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Background: Several germline single nucleotide polymorphisms (SNPs) have been consistently associated with prostate cancer (PCa) risk., Objective: To determine whether there is an improvement in PCa risk prediction by adding these SNPs to existing predictors of PCa., Design, Setting, and Participants: Subjects included men in the placebo arm of the randomized Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial in whom germline DNA was available. All men had an initial negative prostate biopsy and underwent study-mandated biopsies at 2 yr and 4 yr. Predictive performance of baseline clinical parameters and/or a genetic score based on 33 established PCa risk-associated SNPs was evaluated., Outcome Measurements and Statistical Analysis: Area under the receiver operating characteristic curves (AUC) were used to compare different models with different predictors. Net reclassification improvement (NRI) and decision curve analysis (DCA) were used to assess changes in risk prediction by adding genetic markers., Results and Limitations: Among 1654 men, genetic score was a significant predictor of positive biopsy, even after adjusting for known clinical variables and family history (p = 3.41 × 10(-8)). The AUC for the genetic score exceeded that of any other PCa predictor at 0.59. Adding the genetic score to the best clinical model improved the AUC from 0.62 to 0.66 (p<0.001), reclassified PCa risk in 33% of men (NRI: 0.10; p=0.002), resulted in higher net benefit from DCA, and decreased the number of biopsies needed to detect the same number of PCa instances. The benefit of adding the genetic score was greatest among men at intermediate risk (25th percentile to 75th percentile). Similar results were found for high-grade (Gleason score ≥ 7) PCa. A major limitation of this study was its focus on white patients only., Conclusions: Adding genetic markers to current clinical parameters may improve PCa risk prediction. The improvement is modest but may be helpful for better determining the need for repeat prostate biopsy. The clinical impact of these results requires further study., (Copyright © 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Single-nucleotide polymorphisms (SNPs) in five chromosomal regions--three at 8q24 and one each at 17q12 and 17q24.3--have been associated with prostate cancer. Each SNP has only a moderate association, but when SNPs are combined, the association may be stronger., Methods: We evaluated 16 SNPs from five chromosomal regions in a Swedish population (2893 subjects with prostate cancer and 1781 control subjects) and assessed the individual and combined association of the SNPs with prostate cancer., Results: Multiple SNPs in each of the five regions were associated with prostate cancer in single SNP analysis. When the most significant SNP from each of the five regions was selected and included in a multivariate analysis, each SNP remained significant after adjustment for other SNPs and family history. Together, the five SNPs and family history were estimated to account for 46% of the cases of prostate cancer in the Swedish men we studied. The five SNPs plus family history had a cumulative association with prostate cancer (P for trend, 3.93x10(-28)). In men who had any five or more of these factors associated with prostate cancer, the odds ratio for prostate cancer was 9.46 (P=1.29x10(-8)), as compared with men without any of the factors. The cumulative effect of these variants and family history was independent of serum levels of prostate-specific antigen at diagnosis., Conclusions: SNPs in five chromosomal regions plus a family history of prostate cancer have a cumulative and significant association with prostate cancer., (Copyright 2008 Massachusetts Medical Society.)

Background: The consistent finding of a genetic susceptibility to prostate cancer suggests that there are germline sequence variants predisposing individuals to this disease. These variants could be useful in screening and treatment., Methods: We performed an exploratory genome-wide association scan in 498 men with aggressive prostate cancer and 494 control subjects selected from a population-based case-control study in Sweden. We combined the results of this scan with those for aggressive prostate cancer from the publicly available Cancer Genetic Markers of Susceptibility (CGEMS) Study. Single-nucleotide polymorphisms (SNPs) that showed statistically significant associations with the risk of aggressive prostate cancer based on two-sided allele tests were tested for their association with aggressive prostate cancer in two independent study populations composed of individuals of European or African American descent using one-sided tests and the genetic model (dominant or additive) associated with the lowest value in the exploratory study., Results: Among the approximately 60,000 SNPs that were common to our study and CGEMS, we identified seven that had a similar (positive or negative) and statistically significant (P<.01) association with the risk of aggressive prostate cancer in both studies. Analysis of the distribution of these SNPs among 1032 prostate cancer patients and 571 control subjects of European descent indicated that one, rs1571801, located in the DAB2IP gene, which encodes a novel Ras GTPase-activating protein and putative prostate tumor suppressor, was associated with aggressive prostate cancer (one-sided P value = .004). The association was also statistically significant in an African American study population that included 210 prostate cancer patients and 346 control subjects (one-sided P value = .02)., Conclusion: A genetic variant in DAB2IP may be associated with the risk of aggressive prostate cancer and should be evaluated further.

Background: Recent studies using ROMA and Array-CGH suggest that germline copy number polymorphisms (CNPs) involving >100 kb are common in humans., Methods: In this study, we used the Affymetrix GeneChip 100K single nucleotide polymorphisms (SNP) mapping panel to further examine the type and frequency of germline CNPs in the genome. By utilizing the allele intensity data generated while genotyping approximately 116,000 SNPs among 23 subjects from 4 families, we were able to detect multiple CNPs., Results: However, in contrast to several previous studies, we found that CNPs >100 kb are rare in the genome but CNPs involving 100s-1,000s of base pairs are more common., Conclusions: We have demonstrated the utility of this approach, which has an important advantage over other methods because it is able to simultaneously assess both CNPs and SNPs, and therefore has great potential in genetic association studies of common diseases., ((c) 2006 Wiley-Liss, Inc.)

While it is widely appreciated that prostate cancers vary substantially in their propensity to progress to a life-threatening stage, the molecular events responsible for this progression have not been identified. Understanding these molecular mechanisms could provide important prognostic information relevant to more effective clinical management of this heterogeneous cancer. Hence, through genetic linkage analyses, we examined the hypothesis that the tendency to develop aggressive prostate cancer may have an important genetic component. Starting with 1,233 familial prostate cancer families with genome scan data available from the International Consortium for Prostate Cancer Genetics, we selected those that had at least three members with the phenotype of clinically aggressive prostate cancer, as defined by either high tumor grade and/or stage, resulting in 166 pedigrees (13%). Genome-wide linkage data were then pooled to perform a combined linkage analysis for these families. Linkage signals reaching a suggestive level of significance were found on chromosomes 6p22.3 (LOD = 3.0), 11q14.1-14.3 (LOD = 2.4), and 20p11.21-q11.21 (LOD = 2.5). For chromosome 11, stronger evidence of linkage (LOD = 3.3) was observed among pedigrees with an average at diagnosis of 65 years or younger. Other chromosomes that showed evidence for heterogeneity in linkage across strata were chromosome 7, with the strongest linkage signal among pedigrees without male-to-male disease transmission (7q21.11, LOD = 4.1), and chromosome 21, with the strongest linkage signal among pedigrees that had African American ancestry (21q22.13-22.3; LOD = 3.2). Our findings suggest several regions that may contain genes which, when mutated, predispose men to develop a more aggressive prostate cancer phenotype. This provides a basis for attempts to identify these genes, with potential clinical utility for men with aggressive prostate cancer and their relatives.

Although multiple recurrent chromosomal alterations have been identified in prostate cancer cells, the specific genes driving the apparent selection of these changes remain largely unknown. In part, this uncertainty is due to the limited resolution of the techniques used to detect these alterations. In this study, we applied a high-resolution genome-wide method, Affymetrix 100K SNP mapping array, to screen for somatic DNA copy number (CN) alterations among 22 pairs of samples from primary prostate cancers and matched nonmalignant tissues. We detected 355 recurrent deletions and 223 recurrent gains, many of which were novel. As expected, the sizes of novel alterations tend to be smaller. Importantly, among tumors with increasing grade, Gleason sum 6, 7, and 8, we found a significant trend of larger number of alterations in the tumors with higher grade. Overall, gains are significantly more likely to occur within genes (74%) than are deletions (49%). However, when we looked at the most frequent CN alterations, defined as those in > or =4 subjects, we observed that both gains (85%) and deletions (57%) occur preferentially within genes. An example of a novel, recurrent alteration observed in this study was a deletion between the ERG and TMPRSS2 genes on chromosome 21, presumably related to the recently identified fusion transcripts from these two genes. Results from this study provide a basis for a systematic and comprehensive cataloging of CN alterations associated with grades of prostate cancer, and the subsequent identification of specific genes that associated with initiation and progression of the disease. This article contains supplementary material available via the Internet at http://www.interscience.wiley.com/jpages/1045-2257/suppmat, ((c) 2006 Wiley-Liss, Inc.)

Background: Recently identified associations of prostate cancer risk with several genes involved in innate immunity support a role of inflammation in the etiology of prostate cancer. Considering inflammation is regulated by a complex system of gene products, we hypothesize sequence variants in many other genes of this pathway are associated with prostate cancer., Methods: We evaluated 9,275 SNPs in 1,086 genes of the inflammation pathway using a MegAllele genotyping system among 200 familial cases and 200 unaffected controls selected from a large Swedish case-control population (CAPS)., Results: We found that significantly more than the expected numbers of SNPs were significant at a nominal P-value of 0.01, 0.05, and 0.1, providing overall support for our hypothesis. The excess was largest when using a more liberal nominal P-value (0.1); we observed 992 significant SNPs compared with the 854 significant SNPs expected by chance, and this difference was significant based on a permutation test (P = 0.0025). We also began the effort of differentiating true associated SNPs by selecting a small subset of significant SNPs (N = 26) and genotyped these in an independent sample of approximately 1,900 CAPS1 subjects. We were able to confirm 3 of these 26 SNPs. It is expected that many more true associated SNPs will be confirmed among the 992 significant SNPs identified in our pathway screen., Conclusions: Our study provides the first objective support for an association between prostate cancer and multiple modest-effect genes in inflammatory pathways., ((c) 2006 Wiley-Liss, Inc.)

Background: One of the difficulties confronting genetic studies of prostate cancer is the complex and heterogeneous etiology. Given the high population frequency of lesions meeting the histological definition of prostate cancer, a significant portion of men with a positive family history may be diagnosed due to increased surveillance and associated higher likelihood of biopsy. Over diagnosis decreases power to detect genes that increase susceptibility to a clinically significant prostate cancer., Methods: We re-evaluated all 623 men with prostate cancer in our 188 hereditary prostate cancer families and identified a subset of 244 men with more aggressive disease based upon meeting at least one of the following clinical and/or pathologic criteria: tumor grade Gleason score > or = 7, tumor stage T2c or higher, pretreatment PSA > or = 20 ng/ml, rising PSA after treatment, evidence of metastasis, or death from prostate cancer., Results: Genome-wide screens were re-performed by defining men as affected only if they met the criteria for clinically significant disease. The new analyses identified stronger evidence for linkage in Xq27-28 and 22q, as well as several novel loci, including 3p and 9p., Conclusions: Although, these results need to be confirmed in independent studies, our approach represents an important step to overcome the impact of over diagnosis in genetic studies of prostate cancer. Larger studies that incorporate this approach are needed., (Copyright 2005 Wiley-Liss, Inc.)

IL1-RN is an important anti-inflammatory cytokine that modulate the inflammation response by binding to IL1 receptors, and as a consequence inhibits the action of proinflammatory cytokines IL1alpha and IL1beta. In this study, we hypothesise that sequence variants in the IL1-RN gene are associated with prostate cancer risk. The study population, a population-based case-control study in Sweden, consisted of 1383 prostate cancer case patients and 779 control subjects. We first selected 18 sequence variants covering the IL1-RN gene and genotyped these single-nucleotide polymorphisms (SNPs) in 96 control subjects. Gene-specific haplotypes of IL1-RN were constructed and four haplotype-tagging single-nucleotide polymorphisms (htSNPs) were identified (rs878972, rs315934, rs3087263 and rs315951) that could uniquely describe >95% of the haplotypes. All study subjects were genotyped for the four htSNPs. No significant difference in genotype frequencies between cases and controls were observed for any of the four SNPs based on a multiplicative genetic model. Overall there was no significant difference in haplotype frequencies between cases and controls; however, the prevalence of the most common haplotype (ATGC) was significantly higher among cases (38.7%) compared to controls (33.5%) (haplotype-specific P = 0.009). Evaluation of the prostate cancer risk associated with carrying the 'ATGC' haplotype revealed that homozygous carriers were at significantly increased risk (odds ratio (OR) = 1.6, 95% confidence interval (CI) = 1.2-2.2), compared to noncarriers, while no significant association was found among subjects heterozygous for the haplotype (OR = 1.0, 95% CI = 0.8-1.2). Restricting analyses to advanced prostate cancer strengthened the association between the 'ATGC' haplotype and disease risk (OR for homozygous carriers vs noncarriers 1.8, 95% CI = 1.3-2.5). In conclusion, the results from this study support the hypothesis that inflammation has a role of in the development of prostate cancer, but further studies are needed to identify the causal variants in this region and to elucidate the biological mechanism for this association.

Evidence of the existence of major prostate cancer (PC)-susceptibility genes has been provided by multiple segregation analyses. Although genomewide screens have been performed in over a dozen independent studies, few chromosomal regions have been consistently identified as regions of interest. One of the major difficulties is genetic heterogeneity, possibly due to multiple, incompletely penetrant PC-susceptibility genes. In this study, we explored two approaches to overcome this difficulty, in an analysis of a large number of families with PC in the International Consortium for Prostate Cancer Genetics (ICPCG). One approach was to combine linkage data from a total of 1,233 families to increase the statistical power for detecting linkage. Using parametric (dominant and recessive) and nonparametric analyses, we identified five regions with "suggestive" linkage (LOD score >1.86): 5q12, 8p21, 15q11, 17q21, and 22q12. The second approach was to focus on subsets of families that are more likely to segregate highly penetrant mutations, including families with large numbers of affected individuals or early age at diagnosis. Stronger evidence of linkage in several regions was identified, including a "significant" linkage at 22q12, with a LOD score of 3.57, and five suggestive linkages (1q25, 8q13, 13q14, 16p13, and 17q21) in 269 families with at least five affected members. In addition, four additional suggestive linkages (3p24, 5q35, 11q22, and Xq12) were found in 606 families with mean age at diagnosis of < or = 65 years. Although it is difficult to determine the true statistical significance of these findings, a conservative interpretation of these results would be that if major PC-susceptibility genes do exist, they are most likely located in the regions generating suggestive or significant linkage signals in this large study.

Background: Chronic inflammation plays an important role in several human cancers and may be involved in the etiology of prostate cancer. Toll-like receptors (TLRs) are important in the innate immune response to pathogens and in cross-talk between innate immunity and adaptive immunity. Our previous finding of an association of TLR4 gene sequence variants and prostate cancer risk provides evidence for a role of TLRs in prostate cancer. In this study, we investigated whether sequence variants in the TLR6-TLR1-TLR10 gene cluster, residing within a 54-kb region on 4p14, were associated with prostate cancer risk., Methods: We selected 32 single-nucleotide polymorphisms (SNPs) covering these three genes and genotyped these SNPs in 96 control subjects from the Cancer Prostate in Sweden (CAPS) population-based prostate cancer case-control study. Five distinct haplotype blocks were inferred at this region, and we identified 17 haplotype-tagging SNPs (htSNPs) that could uniquely describe >95% of the haplotypes. These 17 htSNPs were then genotyped in the entire CAPS study population (1383 case subjects and 780 control subjects). Odds ratios of prostate cancer for the carriers of a variant allele versus those with the wild-type allele were estimated using unconditional logistic regression., Results: The allele frequencies of 11 of the 17 SNPs were statistically significantly different between case and control subjects (P = .04-.001), with odds ratios for variant allele carriers (homozygous or heterozygous) compared with wild-type allele carriers ranging from 1.20 (95% confidence interval [CI] = 1.00 to 1.43) to 1.38 (95% CI = 1.12 to 1.70). Phylogenetic tree analyses of common haplotypes identified a clade of two evolutionarily related haplotypes that are statistically significantly associated with prostate cancer risk. These two haplotypes contain all the risk alleles of these 11 associated SNPs., Conclusion: The observed multiple associated SNPs at the TLR6-TLR1-TLR10 gene cluster were dependent and suggest the presence of a founder prostate cancer risk variant on this haplotype background. The TLR6-TLR1-TLR10 gene cluster may play a role in prostate cancer risk, although further functional studies are needed to pinpoint the disease-associated variants in this gene cluster.

To identify genes that generally increase the risk of cancer, we performed a systematic search throughout the genome in 188 families primarily ascertained for prostate cancer but which also included individuals with other cancers. We observed significant evidence for linkage between susceptibility to all cancers and markers at 3p24, with a peak HLOD of 3.08 (P=0.0002). Compared to families with less than three other cancers and prostate cancer only, evidence for linkage at this region was stronger among families with at least three other cancers. This is the first reported example of a genome-wide search for general cancer susceptibility genes among hereditary prostate cancer families.

Background: Telomerase activity is increased in most tumors. PinX1 has recently been identified as a critical component in regulating telomerase activity. The PinX1 gene is located within chromosomal region 8p22-23, a region associated with LOH and potentially linked to increased prostate cancer risk., Methods: PINX1 was re-sequenced in 159 hereditary prostate cancer (HPC) probands. Four non-synonymous coding variants were genotyped in 159 HPC families., Results: Thirty-nine polymorphisms were identified in the HPC screening panel. Ten coding polymorphisms were identified, seven (Gln50His, Leu91Met, Gln206His, Arg215Ile, Thr220Ala, Ser254Cys, and Glu414Ala) of which were non-synonymous. The most common variants Thr220Ala and Ser254Cys were not significantly over-transmitted from affected parent to affected offspring., Conclusions: Based on these results, we conclude that PINX1 is not a major factor for HPC risk.

Background: Accumulating epidemiologic and molecular evidence suggest that inflammation is an important component in the etiology of prostate cancer. Macrophage-inhibitory cytokine-1 (MIC-1), a member of the transforming growth factor beta superfamily, is thought to play an important role in inflammation by regulating macrophage activity. We examined whether sequence variants in the MIC-1 gene are associated with the risk of prostate cancer., Methods: The study population, a population-based case-control study in Sweden, consisted of 1383 prostate cancer case patients and 780 control subjects. From 94 of the control subjects, we constructed gene-specific haplotypes of MIC-1 and identified four haplotype-tagging single-nucleotide polymorphisms (SNPs): Exon1+25 (V9L), Exon1+142 (S48T), IVS1+1809, and Exon2+2423 (H6D). All study subjects were genotyped for the four SNPs, and conditional logistic regression analysis was used to estimate odds ratios (ORs) with 95% confidence intervals (CIs)., Results: A statistically significant difference (P =.006) in genotype frequency was observed for the nonsynonymous change H6D (histidine to aspartic acid at position 6) between prostate cancer patients and control subjects. Carriers of the GC genotype, which results in the H6D change, experienced a lower risk of sporadic prostate cancer (OR = 0.80, 95% CI = 0.66 to 0.97) and of familial prostate cancer (OR = 0.61, 95% CI = 0.42 to 0.89) than the CC genotype carriers. In the study population, the proportion of prostate cancer cases attributable to the CC genotype was 7.2% for sporadic cancer and 19.2% for familial cancer. None of the other SNPs or haplotypes was associated with prostate cancer., Conclusion: This study shows an association between a nonsynonymous change (H6D) in the MIC-1 gene and prostate cancer. This finding supports the hypothesis that genetic variation in the inflammatory process contributes to prostate cancer susceptibility.

Background: Prostate cancer represents a substantial public health burden worldwide. It is the second leading cause of cancer death among men in the United States. A family history of the disease is among the most well-established risk factors for prostate cancer. Efforts to localize prostate cancer susceptibility alleles by using genetic linkage analysis methods have been hindered by genetic heterogeneity, incomplete penetrance, disease phenocopies, and the lack of DNA samples from parents of individuals with late-onset prostate cancer., Methods: We performed a combined genome-wide linkage analysis among 426 families from four existing hereditary prostate cancer (HPC) study populations to systematically search for prostate cancer susceptibility genes. To decrease the degree of locus heterogeneity, we analyzed subsets of families with similar clinical and demographic characteristics. Nonparametric multipoint linkage was the primary method of analysis. Results are presented as allele-sharing logarithm of the odds (LOD) scores, and all reported P values are two-sided., Results: The strongest evidence for prostate cancer linkage was found at chromosome region 17q22 (nonparametric multipoint Kong and Cox allele-sharing LOD score = 3.16 at marker D17S787; P =.00007). Stratified analyses revealed several additional chromosomal regions that are likely to segregate prostate cancer susceptibility genes among specific subsets of HPC families, including 15q11 among families with late-onset disease (allele-sharing LOD = 5.57 at marker D15S128; P<.00001) and 4q35 among families with four or more affected family members (allele-sharing LOD = 3.10 at marker D4S1615; P =.00008)., Conclusion: Fine mapping studies to facilitate identification of prostate cancer susceptibility genes in these linked regions are warranted.

The tumor suppressor functions of PTEN and CDKN1B have been extensively characterized. Recent data from mouse models suggest that, for some organs, the combined action of both PTEN and CDKN1B has a stronger tumor suppressor function than each alone; for the prostate, heterozygous knockout of both genes leads to 100% penetrance for prostate cancer. To assess whether such an interaction contributes to an increased risk of prostate cancer in humans, we performed a series of epistatic PTEN and CDKN1B interaction analyses in a collection of 188 high-risk hereditary prostate cancer families. Two different analytical approaches were performed; a nonparametric linkage (NPL) regression analysis that simultaneously models allele sharing at these two regions in all families, and an ordered subset analysis (OSA) that assesses linkage evidence at a target region in a subset of families based on the magnitude of allele sharing at the reference region. The strongest evidence of interaction effect was observed at 10q23-24 and 12p11-13 from both the NPL regression analysis (P = 0.0002) in all families and the OSA analyses in subsets of families. A LOD-delta of 3.15 (P = 0.01) was observed at 10q23-24 among 54 families with the highest NPL scores at 12p11-13, and a LOD-delta of 2.63 (P = 0.02) was observed at 12p11-13 among 34 families with the highest NPL scores at 10q23-24. The evidence for the interaction was stronger when using additional fine-mapping markers in the PTEN (10q23) and CDKN1B (12p13) regions. Our data are consistent with epistatic interactions between the PTEN and CDKN1B genes affecting risk for prostate cancer and demonstrate the utility of modeling epistatic effects in linkage analysis to detect susceptibility genes of complex diseases., (Copyright 2004 Springer-Verlag)

Background: The macrophage scavenger receptor 1 (MSR1) gene on chromosome 8p22 was recently reported as a candidate gene for hereditary prostate cancer (HPC). Here, we further elucidate the role of MSR1 in both Swedish families with HPC and in a cohort of unselected prostate cancer., Methods: DNA samples from 83 Swedish HPC families and 215 unselected population based cases of prostate cancer as well as 425 age-matched controls were genotyped., Results: A total of 18 variants were identified, including 2 exonic, 7 intronic changes, and 9 changes in the 5'- or 3'-uncoding region. Of the two exonic changes, one previously reported truncation mutation was identified, a R293X nonsense mutation. This mutation was found in 2 of the 83 (2.4%) HPC families. The R293X mutation was found more frequently in men with PC (4.9%) than in unaffected men (2.7%), consistent with previous published results, however our results were not significant (P = 0.16). To additionally test for potential association of common sequence variants and increased risk for the disease, five common polymorphisms (PRO3, INDEL1, IVS5-57, P275A, INDEL7) were genotyped in the group of 215 prostate cancer cases and 425 age-matched controls. No association between any of the five common sequence variants and prostate cancer were found., Conclusion: Our results suggest that mutations in MSR1 gene might play a role in prostate cancer susceptibility, particularly the R293X mutation. This study warrants further investigations of the role of MSR1 in prostate cancer etiology., (Copyright 2004 Wiley-Liss, Inc.)

Inflammation has been implicated as an etiological factor in several human cancers. Growing evidence suggests that chronic inflammation may also play a role in the etiology of prostate cancer. Considering that genetic susceptibility is a major risk factor for this disease, we hypothesize that sequence variants in genes that regulate inflammation may modify individual susceptibility to prostate cancer. The lipopolysaccharide receptor Toll-like receptor 4 (TLR4) is a central player in the signaling pathways of the innate immune response to infection by Gram-negative bacteria and is an important candidate inflammatory gene. We performed a systematic genetic analysis of TLR4 sequence variants by evaluating eight single-nucleotide polymorphisms that span the entire gene among 1383 newly diagnosed prostate cancer patients and 780 age- and residence-matched controls in Sweden. We found an association between a sequence variant (11381G/C) in the 3'-untranslated region of the TLR4 gene and prostate cancer risk. The frequency of the variant genotypes (CG or CC) was significantly higher in the patients (24.1%) than in the controls (19.7%; P = 0.02). The frequency of risk genotypes among patients diagnosed before the age of 65 years was even higher (26.3%). Compared with men who had the wild-type genotype of this single-nucleotide polymorphism (GG), those with GC or CC genotypes had a 26% increased risk for prostate cancer (odds ratio, 1.26; 95% confidence interval, 1.01-1.57) and 39% increased risk increased risk for early onset prostate cancer (before age 65 years; odds ratio, 1.39; 95% confidence interval, 1.02-1.91). The risk attributable to this variant for prostate cancer in Sweden was estimated to be 4.9%. Although the biological mechanism of the observed association remains to be elucidated, our finding supports a role for a bacteria-associated response pathway, possibly acting via inflammation, in the development of prostate cancer.

The loss of cell cycle control is believed to be an important mechanism in the promotion of carcinogenesis. CDKN1B (p27) belongs to the Cip/Kip family and functions as an important cell cycle gatekeeper. Several lines of evidence from clinical studies and laboratory experiments demonstrate that CDKN1B is an important tumor suppressor gene in prostate cancer etiology. In addition, a case-control study has shown that the 326T/G (V109G) polymorphism in CDKN1B is associated with advanced prostate cancer. In light of the evidence for linkage between the chromosomal location of the CDKN1B gene (12p13) and prostate cancer susceptibility in several hereditary prostate cancer (HPC) populations, we hypothesized that sequence variants of CDKN1B play a role in HPC. To test this hypothesis, we first resequenced this gene in 96 HPC probands to identify germ-line mutations and sequence variants. We then genotyped the identified sequence variants among all family members of 188 HPC families and tested for their cosegregation with prostate cancer. In total, 10 sequence variants were identified, including three nonsynonymous changes. A family-based test, which is free from the effects of population stratification, revealed a significant association between single nucleotide polymorphism (SNP) -79C/T and prostate cancer (with a nominal P of 0.0005). The C allele of -79C/T was overtransmitted from parents to their affected offspring. Evidence for this association was primarily contributed by affected offspring whose age at diagnosis was <65 years. Together with the previous association study in a sporadic prostate cancer population, our new findings additionally suggest that germ-line variants of this gene play a role in prostate cancer susceptibility.

Background: Although the subject of intensive study, the genetic influences responsible for familial clustering of prostate cancer remain largely unidentified. Genome-wide scans for linkage in prostate cancer families can be used to systematically search for genes capable of affecting risk for the disease., Methods: All available family members from 188 families, each having at least three first-degree relatives affected with prostate cancer, were genotyped at 406 markers distributed across the genome at average intervals of less than 10 cM. Genotype data was analyzed using primarily a non-parametric, multipoint approach, although parametric analyses were performed as well., Results: The strongest evidence for linkage was observed at D4S1615, at 4q21 (LOD of 2.8, P = 0.0002). Two other regions had LOD scores over 2.0: at 9q34 (marker D9S1826, LOD = 2.17, P = 0.0008) and at 2q23 (marker D2S151, LOD = 2.03, P = 0.001). An additional 12 regions had LOD scores over 1.0, including markers at 1q24-25 and 7q22 having scores >1.6. Stratifying the linkage results by age of diagnosis indicated that the linkages to chromosomes 2 and 4 were strongest in families with early and late ages of diagnosis, respectively., Conclusions: Our data implicate several new loci as harboring prostate cancer susceptibility genes, and provide confirmatory evidence of linkage at several loci identified previously in other genome-wide scans, including the three regions (4q21, 9q34, and 2q23) with strongest evidence for prostate cancer linkage. These data also emphasize the need to combine linkage data from large numbers of prostate cancer families in efforts to effectively address the extensive heterogeneity that characterizes genetic aspects of this disease., (Copyright 2003 Wiley-Liss, Inc.)

Because androgens likely play a key role in prostate growth and prostate cancer development, variants of genes involved in androgen biosynthesis may be related to prostate cancer risk. The enzyme P450c17alpha, encoded by the CYP17 gene, catalyzes the conversion of progesterone and pregnenolone into precursors of potent androgens. In the 5' promoter region of the CYP17 gene, a T (A1 allele) to C substitution (A2 allele) has been hypothesized to increase CYP17 gene expression, resulting in higher levels of androgens. To investigate a possible role of CYP17 in prostate diseases, we evaluated the risk of prostate cancer and benign prostatic hyperplasia (BPH) in relation to variation in CYP17 genotype in a population-based case-control study conducted in Shanghai, China. The study included 174 prostate cancer cases, 182 BPH cases and 274 population controls. We observed no statistically significant overall associations of CYP17 genotypes with prostate cancer risk, although associations of the A1/A1 (odds ratio (OR) =1.42, 95% confidence interval (CI) 0.83-2.48) and A1/A2 (OR 1.41, 95% CI 0.91-2.17) genotypes with prostate cancer were suggested. A similar association of the A1/A1 genotype with BPH was suggested. We found no associations of CYP17 genotypes with serum sex hormone levels or other biomarkers after correction for multiple comparisons. Large population-based studies are needed to clarify whether CYP17 plays a role in prostate cancer risk and whether genotype effects vary in different racial/ethnic and other subgroups., (Copyright 2003 Wiley-Liss, Inc.)

CYP1B1 has been evaluated as a candidate gene for various cancers because of its function in activating environmental procarcinogens and catalysing the conversion of oestrogens to genotoxic catechol oestrogens. To test the hypothesis that genetic polymorphisms in the CYP1B1 gene may associate with the risk for prostate cancer (CaP), we compared the allele, genotype, and haplotype frequencies of 13 single nucleotide polymorphisms (SNPs) of CYP1B1 among 159 hereditary prostate cancer (HPC) probands, 245 sporadic CaP cases, and 222 unaffected men. When each of the SNPs was analysed separately, marginally significant differences were observed for allele frequencies between sporadic cases and controls for three consecutive SNPs (-1001C/T, -263G/A, and -13C/T, P=0.04-0.07). Similarly, marginally significant differences between sporadic cases and controls in the frequency of variant allele carriers were observed for five consecutive SNPs (-1001C/T, -263G/A, -13C/T, +142C/G, and +355G/T, P=0.02-0.08). Interestingly, when the combination of these five SNPs was analysed using a haplotype approach, a larger difference was found (P=0.009). One frequent haplotype (C-G-C-C-G of -1001C/T, -263G/A, -13C/T, +142C/G, and +355G/T) was associated with an increased risk for CaP, while the other frequent haplotype (T-A-T-G-T) was associated with a decreased risk for CaP. These findings suggest that genetic polymorphisms in CYP1B1 may modify the risk for CaP.

CYP1A1 is likely to play an important role in the etiology of CaP through its function in activating environmental procarcinogens and catalyzing the oxidative metabolites of estrogens. To test the hypothesis that genetic polymorphisms in the CYP1A1 gene may be associated with the risk for CaP, we compared the allele, genotype and haplotype frequencies of 3 SNPs (3801T>C, 2455A>G and 2453C>A) of CYP1A1 among 159 HPC probands, 245 sporadic CaP cases and 222 unaffected men. Two SNPs (3801T>C and 2455A>G) were each individually associated with CaP risk when the allele and genotype frequencies were compared between CaP patients and unaffected controls. Furthermore, a combined SNP analysis using a haplotype approach revealed an even stronger association in Caucasians. Specifically, 4 major haplotypes (T-A-C, C-A-C, C-G-C and T-A-A) accounted for 99.8% of all observed haplotypes. These 4 haplotypes correspond to the previously described nomenclature (CYP1A1*1A, CYP1A1*2A, CYP1A1*2B and CYP1A1*4). The frequencies of these 4 haplotypes were significantly different among CaP patients and controls. The haplotype T-A-C (CYP1A1*1A) was significantly associated with increased risk for CaP, and the haplotype C-A-C (CYP1A1*2A) was significantly associated with decreased risk for CaP. These findings suggest that genetic polymorphisms in CYP1A1 may modify the risk for CaP., (Copyright 2003 Wiley-Liss, Inc.)

A gene or genes on chromosome 8p22-23 have been implicated in prostate carcinogenesis by the observation of frequent deletions of this region in prostate cancer cells. More recently, two genetic linkage studies in hereditary prostate cancer (HPC) families suggest that germline variation in a gene in this region may influence prostate cancer susceptibility as well. DLC1 (deleted in liver cancer), a gene in this interval, has been proposed as a candidate tumor suppressor gene because of its homology (86% similarity) with rat p122 RhoGAP, which catalyzes the conversion of active GTP-bound rho complex to the inactive GDP-bound form, and thus suppresses Ras-mediated oncogenic transformation. A missense mutation and three intronic insertions/deletions in 126 primary colorectal tumors have been previously identified. However, there are no reports of DLC1 mutation screening in prostate tumors or in germ line DNA of prostate cancer patients. In this study, we report the results of the first mutation screen and association study of DLC1 in genomic DNA samples from hereditary and sporadic prostate cancer patients. The PCR products in the 5' UTR, all 14 exons, exon-intron junctions, and 3' UTR were directly sequenced in 159 HPC probands. Eight exonic nucleotide polymorphisms (SNPs) were identified, only one of which resulted in an amino acid change. Twenty-three other SNPs were identified in intronic regions. Seven informative SNPs that spanned the complete DLC1 gene were genotyped in an additional 249 sporadic cases and 222 unaffected controls. No significant difference in the allele and genotype frequencies were observed among HPC probands, sporadic cases, and unaffected controls. These results suggest that DLC1 is unlikely to play an important role in prostate cancer susceptibility.

Background: Recent evidence suggests that genetic variation in the promoter of the prostate-specific antigen (PSA) gene may contribute to individual variation in serum PSA levels. However, polymorphisms associated with variations in PSA levels have not been identified., Methods: We used the polymerase chain reaction to amplify the promoter region of the PSA genes (nucleotide positions -3873 to -5749 with respect to the start of transcription) of 409 healthy white men at risk for lung disease. Polymerase chain reaction products were sequenced to identify polymorphisms in the PSA gene promoter and to genotype the men for common single nucleotide polymorphisms (SNPs) and were cloned into luciferase reporter constructs to assay PSA promoter activity in human LNCaP prostate cancer cells. Analysis of variance was used to test the association of polymorphism frequencies with mean serum PSA levels. All statistical tests were two-sided., Results: The -4643G/A SNP (G allele) had a 21.2% prevalence and was associated with increases in serum PSA levels (P =.017) and PSA promoter activity (P<.001). The -5412C/T SNP (C allele) had a 22.0% prevalence and was associated with an increase in serum PSA levels (P =.0015). The -5429T/G SNP (G allele) had a 23.0% prevalence, was associated with an increase in serum PSA levels (P =.021), and was in linkage disequilibrium with the -5412C/T SNP. The promoter activity of the -5412 C/-5429 G haplotype was higher than that of the -5412 T/-5429 T haplotype (P<.001)., Conclusions: Genetic variations in the PSA promoter are associated with serum PSA levels in men without prostatic disease. PSA promoter genotype information may help to refine models of PSA cutoff values.

Both rare germ-line mutations and common sequence variants of the macrophage scavenger receptor 1 (MSR1) gene have recently been implicated as potential prostate cancer susceptibility factors. However, existing studies are limited by the referral-based nature of samples and a paucity of African-American participants. In this context, we evaluated the association of germ-line mutations and common MSR1 sequence variants with prostate cancer risk in a case control study of a community-based sample of 134 African-American men with prostate cancer and 340 unaffected controls. In our sample, the rare Asp174Tyr missense change was identified nearly twice as frequently in men with prostate cancer (6.8%) compared with unaffected controls (3.6%; P = 0.14). Moreover, significantly different allele frequencies between cases and controls were observed for one of the sequence variants, IVS5-59 (P = 0.02). Taken together, our results provide some additional support for the hypothesis that selected, rare MSR1 mutations are associated with increased prostate cancer susceptibility among African-American men.

Background: The 5 alpha-reductase type II (SRD5A2) catalyzes the conversion of testosterone into the more potent androgen, dihydrotestosterone (DHT), and is thus believed to be the key enzyme for the control of intracellular DHT level in the prostate. Several single nucleotide polymorphisms (SNPs) in the SRD5A2 gene have been found to alter enzymatic activities and were associated with prostate cancer risk or clinical features in several case-control studies. However, the role of SRD5A2 sequence variants in the susceptibility to hereditary prostate cancer (HPC) has not been evaluated to date., Methods: Three SNPs in the SRD5A2 gene (A49T, V89L, and C682G) and two microsatellite markers near SRD5A2 were genotyped in 159 HPC families to assess their linkage to prostate cancer. In addition, the three SNPs were also genotyped in 245 sporadic cases and 222 unaffected controls to assess their association with hereditary and sporadic prostate cancer., Results: Weak evidence for linkage in the SRD5A2 chromosomal region was observed in the 159 HPC families (HLOD = 0.87, P = 0.04). Stronger evidence for linkage was observed in Caucasian families (HLOD = 1.10, P = 0.02). When stratified by the SNP A49T, no significant evidence for linkage was observed in families with or without the "T" allele. Similarly, family-based association tests failed to observe significant over-transmission of any risk alleles of SNPs A49T, V89L, and C682G to affected offspring. Finally, no significant differences in the distributions of SNPs A49T, V89L, and C682G were found among the HPC probands, sporadic cases, and controls., Conclusions: Polymorphisms of SRD5A2 are unlikely to significantly increase susceptibility to hereditary or sporadic prostate cancer in the study populations., (Copyright 2003 Wiley-Liss, Inc.)

Rare germline mutations of macrophage scavenger receptor 1 (MSR1) gene were reported to be associated with prostate cancer risk in families with hereditary prostate cancer (HPC) and in patients with non-HPC (Xu et al. 2002). To further evaluate the role of MSR1 in prostate cancer susceptibility, at Johns Hopkins Hospital, we studied five common variants of MSR1 in 301 patients with non-HPC who underwent prostate cancer treatment and in 250 control subjects who participated in prostate cancer-screening programs and had normal digital rectal examination and PSA levels (<4 ng/ml). Significantly different allele frequencies between case subjects and control subjects were observed for each of the five variants (P value range.01-.04). Haplotype analyses provided consistent findings, with a significant difference in the haplotype frequencies from a global score test (P=.01). Because the haplotype that is associated with the increased risk for prostate cancer did not harbor any of the known rare mutations, it appears that the observed association of common variants and prostate cancer risk are independent of the effect of the known rare mutations. These results consistently suggest that MSR1 may play an important role in prostate carcinogenesis.

The enzyme alpha-methylacyl-CoA racemase (AMACR) plays an important role in peroxisomal beta-oxidation of branched-chain fatty acid and therefore is relevant to carcinogenesis. The involvement of AMACR in prostate cancer (CaP) is implicated by the recent observation that expression of AMACR is consistently and extensively up-regulated in CaP. This observation is of particular interest, given previous findings from epidemiological studies that red meat and dairy products, major sources of branched-chain fatty acid, are associated with CaP risk and from linkage studies that the AMACR gene region at 5p13 is linked to a CaP susceptibility gene. In this study, we hypothesize that sequence variants in AMACR may alter the risk for CaP. To test this hypothesis, we sequenced all five exons, exon-intron junctions, the promoter region, and 3'-untranslated region of AMACR in germ-line DNA samples of 96 probands from hereditary CaP (HPC) families. Seventeen sequence variants, including five novel (R118Q, V185A, P238S, Q239H, and L250R) and five known (M9V, S52P, D175G, S201L, and K277E) missense changes, were identified. Six of these variants are at conserved residues among the rat and mouse AMACR. Eleven of these single nucleotide polymorphisms were genotyped in a total of 159 HPC probands, 245 sporadic cases, and 211 unaffected controls to assess their association with CaP risk. Significantly different genotype frequencies between HPC probands and unaffected controls were found for several missense changes, including M9V (P = 0.03), G1175D (P = 0.02), S291L (P = 0.02), and K277E (P = 0.02). Haplotype analysis provided stronger evidence for association (P = 0.001). Furthermore, the AMACR sequence variants strongly cosegregate with CaP in HPC families (log of odds = 3.78; P = 0.00006), especially in the subset of families whose probands carry the "A-A" haplotype of M9V and D175G (log of odds = 4.34; P = 0.000008). These results suggest that sequence variants in AMACR may be associated with CaP risk.

Background: 1,25-dihydroxyvitamin D(3) has been shown to have antiproliferative properties on normal and neoplastic prostatic cells. 25-hydroxyvitamin D(3) 1-alpha-hydroxylase, the enzyme that catalyzes the final step of vitamin D synthesis, converting 25-hydroxyvitamin D(3) to 1,25-dihydroxyvitamin D(3), is expressed in the prostate., Methods: The human 25-hydroxyvitamin D(3) 1-alpha-hydroxylase gene (CYP27B1) was resequenced in a case/control panel consisting of 64 individuals (48 Caucasians and 16 African Americans), with equal numbers of hereditary prostate cancer cases, sporadic cases, and unaffected controls. Three frequent single nucleotide polymorphisms (SNPs) were genotyped in 245 prostate cancer cases and 222 controls., Results: Six noncoding SNPs were identified in the CYP27B1 gene. No significant difference was found in allele and genotype frequencies between sporadic cases and unaffected controls for the three genotyped SNPs., Conclusion: This study suggests that the CYP27B1 gene does not play a major role as a prostate cancer susceptibility gene., (Copyright 2002 Wiley-Liss, Inc.)

Deletions on human chromosome 8p22-23 in prostate cancer cells and linkage studies in families affected with hereditary prostate cancer (HPC) have implicated this region in the development of prostate cancer. The macrophage scavenger receptor 1 gene (MSR1, also known as SR-A) is located at 8p22 and functions in several processes proposed to be relevant to prostate carcinogenesis. Here we report the results of genetic analyses that indicate that mutations in MSR1 may be associated with risk of prostate cancer. Among families affected with HPC, we identified six rare missense mutations and one nonsense mutation in MSR1. A family-based linkage and association test indicated that these mutations co-segregate with prostate cancer (P = 0.0007). In addition, among men of European descent, MSR1 mutations were detected in 4.4% of individuals affected with non-HPC as compared with 0.8% of unaffected men (P = 0.009). Among African American men, these values were 12.5% and 1.8%, respectively (P = 0.01). These results show that MSR1 may be important in susceptibility to prostate cancer in men of both African American and European descent.

The 8p22 through p23 region has been identified as a potential site for genes associated with prostate cancer. The gene LZTS1 has been mapped to the 8p22 through p23 region and identified as a potential tumor suppressor based on loss of heterozygosity studies using primary esophageal tumors. Sequence analysis of mRNA from various tumors has revealed multiple mutations and aberrant mRNA transcripts. The most recent report associates LZTS1 function with stabilization of p34(cdc2) during the late S-G2/M stage of mitosis, affecting normal cell growth. In this study, a detailed DNA sequence analysis of LZTS1 was performed in a screening panel consisting of sporadic and hereditary prostate cancer (HPC) cases and unaffected controls. Twenty-four SNP, 15 of which were novel, were identified in germline DNA. Four coding SNP were identified. Eleven informative SNP were genotyped in 159 HPC probands, 245 sporadic prostate cancer cases, and 222 unaffected controls. Four of these SNP were statistically significant for association with prostate cancer (P < or = 0.04). These results add evidence supporting a role of LZTS1 in prostate cancer risk.

Testing for serum prostate-specific antigen (PSA) levels has been widely used to screen for prostate cancer. However, PSA testing has low specificity and sensitivity because PSA is not prostate cancer-specific. PSA is encoded by the APS gene, and the expression of this gene is regulated by androgens. W. Xue et al. Cancer Res., 60: 839-841, 2000 reported recently that serum PSA levels are associated with a G/A polymorphism at androgen responsive element 1 (ARE1) of APS and/or the CAG repeats in exon 1 of the androgen receptor (AR) gene. This result, if confirmed, may significantly increase the specificity and sensitivity of PSA testing by incorporating genotype-specific thresholds. In this study, we tested for the association between serum PSA levels and these single nucleotide polymorphisms (SNPs) in a large sample of 518 men. For the AR gene, we observed slightly (but not statistically significant) higher mean serum PSA levels in men with shorter CAG repeats (

8-Hydroxyguanine is a mutagenic base lesion produced by reactive oxygen species. The hOGG1 gene encodes a DNA glycosylase/AP lyase that can suppress the mutagenic effects of 8-hydroxyguanine by catalyzing its removal from oxidized DNA. A population-based (245 cases and 222 controls) and family-based (159 hereditary prostate cancer families) association study was performed to test the hypothesis that sequence variants of hOGG1 increase susceptibility to prostate cancer. We found that the genotype frequency of two sequence variants (11657A/G and Ser326Cys) was significantly different between cases and controls. The association with 11657A/G is confirmed and strengthened by our family-based association study. These results suggest that sequence variants in this gene are associated with prostate cancer risk, presumably through defective DNA repair function of hOGG1.

3beta-hydroxysteroid dehydrogenases (HSD3Bs), encoded by the HSD3B gene family at 1p13, have long been hypothesized to have a major role in prostate cancer susceptibility. The recent reports of a prostate cancer linkage at 1p13 provided additional evidence that HSD3B genes may be prostate cancer susceptibility genes. To evaluate the possible role of HSD3B genes in prostate cancer, we screened a panel of DNA samples collected from 96 men with or without prostate cancer for sequence variants in the putative promoter region, exons, exon-intron junctions, and 3'-untranslated region of HSD3B1 and HSD3B2 genes by direct sequencing. Eleven single nucleotide polymorphisms (SNPs) were identified, four of which, including a missense change (B1-N367T), were informative. These four SNPs were further genotyped in a total of 159 hereditary prostate cancer probands, 245 sporadic prostate cancer cases, and 222 unaffected controls. Although a weak association between prostate cancer risk and a missense SNP (B1-N367T) was found, stronger evidence for association was found when the joint effect of the two genes was considered. Men with the variant genotypes at either B1-N367T or B2-c7519g had a significantly higher risk to develop prostate cancer, especially the hereditary type of prostate cancer. Most importantly, the subset of hereditary prostate cancer probands, whose families provided evidence for linkage at 1p13, predominantly contributed to the observed association. Additional studies are warranted to confirm these findings.

Androgen receptor (AR) has long been hypothesized to play an important role in prostate cancer etiology. Two trinucleotide repeat polymorphisms (CAG and GGC repeats in exon 1 of the AR gene) have been investigated as risk factors for prostate cancer in several studies. However, the results are inconclusive, probably because of the variations of study designs, characteristics of study samples, and choices of analytical methods. In this study, we evaluated evidence for linkage and association between the two AR repeats and prostate cancer by using the following comprehensive approaches: (1) a combination of linkage and association studies, (2) a test for linkage by parametric analysis and the male-limited X-linked transmission/disequilibrium test (XLRC-TDT), (3) a test for association by using both population-based and family-based tests, and (4) a study of both hereditary and sporadic cases. A positive but weak linkage score (HLOD=0.49, P=0.12) was identified in the AR region by parametric analysis; however, stronger evidence for linkage in the region, especially at the GGC locus, was observed in the subset of families whose proband had < or = 16 GGC repeats (HLOD=0.70, P=0.07) or by using XLRC-TDT ( z'=2.65, P=0.008). Significantly increased frequencies of the < or = 16 GGC repeat alleles in 159 independent hereditary cases (71%) and 245 sporadic cases (68%) cases compared with 211 controls (59%) suggested that GGC repeats were associated with prostate cancer ( P=0.02). Evidence for the association between the < or = 16 GGC repeats and prostate cancer risk was stronger with XLRC-TDT ( z'=2.66, P=0.007). No evidence for association between the CAG repeats and prostate cancer risk was observed. The consistent results from both linkage and association studies strongly implicate the GGC repeats in the AR as a prostate cancer susceptibility gene. Further studies on this polymorphism in other independent data sets and functional analysis of the GGC repeat length on AR activity are warranted.

Androgens are essential for prostate development, growth and maintenance and the association between androgen levels and prostate cancer is well established. Since the CYP17 gene encodes the enzyme cytochrome P450c17alpha, which mediates 17alpha-hydroxylase and 17,20-lyase activities in the androgen biosynthesis pathway, sequence variations in the gene and association with increased risk to prostate cancer has been studied. In particular, several groups have studied the association between a polymorphism in the 5' promoter region and prostate cancer using a population-based association approach. However, the results from these studies were inconclusive. To further study this polymorphism and its possible role in hereditary prostate cancer (HPC), we performed a genetic linkage analysis and family-based association analysis in 159 families, each of which contains at least 3 first-degree relatives with prostate cancer. In addition, we performed a population-based association analysis to compare the risk of this polymorphism to hereditary and sporadic prostate cancer in 159 HPC probands, 249 sporadic prostate cancer patients and 211 unaffected control subjects. Evidence for linkage at the CYP17 gene region was found in the total 159 HPC families (LOD = 1.3, p = 0.01, at marker D10S222). However, family-based association tests did not provide evidence for overtransmission of either allele of the CYP17 polymorphism to affected individuals in the HPC families. The allele and genotype frequencies of the polymorphism were not statistically different among the HPC probands, sporadic cases and unaffected control subjects. In conclusion, our results suggest that the CYP17 gene or other genes in the region may increase the susceptibility to prostate cancer in men; however, the polymorphism in the 5' promoter region has a minor role if any in increasing prostate cancer susceptibility in our study sample., (Copyright 2001 Wiley-Liss, Inc.)

Multiple lines of evidence have implicated the short arm of chromosome 8 as harboring genes important in prostate carcinogenesis. Although most of this evidence comes from the identification of frequent somatic alterations of 8p loci in prostate cancer cells (e.g., loss of heterozygosity), studies have also suggested a role for 8p genes in mediation of inherited susceptibility to prostate cancer. To further examine this latter possibility, we performed linkage analyses, in 159 pedigrees affected by hereditary prostate cancer (HPC), using 24 markers on the short arm of chromosome 8. In the complete set of families, evidence for prostate cancer linkage was found at 8p22-23, with a peak HLOD of 1.84 (P=.004), and an estimate of the proportion of families linked (alpha) of 0.14, at D8S1130. In the 79 families with average age at diagnosis >65 years, an allele-sharing LOD score of 2.64 (P=.0005) was observed, and six markers spanning a distance of 10 cM had LOD scores >2.0. Interestingly, the small number of Ashkenazi Jewish pedigrees (n=11) analyzed in this study contributed disproportionately to this linkage. Mutation screening in HPC probands and association analyses in case subjects (a group that includes HPC probands and unrelated case subjects) and unaffected control subjects were carried out for the putative prostate cancer-susceptibility gene, PG1, previously localized to the 8p22-23 region. No statistical differences in the allele, genotype, or haplotype frequencies of the SNPs or other sequence variants in the PG1 gene were observed between case and control subjects. However, case subjects demonstrated a trend toward higher homozygous rates of less-frequent alleles in all three PG1 SNPs, and overtransmission of a PG1 variant to case subjects was observed. In summary, these results provide evidence for the existence of a prostate cancer-susceptibility gene at 8p22-23. Evaluation of the PG1 gene and other candidate genes in this area appears warranted.

Prostate cancer is the most common malignancy diagnosed in men in the US. Genetic susceptibility to prostate cancer has been well documented. A region at chromosome 20q13 (HPC20) has been reported to be linked to a prostate cancer susceptibility gene. To confirm this finding, we genotyped 16 markers spanning approximately 95 cM on chromosome 20 in 159 hereditary prostate cancer (HPC) families. Positive (but not statistically significant) linkage scores were observed from 20pter to 20q11, with the highest non-parametric linkage (NPL) score for the complete dataset of 1.02 (P=0.15) being observed at D20S195 at 20q11. Evidence for linkage from parametric analyses with a dominant or a recessive model was weak. Interestingly, consistent with the original findings of linkage to 20 g higher linkage scores were observed in the subsets of families with a later age at diagnosis (> or =65 years; n=80, NPL=1.94, P=0.029 at D20S186), fewer than five affected family members (n=69, NPL=1.74, P=0.037 at D20S889), or without male-to-male disease transmission (n=60, NPL=1.01, P=0.15 at D20S117). The region with positive linkage scores spanned approximately 60 cM from 20pter to 20q11 in these subsets of families. Our results are consistent with a prostate cancer susceptibility locus on chromosome 20.

Three prostate cancer susceptibility genes have been reported to be linked to different regions on chromosome 1: HPC1 at 1q24-25, PCAP at 1q42-43, and CAPB at 1p36. Replication studies analyzing each of these regions have yielded inconsistent results. To evaluate linkage across this chromosome systematically, we performed multipoint linkage analyses with 50 microsatellite markers spanning chromosome 1 in 159 hereditary prostate cancer families (HPC), including 79 families analyzed in the original report describing HPC1 linkage. The highest lod scores for the complete dataset of 159 families were observed at 1q24-25 at which the parametric lod score assuming heterogeneity (hlod) was 2.54 (P=0.0006) with an allele sharing lod of 2.34 (P=0.001) at marker D1S413, although only weak evidence was observed in the 80 families not previously analyzed for this region (hlod=0.44, P=0.14, and allele sharing lod=0.67, P=0.08). In the complete data set, the evidence for linkage across this region was very broad, with allele sharing lod scores greater than 0.5 extending approximately 100 cM from 1p13 to 1q32, possibly indicating the presence of multiple susceptibility genes. Elsewhere on chromosome 1, some evidence of linkage was observed at 1q42-43, with a peak allele sharing lod of 0.56 (P=0.11) and hlod of 0.24 (P=0.25) at D1S235. For analysis of the CAPB locus at 1p36, we focused on six HPC families in our collection with a history of primary brain cancer; four of these families had positive linkage results at 1p36, with a peak allele sharing lod of 0.61 (P=0.09) and hlod of 0.39 (P=0.16) at D1S407 in all six families. These results are consistent with the heterogeneous nature of hereditary prostate cancer, and the existence of multiple loci on chromosome 1 for this disease.

To investigate the relationship between HPC2/ELAC2 and prostate cancer risk, we performed the following analyses: (1) a linkage study of six markers in and around the HPC2/ELAC2 gene at 17p11 in 159 pedigrees with hereditary prostate cancer (HPC); (2) a mutation-screening analysis of all coding exons of the gene in 93 probands with HPC; (3) family-based and population-based association study of common HPC2/ELAC2 missense variants in 159 probands with HPC, 249 patients with sporadic prostate cancer, and 222 unaffected male control subjects. No evidence for linkage was found in the total sample, nor in any subset of pedigrees based on characteristics that included age at onset, number of affected members, male-to-male disease transmission, or race. Furthermore, only the two previously reported missense changes (Ser217Leu and Ala541Thr) were identified by mutational analysis of all HPC2/ELAC exons in 93 probands with HPC. In association analyses, family-based tests did not reveal excess transmission of the Leu217 and/or Thr541 alleles to affected offspring, and population-based tests failed to reveal any statistically significant difference in the allele frequencies of the two polymorphisms between patients with prostate cancer and control subjects. The results of this study lead us to reject the three alternative hypotheses of (1) a highly penetrant, major prostate cancer-susceptibility gene at 17p11, (2) the allelic variants Leu217 or Thr541 of HPC2/ELAC2 as high-penetrance mutations, and (3) the variants Leu217 or Thr541 as low-penetrance, risk-modifying alleles. However, we did observe a trend of higher Leu217 homozygous carrier rates in patients than in control subjects. Considering the impact of genetic heterogeneity, phenocopies, and incomplete penetrance on the linkage and association studies of prostate cancer and on the power to detect linkage and association in our study sample, our results cannot rule out the possibility of a highly penetrant prostate cancer gene at this locus that only segregates in a small number of pedigrees. Nor can we rule out a prostate cancer-modifier gene that confers a lower-than-reported risk. Additional larger studies are needed to more fully evaluate the role of this gene in prostate cancer risk.

Background: Two genes responsible for hereditary breast cancer (BRCA1 and BRCA2) have been identified, and predisposing mutations identified. Several studies have provided evidence that germline mutations in BRCA1 and BRCA2 confer an increased risk of prostate cancer. Based on these findings, one might expect to find an increased frequency of mutations in these genes in family clusters of prostate cancer. The Ashkenazi Jewish population is unique in that it has an approximate 2% incidence of specific founder BRCA1 and BRCA2 mutations (i.e., 185delAG and 5382insC in BRCA1, and 6174delT in BRCA2)., Methods: To address the question of whether or not mutations in either of these genes were overrepresented in prostate cancer families, we searched for these mutations in germline DNA samples collected from affected and unaffected members of 18 Ashkenazi Jewish families, each having at least 3 first-degree relatives affected with prostate cancer., Results: No mutations were found in the BRCA1 gene in any of the 47 individuals tested. One individual possessed a BRCA2 mutation (6174delT). This individual was unaffected at the time of analysis, but had an affected paternal uncle, and an affected first cousin, neither of whom harbored the mutant gene., Conclusions: In this sample of Ashkenazi prostate cancer families, the frequency of founder BRCA1 and BRCA2 mutations was not elevated, suggesting that such mutations will account for only a small, perhaps minimal, fraction of familial prostate cancer.

In a recent study of 91 families having at least three first degree relatives with prostate cancer, we reported the localization of a major susceptibility locus for prostate cancer (HPC1) to chromosome 1 [band q24; J. R. Smith et al., Science (Washington DC), 274: 1371-1373, 1996]. There was significant evidence for locus heterogeneity, with an estimate of 34% of the families being linked to this locus. In this report, we investigate the importance of age at diagnosis of prostate cancer and number of affected individuals within a family as variables in the linkage analysis of an expanded set of markers on 1q24. Under two different models for the prostate cancer locus, we find that the evidence for linkage to HPC1 is provided primarily by large (five or more members affected) families with an early average age at diagnosis. Specifically, for 40 North American families with an average age at diagnosis <65 years, the multipoint lod score is 3.96, whereas for 39 families with an older average age at diagnosis, this value is -0.84. Assuming heterogeneity, the proportion of families linked is 66% for the 14 families with the earliest average ages at diagnoses, but it decreases to 7% for the families with the latest ages at diagnoses. A similar age effect is observed in 12 Swedish pedigrees analyzed. To test the hypotheses generated by these analyses, we examined an additional group of 13 newly identified prostate cancer families. Overall, these families provided additional evidence for linkage to this region (nonparametric linkage Z = 1.91; P = 0.04 at marker D1S1660), contributed primarily by the families in this group with early age at diagnosis [nonparametric linkage Z = 2.50 (P = 0.01) at D1S422]. These results are consistent with the existence of a locus in this region that predisposes men to develop early-onset prostate cancer.

Context: Approximately 9% of prostate cancer cases have been estimated to result from inheritance of mutated prostate cancer susceptibility genes. Few data exist as to whether there are clinical differences between prostate cancers that are inherited and those that occur in the general population., Objective: To investigate phenotypic characteristics of families potentially linked to the hereditary prostate cancer 1 (HPC1) locus on chromosome 1q24-25., Design: Retrospective case study in which clinical data were extracted from medical and pathological records. FAMILIES: A total of 74 North American families with hereditary prostate cancer. Prostate cancer cases from the National Cancer Data Base were used as a reference population for comparison., Main Outcome Measures: The families were divided into 2 groups: either potentially linked (33 families with 133 men with prostate cancer), and thus likely to be carrying an altered HPC1 gene, or potentially unlinked (41 families with 172 men with prostate cancer), on the basis of haplotype analysis in the region of HPC1. The age at diagnosis of prostate cancer, serum prostate-specific antigen levels, digital rectal examination status, stage, grade, primary treatment of prostate cancers, and occurrence of other cancers were compared between the groups., Results: The mean age at diagnosis of prostate cancer for men in potentially linked families was significantly lower than for men in potentially unlinked families (63.7 vs 65.9 years, respectively, P=.01; mean age at diagnosis in the reference population was 71.6 years). Higher-grade cancers (grade 3) were more common in potentially linked families, and advanced-stage disease was found in 41% of the case patients in potentially linked families compared with 31% in both the potentially unlinked families and the reference groups (P=.03 for the latter comparison). In the other clinical parameters, we found no significant differences between the groups. A modest excess of breast cancer and colon cancer was found in potentially linked families in comparison with potentially unlinked families, but this difference was not statistically significant., Conclusions: Families that provide evidence for segregation of an altered HPC1 gene are characterized by multiple cases of prostate cancer that, in most respects, are indistinguishable from nonhereditary cases. However, 3 characteristics were observed: younger age at diagnosis, higher-grade tumors, and more advanced-stage disease. Our study shows that a significant fraction of hereditary prostate cancers are diagnosed in advanced stages, emphasizing the clinical importance of early detection in men potentially carrying prostate cancer susceptibility genes. These findings support the current recommendations to screen men with a positive family history of prostate cancer beginning at age 40 years.

Despite its high prevalence, very little is known regarding genetic predisposition to prostate cancer. A genome-wide scan performed in 66 high-risk prostate cancer families has provided evidence of linkage to the long arm of chromosome 1 (1q24-25). Analysis of an additional set of 25 North American and Swedish families with markers in this region resulted in significant evidence of linkage in the combined set of 91 families. The data provide strong evidence of a major prostate cancer susceptibility locus on chromosome 1.