. ELAC2 and RNASEL SNP analysis may prove useful in determining which patients are at risk for developing clinically significant prostate carcinoma.     

Chromosome 8q24 risk variants in hereditary and non-hereditary prostate cancer patients

BACKGROUND: Multiple variants in three regions at 8q24 are consistently found to be associated with prostate cancer (PCa) risk in population-based association studies. The role that these variants may play in familial prostate cancer risk has not been extensively investigated. METHODS: We evaluated 12 SNPs at three 8q24 regions using population-based association and family-based linkage and association methods in hereditary PCa (HPC) probands and their families, non-HPC patients, and unaffected screened controls, all recruited at Johns Hopkins Hospital. RESULTS: For multiple variants in Region 1 (e.g., rs1447295) and Region 2 (e.g., rs16901979), we found statistically significantly higher frequencies of previously identified risk alleles and genotypes in HPC probands than in unaffected controls. Furthermore, in Region 2 the risk alleles were statistically significantly more frequent in HPC probands than in non-HPC patients. Family-based transmission tests found risk alleles of SNPs in Region 2, but not in Regions 1 and 3, were significantly over-transmitted to affected men in these families. We found little evidence supporting PCa linkage at 8q24 in 168 HPC families, in part explained by the observation of multiple, different risk allele-containing haplotypes segregating in the vast majority of these families. CONCLUSIONS: Our study further supports the presence of PCa susceptibility loci at 8q24, particular at Region 2, and also provides evidence that these SNPs play an important role in familial prostate cancer. Large family-based studies are needed to confirm our novel findings.     

Polymorphisms in the androgen receptor and type II 5 alpha-reductase genes and prostate cancer prognosis

BACKGROUND: Cytosine-adenine-guanine repeat length of the androgen receptor gene and the A49T and V89L polymorphisms of the 5 alpha-reductase (SRD5A2) gene have been associated with prostate cancer. METHODS: We investigated the relationship of the three genetic polymorphisms to tumor grade among 211 men who had undergone radical prostatectomy. Subjects had prostate cancer <3 cm(3) with a percentage of cancer represented by Gleason grade 4 or 5 (% Gleason grade 4/5) of either > or = 20% or < or = 5%. We also examined the association between those genetic markers and prostate specific antigen (PSA) failure among 112 subjects with > or = 20% Gleason grade 4/5. RESULTS: In cross-sectional analysis, none of the polymorphisms was a significant predictor of % Gleason grade 4/5. In longitudinal analysis, the LL genotype at the V89L site was associated with statistically significant four- to sixfold increase in PSA failure risk after adjustment for clinicopathologic variables. CONCLUSIONS: We observed poorer prognosis among men with the LL genotype at codon 89 of the SRD5A2 gene. Lack of consistency between studies must be resolved before clinical utility of this marker is established.     

Description of the International Consortium For Prostate Cancer Genetics, and failure to replicate linkage of hereditary prostate cancer to 20q13

The International Consortium for Prostate Cancer Genetics (ICPCG) is an international collaborative effort to pool pedigrees with hereditary prostate cancer (PC) in order to replicate linkage findings for PC. A strength of the ICPCG is the large number of well-characterized pedigrees, allowing linkage analyses within large subsets. Given the heterogeneity and complexity of PC, the historical difficulties of synthesizing different studies reporting positive and negative linkage replication, and the use of different statistical analysis methods and different stratification criteria, the ICPCG provides a valuable resource to evaluate linkage for hereditary PC. To date, linkage of chromosome 20 (HPC20) to hereditary PC has been one of the strongest linkage signals, yet the efforts to replicate this linkage have been limited. This paper reports a linkage analysis of chromosome 20 markers for 1,234 pedigrees with multiple cases of PC ascertained through the ICPCG, and represents the most thorough attempt to confirm or refute linkage to chromosome 20. From the original 158 Mayo pedigrees in which linkage was detected, the maximum heterogeneity LOD (HLOD) score, under a recessive model, was 2.78. In contrast, for the 1,076 pedigrees not included in the original study, the maximum HLOD score (recessive model) was 0.06. Although, a few small linkage signals for chromosome 20 were found in various strata of this pooled analysis, this large study failed to replicate linkage to HPC20. This study illustrates the value of the ICPCG family collection to evaluate reported linkage signals and suggests that the HPC20 region does not make a major contribution to PC susceptibility.     

Polymorphisms in the 5alpha reductase type 2 gene and urologic measures of BPH

BACKGROUND: The objective of the study was to examine associations between SRD5A2 polymorphisms and measures of benign prostatic hyperplasia (BPH). METHODS: Participants were 510 Caucasian men (median age 60 years), randomly selected from the Olmsted County, MN community to participate in a longitudinal study of BPH. From 1990 through 2000, biennial measurements of lower urinary tract symptom severity (assessed from the American Urological Association Symptom Index, AUASI), peak urinary flow rates (Qmax), and prostate volume were made. Genotyping of SRD5A2 V89L, A49T, and TA repeat polymorphisms were performed. RESULTS: Compared with the VV genotype, the LL genotype was associated with an enlarged prostate (Hazard ratio (HR)=1.62, 95% confidence interval (CI)=1.06, 2.43) but not with AUASI, Qmax, or PSA. The A49T and TA repeat polymorphisms were not associated with BPH. When the LL/VL, AT/TT, and TA0/TA0 genotypes were considered high risk, the number of high risk genotypes increased with increasing prostate volume (32.3, 30.7, 34.1, and 38.7, respectively, P for trend=0.04). CONCLUSIONS: These findings do not demonstrate consistent associations between SRD5A2 genotypes and BPH. However, they suggest that the associations of V89L polymorphisms and prostate volume should be investigated further.     

睾酮5-α还原酶Ⅱ基因V89L多态性与前列腺癌预后关系的研究

目的:探讨睾酮5-α还原酶Ⅱ(SRD5A2)基因V89L多态性与影响前列腺癌预后因素的关系。方法:对V89L多态性位点用Rsa-1限制性内切酶进行酶切鉴定,观察112例前列腺癌患者和89例BPH患者的V89L(VV、VL、LL)多态性分布情况的差异及其多态性与前列腺癌患者年龄、前列腺特异性抗原(PSA)、游离PSA/总PSA值(tPSA/fPSA,F/T)、Gleason评分、临床分期的关系。结果:前列腺癌组112例与BPH组89例的V89L基因频度风险无显著性差异(χ2=3.606,df=2,P=0.165)。前列腺癌组VV和VL+LL基因型与fPSA、tPSA、F/T、T分期、Gleason评分差异无显著性(P>0.05)。VV和VL+LL各评价预后指标差异无显著性(P>0.05)。分段评价PSA水平、Gleason评分、临床分期、年龄,均与两种基因型无相关性(P>0.05)。结论:V89L多态性与预后无明显关系,但是可能与前列腺癌的风险存在间接的关系。     

Allelic imbalance in hereditary and sporadic prostate cancer

BACKGROUND: In this study, we evaluate the pattern of allelic imbalance (AI) in both sporadic prostate cancer (SPC) and hereditary prostate cancer (HPC) at loci that frequently show allelic imbalance in sporadic prostate cancer, or are believed to have a putative role in the disease. METHODS: DNA obtained from 35 sporadic tumors and 46 hereditary tumors were tested for AI, by using a panel of 35 microsatellite markers. RESULTS: Chromosomal regions that display high frequencies of AI (>or=30%) in HPC include 1q, 5q, 7q, 8p, 13q, 16q, 17q, 18q, and 20q. In SPC, high frequencies of AI were found at 5q, 7q, 8p, 10q, 13q. Main differences (delta >or= 20%) in AI between HPC and SPC were at 1q, 10q, 17q, 18q, and 20q. CONCLUSION: AI at the prostate cancer susceptibility loci HPC1, PCaP, and HPC20 was seen more often in HPC compared with SPC. It appears that there are marked differences in the pattern of AI between sporadic and hereditary PCa.