Role In Prostate Cancer Susceptibility Research Articles

The HOXB13 variant X285K is associated with clinical significance and early age at diagnosis in African American prostate cancer patients.

Recently, a novel HOXB13 variant (X285K) was observed in men of African descent with prostate cancer (PCa) in Martinique. Little is known about this or other variants in HOXB13 which may play a role in PCa susceptibility in African-American (AA) men. We sequenced HOXB13 in an AA population of 1048 men undergoing surgical treatment for PCa at Johns Hopkins Hospital. Seven non-synonymous germline variants were observed in the patient population. While six of these variants were seen only once, X285K was found in eight patients. In a case-case analysis, we find that carriers of this latter variant are at increased risk of clinically significant PCa (1.2% carrier rate in Gleason Score ≥7 PCa vs. 0% in Gleason Score <7 PCa, odds ratio, OR = inf; 95% Confidence Interval, 95%CI:1.05-inf, P = 0.028), as well as PCa with early age at diagnosis (2.4% carrier rate in patients <50 year vs. 0.5% carrier rate in patients ≥50 year, OR = 5.25, 95% CI:1.00-28.52, P = 0.03). While this variant is rare in the AA population (~0.2% MAF), its ancestry-specific occurrence and apparent preferential association with risk for the more aggressive disease at an early age emphasizes its translational potential as an important, novel PCa susceptibility marker in the high-risk AA population.

An exome-wide rare variant analysis of Korean men identifies three novel genes predisposing to prostate cancer

Since prostate cancer is highly heritable, common variants associated with prostate cancer have been studied in various populations, including those in Korea. However, rare and low-frequency variants have a significant influence on the heritability of the disease. The contributions of rare variants to prostate cancer susceptibility have not yet been systematically evaluated in a Korean population. In this work, we present a large-scale exome-wide rare variant analysis of 7,258 individuals (985 cases with prostate cancer and 6,273 controls). In total, 19 rare variant loci spanning 7 genes contributed to an association with prostate cancer susceptibility. In addition to replicating previously known susceptibility genes (e.g., CDYL2, MST1R, GPER1, and PARD3B), 3 novel genes were identified (FDR q < 0.05), including the non-coding RNAs ENTPD3-AS1, LOC102724438, and protein-coding gene SPATA3. Additionally, 6 pathways were identified based on identified variants and genes, including estrogen signaling pathway, signaling by MST1, IL-15 production, MSP-RON signaling pathway, and IL-12 signaling and production in macrophages, which are known to be associated with prostate cancer. In summary, we report novel genes and rare variants that potentially play a role in prostate cancer susceptibility in the Korean population. These observations demonstrated a path towards one of the fundamental goals of precision medicine, which is to identify biomarkers for a subset of the population with a greater risk of disease than others.

Fine-Mapping of IL16 Gene and Prostate Cancer Risk in African Americans

Prostate cancer is the most common type of cancer among men in the United States, and its incidence and mortality rates are disproportionate among ethnic groups. Although genome-wide association studies of European descents have identified candidate loci associated with prostate cancer risk, including a variant in IL16, replication studies in African Americans (AA) have been inconsistent. Here we explore single-nucleotide polymorphism (SNP) variation in IL16 in AAs and test for association with prostate cancer. Association tests were conducted for 2,257 genotyped and imputed SNPs spanning IL16 in 605 AA prostate cancer cases and controls from Washington, D.C. Eleven of them were also genotyped in a replication population of 1,093 AAs from Chicago. We tested for allelic association adjusting for age, global and local West African ancestry. Analyses of genotyped and imputed SNPs revealed that a cluster of IL16 SNPs were significantly associated with prostate cancer risk. The strongest association was found at rs7175701 (P = 9.8 × 10(-8)). In the Chicago population, another SNP (rs11556218) was associated with prostate cancer risk (P = 0.01). In the pooled analysis, we identified three independent loci within IL16 that were associated with prostate cancer risk. SNP expression quantitative trait loci analyses revealed that rs7175701 is predicted to influence the expression of IL16 and other cancer-related genes. Our study provides evidence that IL16 polymorphisms play a role in prostate cancer susceptibility among AAs. Our findings are significant given that there has been limited focus on the role of IL16 genetic polymorphisms on prostate cancer risk in AAs.

Evaluation of PPP2R2A as a prostate cancer susceptibility gene: a comprehensive germline and somatic study

PPP2R2A, mapped to 8p21.2, codes for the α isoform of the regulatory B55 subfamily of protein phosphatase 2 (PP2A). PP2A is one of the four major serine/threonine phosphatases and is implicated in the negative control of cell growth and division. Because of its known functions and location within a chromosomal region where evidence for linkage and somatic loss of heterozygosity was found, we hypothesized that either somatic copy number changes or germline sequence variants in PPP2R2A may increase prostate cancer (PCa) risk. We examined PPP2R2A deletion status in 141 PCa samples using Affymetrix SNP arrays. It was found that PPP2R2A was commonly (67.1%) deleted in tumor samples, including a homozygous deletion in three tumors (2.1%). We performed a mutation screen for PPP2R2A in 96 probands of hereditary prostate cancer families. No high risk mutations were identified. In addition, we re-analyzed 10 SNPs of PPP2R2A in sporadic PCa cases and controls. No significant differences in the allele and genotype frequencies were observed among either PCa cases and controls or PCa aggressive and non-aggressive cases. Taken together, these results suggest that a somatic deletion rather than germline sequence variants of PPP2R2A may play a more important role in PCa susceptibility.

Germ-line sequence variants of PTEN do not have an important role in hereditary and non-hereditary prostate cancer susceptibility

PTEN (phosphatase and tensin homolog deleted on chromosome 10) functions as a major tumor suppressor gene and is frequently deleted in different types of tumors including prostate cancer (PCa). It was hypothesized that germ-line genetic changes of PTEN affect susceptibility to PCa. Both common (with a minor allele frequency 5%) and rare (with a minor allele frequency <5%) germ-line variants of PTEN were comprehensively evaluated. A total of 15 germ-line variants were identified by re-sequencing the PTEN gene, including 5' untranslated region, all nine exons, exon-intron junctions and 3' untranslated region, in 188 probands of hereditary prostate cancer (HPC) families recruited from Johns Hopkins Hospital. Two microsatellite markers surrounding PTEN were used to test the co-segregation of 10 rare variants, which may give rise to highly penetrance in HPC. Two common single nucleotide polymorphisms (SNPs) were evaluated in the 188 HPC families using a family-based association study approach. To study low penetrant SNPs in PCa susceptibility, 33 SNPs covering PTEN were selected from the whole genome-wide association studies (GWAS) from our available case-control studies in Sweden (Cancer of the Prostate in Sweden (CAPS)) and the publicly available cancer genetic markers of susceptibility (CGEMS) study. Germ-line copy-number variations (CNVs) in PTEN were assessed in CAPS. Co-segregation of germ-line variants and PCa was not observed among HPC families and no significant differences in the allele frequencies were observed in sporadic cases and controls, aggressive and non-aggressive PCa (P>0.05). These results suggest that germ-line variants in PTEN do not have an important role in PCa susceptibility.

Abstract 2769: Evaluation of PPP2R2A as a prostate cancer susceptibility gene: Comprehensive germline and somatic study

Abstract PPP2R2A, a gene mapped to 8p21.2, encodes α isoform of the regulatory B55 subfamily of the protein phosphatase 2 (PP2A). PP2A is one of the four major Ser/Thr phosphatases, and is implicated in the negative control of cell growth and division. Because of its known functions and its location within a chromosomal region where evidence for linkage and somatic loss of heterozygosity were found, we hypothesized that either germline sequence variants or somatic copy number changes in PPP2R2A may increase prostate cancer (PCa) risk. To address this, we first sequenced PPP2R2A in 96 probands of hereditary prostate cancer (HPC) families recruited at John Hopkins Hospital; each family had at least three first-degree relatives affected with prostate cancer. Twenty-five germ-line variants were identified in this analysis, including 15 known SNPs and 10 new sequence variants. Most new sequence variants were rare, except 2 new sequence variants with minor allele frequency (MAF) ≥ 0.05 (−482T/C MAF=0.072 and -78C/G MAF=0.058). Thereafter, it was less likely that these sequence variants of PPP2R2A would be co-segregated with PCa. Second, to see if there are any genetic variants in PPP2R2A associated with sporadic PCa, we analyzed 10 SNPs of 15 known SNPs that span the complete PPP2R2A gene in Cancer Genetic Markers of Susceptibility (CGEMS, 737 cases and 1,105 controls) and in Cancer of the Prostate in Sweden (CAPS, 498 cases and 494 controls) from a Sweden population, as genotypes of these 10 SNPs had already been available in both studies. No consistent significant differences in the allele and genotype frequencies were observed among these sporadic PCa cases and controls. Finally, we examined the deletion status in 141 clinical PCa samples from John Hopkins using Affymetrix 6.0 SNP arrays. With the allele-specific analysis of intensities from all paired tumor and normal tissue samples, it was found that PPP2R2A was commonly (67.1%) deleted in these tumor samples including a homozygous deletion in 3 tumors (2.1%). These results suggest that somatic deletion rather than germline sequence variants of PPP2R2A may play a more important role in prostate cancer susceptibility. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2769. doi:10.1158/1538-7445.AM2011-2769

Association between polymorphisms of TP53 and MDM2 and prostate cancer risk in southern Chinese

Alterations in the TP53 and MDM2 genes appear to be important in the development of many human tumors, but evidence is conflicting on associations between polymorphisms in these genes and risk of prostate cancer (PCa). The influence of TP53 codon 72, MDM2 SNP309, and MDM2 C1797G polymorphisms in southern Chinese PCa patients was investigated. In the comparison of genotype distributions of TP53 codon 72 between cases and controls, the adjusted odds ratios for PCa associated with the Pro/Pro, Arg/Pro, and Arg/Arg genotypes were 1.00, 1.89 (95% CI = 1.20–2.97), and 2.01 (95% CI = 1.11–3.64), respectively; however, MDM2 SNP309 and C1797G did not show any significant difference between cases and controls. When TP53 and MDM2 polymorphisms were combined based on the numbers of variant risk alleles (i.e., G-allele of TP53 codon 72, G-allele of MDM2 SNP309, and G-allele of MDM2 C1797G), individuals with 3–5 variants had a 1.56-fold greater risk of PCa than those with 0–2 variants (95% CI = 1.07–2.26). Moreover, subjects with 0–2 variants had 33.3% positive p53 expression, whereas subjects with 3–5 variants had 23.3% p53 expression ( P = 0.39). These findings suggest that TP53 and MDM2 polymorphisms play a role in PCa susceptibility in southern Chinese Han population.

Brca2 and Trp53 Deficiency Cooperate in the Progression of Mouse Prostate Tumourigenesis

Epidemiological studies have shown that one of the strongest risk factors for prostate cancer is a family history of the disease, suggesting that inherited factors play a major role in prostate cancer susceptibility. Germline mutations in BRCA2 predispose to breast and ovarian cancer with its predominant tumour suppressor function thought to be the repair of DNA double-strand breaks. BRCA2 has also been implicated in prostate cancer etiology, but it is unclear the impact that mutations in this gene have on prostate tumourigenesis. Here we have undertaken a genetic analysis in the mouse to determine the role of Brca2 in the adult prostate. We show that deletion of Brca2 specifically in prostate epithelia results in focal hyperplasia and low-grade prostate intraepithelial neoplasia (PIN) in animals over 12 months of age. Simultaneous deletion of Brca2 and the tumour suppressor Trp53 in prostate epithelia gave rise to focal hyperplasia and atypical cells at 6 months, leading to high-grade PIN in animals from 12 months. Epithelial cells in these lesions show an increase in DNA damage and have higher levels of proliferation, but also elevated apoptosis. Castration of Brca2;Trp53 mutant animals led to regression of PIN lesions, but atypical cells persisted that continued to proliferate and express nuclear androgen receptor. This study provides evidence that Brca2 can act as a tumour suppressor in the prostate, and the model we describe should prove useful in the development of new therapeutic approaches.

684 NOVEL CANDIDATE GENE FOR PROSTATE CANCER (PC) SUSCEPTIBILITY, FARNECYL-DIPHOSPHATE FARNECYLTRANSFERASE 1 (FDFT1) : ASSOCIATIONS OF FDFT1 GENE VARIANTS WITH PC RISK, AND FDFT1 PROTEIN FUNCTION EVALUATION IN PC CELLS

You have accessJournal of UrologyProstate Cancer: Basic Research V1 Apr 2010684 NOVEL CANDIDATE GENE FOR PROSTATE CANCER (PC) SUSCEPTIBILITY, FARNECYL-DIPHOSPHATE FARNECYLTRANSFERASE 1 (FDFT1): ASSOCIATIONS OF FDFT1 GENE VARIANTS WITH PC RISK, AND FDFT1 PROTEIN FUNCTION EVALUATION IN PC CELLS Hiroshi Matsui, Yuji Fukuma, Tatsuya Hamano, Hidekazu Koike, Yoshitaka Sekine, Nobuaki Ohtake, Seiji Nakata, and Kazuhiro Suzuki Hiroshi MatsuiHiroshi Matsui Maebashi, Japan More articles by this author , Yuji FukumaYuji Fukuma Maebashi, Japan More articles by this author , Tatsuya HamanoTatsuya Hamano Maebashi, Japan More articles by this author , Hidekazu KoikeHidekazu Koike Maebashi, Japan More articles by this author , Yoshitaka SekineYoshitaka Sekine Maebashi, Japan More articles by this author , Nobuaki OhtakeNobuaki Ohtake Takasaki, Japan More articles by this author , Seiji NakataSeiji Nakata Ashikaga, Japan More articles by this author , and Kazuhiro SuzukiKazuhiro Suzuki Maebashi, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.1083AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES We previously conducted genome-wide linkage analyses in 44 nuclear Japanese families affected with PC and concluded PC susceptibilities in Japan to be closely linked to D8S550 on 8p23 and D1S2667 on 1p36. The FDFT1 gene exists just under the peak marker, D8S550, on 8p23. This gene encodes squalene synthase (SQS), an important enzyme in the sterol branch of the mevalonic acid pathway. Relationships between lipid metabolism and PC, as well as epidemiological factors, appear to be underlying mechanisms. Herein, we evaluated the associations between FDFT1 variants and PC risk in the Japanese population and the function of SQS in PC cells. METHODS 1. Association study of FDFT1 polymorphisms: Probands from 115 families with familial PC (FPC), 138 with sporadic PC and 119 with benign prostatic hyperplasia as controls were studied. All study subjects belonged to the Japanese ethnic group. Genomic DNA was isolated from whole blood cells and genotyping of 5 SNPs (rs2645429, rs11549147, hCV25649966, rs1804473, rs2294136) was done using the TaqMan SNP Genotyping Assay. The associations of these SNP genotypes with FPC were evaluated using the chi-square test. 2. SQS functional analyses in PC cells: We found an association between being an A allele carrier of SNP rs2645429 and FPC. SNP rs2645429 is located in the FDFT1 promoter region. Vectors mutating this site to GG and to AA, prepared using mutagenesis, were transfected into COS-1 and LNCaP cells, respectively. We evaluated FDFT1 gene expression using Promoter-Reporter Assays and investigated changes in LNCaP and PC-3 cell proliferation with knock-down of FDFT1 using siRNA. RESULTS The odds ratio for the A allele carrier of SNP rs2645429 at the FDFT1 promoter region (1.86 [95% CI: 1.10-3.13, P=0.026]) was significantly higher in FPC than controls. The promoter-reporter assay revealed FDFT1 promoter activity to be decreased with the GG genotype at rs2645429 versus the AA genotype. The proliferation of PC cells was suppressed by FDFT1 knock-down using siRNA. CONCLUSIONS The significant differences in the A allele carrier at SNP rs2645429 between FPC and unaffected controls observed in this study are therefore considered to support the premise that the FDFT1 gene plays a significant role in PC susceptibility. SQS also appears to be involved in PC cell proliferation. © 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e267 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Hiroshi Matsui Maebashi, Japan More articles by this author Yuji Fukuma Maebashi, Japan More articles by this author Tatsuya Hamano Maebashi, Japan More articles by this author Hidekazu Koike Maebashi, Japan More articles by this author Yoshitaka Sekine Maebashi, Japan More articles by this author Nobuaki Ohtake Takasaki, Japan More articles by this author Seiji Nakata Ashikaga, Japan More articles by this author Kazuhiro Suzuki Maebashi, Japan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

The UGT2B17 gene deletion is not associated with prostate cancer risk

Deletion polymorphism of the UDP-glucuronosyltransferase 2B17 (UGT2B17) gene has been associated with an increased prostate cancer risk in two previous independent studies. Here we determine the risk in a large-scale population-based case-control study. Genotyping was conducted with a 5'-nuclease activity assay to distinguish those with one or two UGT2B17 gene copies (ins/del and ins/ins) from individuals homozygous for the deletion (del/del) allele. In contrast to previous findings, no association between the UGT2B17 deletion polymorphism and prostate cancer risk was found. Furthermore the UGT2B17 gene deletion did not affect the risk for prostate cancer specific death. The UGT2B17 deletion polymorphism does not play a major role in prostate cancer susceptibility as previously indicated.

Implications for Prostate Cancer of Insulin-Like Growth Factor-I (IGF-I) Genetic Variation and Circulating IGF-I Levels

Elevated levels of circulating IGF-I have consistently been associated with increased prostate cancer risk. We recently found a haplotype in the 3' region of the IGF-I gene associated with increased risk of prostate cancer, and we hypothesized that the observed association is mediated by circulating IGF-I. We analyzed haplotypes and three haplotype-tagging single nucleotide polymorphisms (htSNPs) in the 3' region of the IGF-I gene in relation to circulating levels IGF-I in 698 control subjects from the CAncer Prostate in Sweden (CAPS) study and 575 cases and controls from the prospective Northern Sweden Health and Disease Cohort (NSHDC) study. We also performed a meta-analysis of these two and four other association studies on genetic variation in the 3' region of the IGF-I gene in relation to circulating IGF-I levels. The IGF-I haplotype previously associated with prostate cancer risk, labeled "TCC," was associated with elevated levels of IGF-I in the CAPS study (P = 0.02), but not in the NSHDC study. In contrast, two of the three IGF-I htSNPs tagging this haplotype, rs6220 and rs7136446, were associated with elevated levels of IGF-I in the NSHDC (P = 0.03 and P = 0.04, respectively), but not in the CAPS study. In the meta-analysis, the TCC haplotype and the rs6220 SNP were associated with elevated levels of circulating IGF-I (P = 0.001 and P < 0.0001, respectively). Genetic variation in the 3' region of the IGF-I gene seems to influence circulating levels of IGF-I. This observation is consistent with the hypothesis that variation in the IGF-I gene plays a role in prostate cancer susceptibility by influencing circulating levels of IGF-I.

Interleukin-6 Sequence Variants Are not Associated with Prostate Cancer Risk

Interleukin-6 Sequence Variants Are not Associated with Prostate Cancer Risk

A polymorphism in the CDKN1B gene is associated with increased risk of hereditary 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.

Analysis of the macrophage scavenger receptor 1 gene in Swedish hereditary and sporadic prostate cancer.

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. 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. 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. 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.

A p53 codon 72 polymorphism associated with prostate cancer development and progression in Japanese.

An association between the Pro/Pro genotype of p53 codon 72 and a lower risk of prostate cancer in Caucasians was recently reported. However, the association of this polymorphism with prostate cancer risk in a Japanese population has not been clarified. We performed a case-control study consisting of 114 prostate cancer patients and 105 noncancer controls. Sixty-nine percent (79 of 114) of the patients had a positive family history. The genotypic frequencies in the controls were 39.0% for Arg/Arg, 54.3% for Arg/Pro and 6.7% for Pro/Pro; they were in Hardy-Weinberg equilibrium. When a comparison of the distribution of the p53 codon 72 polymorphism was made between patients with a first-degree family history and all control subjects, the adjusted odds ratios (ORs) for prostate cancer associated with the Arg/Arg, Arg/Pro and Pro/Pro genotypes were 1.00, 0.99 [95% confidence interval (CI) 0.53-1.88] and 2.80 (95% CI 1.04-7.53), respectively. When stratification of cases was performed based on clinical stage (localized or metastatic cancer) and pathological grade (a Gleason score of <7 or > or =7), there tended to be a greater number of patients with localized cancers among those patients with the Arg/Pro genotype than among those with the Arg/Arg genotype (overall cases: age-adjusted OR 0.36, 95% CI 0.13-1.00, p = 0.049; positive family history cases: age-adjusted OR 0.25, 95% CI 0.075-0.84, p = 0.025). In addition, there tended to be a greater number of patients with low-grade cancers among those with the Pro/Pro genotype than among those with other genotypes (overall cases: age-adjusted OR 0.41, 95% CI 0.13-1.30, p = 0.13; positive family history cases: age-adjusted OR 0.20, 95% CI 0.004-0.89, p = 0.035). The present findings suggest that the Pro/Pro genotype of p53 codon 72 played a role in prostate cancer susceptibility in a Japanese population. However, the Pro allele did not appear to worsen such clinical parameters as clinical stage or pathological grade.

A p53 Codon 72 Polymorphism Associated with Prostate Cancer Development and Progression in Japanese

An association between the Pro/Pro genotype of p53 codon 72 and a lower risk of prostate cancer in Caucasians was recently reported. However, the association of this polymorphism with prostate cancer risk in a Japanese population has not been clarified. We performed a case-control study consisting of 114 prostate cancer patients and 105 noncancer controls. Sixty-nine percent (79 of 114) of the patients had a positive family history. The genotypic frequencies in the controls were 39.0% for Arg/Arg, 54.3% for Arg/Pro and 6.7% for Pro/Pro; they were in Hardy-Weinberg equilibrium. When a comparison of the distribution of the p53 codon 72 polymorphism was made between patients with a first-degree family history and all control subjects, the adjusted odds ratios (ORs) for prostate cancer associated with the Arg/Arg, Arg/Pro and Pro/Pro genotypes were 1.00, 0.99 [95% confidence interval (CI) 0.53–1.88] and 2.80 (95% CI 1.04–7.53), respectively. When stratification of cases was performed based on clinical stage (localized or metastatic cancer) and pathological grade (a Gleason score of <7 or ≧7), there tended to be a greater number of patients with localized cancers among those patients with the Arg/Pro genotype than among those with the Arg/Arg genotype (overall cases: age-adjusted OR 0.36, 95% CI 0.13–1.00, p = 0.049; positive family history cases: age-adjusted OR 0.25, 95% CI 0.075–0.84, p = 0.025). In addition, there tended to be a greater number of patients with low-grade cancers among those with the Pro/Pro genotype than among those with other genotypes (overall cases: age-adjusted OR 0.41, 95% CI 0.13–1.30, p = 0.13; positive family history cases: age-adjusted OR 0.20, 95% CI 0.004–0.89, p = 0.035). The present findings suggest that the Pro/Pro genotype of p53 codon 72 played a role in prostate cancer susceptibility in a Japanese population. However, the Pro allele did not appear to worsen such clinical parameters as clinical stage or pathological grade.

Evaluation of DLC1 as a prostate cancer susceptibility gene: mutation screen and association study

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.

Risk of Prostate Cancer in Relation to Polymorphisms of Metabolic Genes

The study of associations between genetic polymorphisms of metabolic enzymes and prostate cancer risk can provide insight into the potential etiologic role of xenobiotics in prostate cancer development. To date there is little evidence that the incidence of prostate cancer is influenced by any of the genetic polymorphisms described above. However, the number of subjects studied generally has been small, so it would be premature to conclude that the substances metabolized by enzymes encoded by these candidate genes are not of carcinogenic importance, or to conclude that the polymorphisms of these genes do not play a role in prostate cancer susceptibility. Larger-scale studies of these and other genes, such as genes that repair cellular damage and regulate cell growth, are needed. Since gene-gene and gene-environment interactions may contribute to cancer risk, it would be desirable to conduct studies in which both biomarkers (or other measures) of exposure and polymorphisms of multiple genes are examined.