Risk Of Sporadic Prostate Cancer Research Articles

Association of Arg462Gln Polymorphism in RNASEL Gene With the Risk of Prostate CancerAmong Iranian Population

In the July issue of “Gene, Cell and Tissue”, R462Q Mutation in Prostate Cancer Specimens 1 investigated the effect of Arg462Gln polymorphism in sporadic prostate cancer patients among Iranian population. The study samples comprised of formalin fixed paraffin embedded specimen obtained from 51 histopathologically confirmed specimens from patients with prostate cancer and 70 from control individuals with non-cancerous prostate (prostatitis, hyperplasia). RNASEL Arg462Gln or G1385A polymorphism analysis performed using ARMS (Amplification Refractory Mutation System) PCR with allele specific primers were used to detect single-base substitution. This was followed by the association analysis between RNASEL genotype and prostate cancer. The authors could not find any significant association between the polymorphism and risk of disease. Few years back a worldwide epidemiological survey on prostate cancer revealed that it is the third leading causes of death in developed countries such as United States and emphasized that it is becoming a growing health concern in the developing nations as well 2. Like any other complex neoplastic disorder both genetic and non genetic factors interact in its development and progression 3. Age, ethnic background and family history are the three main epidemiological risk factors for this disease out of which family history is the strongest contributor. Based on family history, prostate cancer can be classified into sporadic, familial and hereditary. Hereditary predispositions are quite rare and contribute to less than 5% of the cases while familial cases account for 10-20% of cases. The rest are sporadic cases with typically only one person in their family who were diagnosed with the disease 4. Numerous studies have been conducted to identify the prostate cancer susceptibility genes using linkage analysis. Smith et al. identified the first susceptibility locus, designated as HPC1, which mapped to the long arm of chromosome 1 (1q24-25) (5), few years later, Carpten et al. reported RNASEL gene as one of the candidate for HPC1 (6). RNASEL is an endonuclease involving in apoptotic and antiviral activities of interferons. Along with truncating mutations in this gene, several missense variants were reported by Rokman et al. by screening the entire coding sequence of RNASEL using Single-strand conformation polymorphism (SSCP) (7). The Arg462Gln variant has a significant role in hereditary prostate cancer as the variant has three times less enzymatic activity compared to the wild genotype (8). They also reported that heterozygous individuals had double the risk of prostate cancer compared to the noncarrier cases with hereditary prostate cancer, but at the same time various studies did not find any association between sporadic prostate cancer and this variation in Caucasian and African American population (8, 9). The statistical analysis has been limited to unadjusted risk calculation. The risk calculation after adjustment to the age and clinical parameters would be a better approach. The control DNA was taken from hyperplastic prostate tissue so this tissue may not represent as a proper control sample. It is better to use DNA samples obtained from healthy individuals as the healthy control. Moreover the sample size is very small for any association study thus; a larger sample size is certainly warranted in future. Sometimes, ARMS PCR may produce incorrect genotypes, especially in homozygotes, so, it is better to recheck the genotypes by alternate sequencing methods. The authors did not find any association between Arg462Gln polymorphism and the risk of sporadic prostate cancer. Despite the limitations, this study is important as it may be first of its kind among Iranian population.

Association between estrogen receptor alpha PvuII polymorphism and prostate cancer risk

Accumulating evidence has suggested that estrogen receptor alpha (ER-α) PvuII polymorphism might be involved in the development of prostate cancer (PCa). However, the results have been inconsistent. We therefore performed a meta-analysis to clarify the associations between ER-α PvuII polymorphism and PCa. A comprehensive search was conducted to identify all case-control studies of ER-α PvuII polymorphism and PCa risk. We used odds ratios (ORs) to assess the strength of the association and 95% confidence intervals (CIs) to give a sense of the precision of the estimate. A total of 14 studies were found to be eligible for meta-analyses of PvuII variant. Results from this study showed that ER-α PvuII polymorphism were significantly associated with PCa risk under all genetic models in overall population (homogeneous codominant model, OR = 1.57, 95% CI = 1.11-2.21, P = 0.010; heterogeneous codominant model, OR = 1.37, 95% CI = 1.06-1.77, P = 0.02; recessive model, OR = 1.27, 95% CI = 1.02-1.57, P = 0.03; dominant model, OR = 1.40, 95% CI = 1.09-1.79, P = 0.009; and allelic model, OR = 1.25, 95% CI = 1.06-1.48, P = 0.010). Further sensitivity analysis confirmed the significant association. In subgroup analyses stratified by PCa type, there was a significant association between PvuII polymorphism and sporadic PCa risk under both Caucasians and Asians. The meta-analysis indicated elected PvuII polymorphism of ER-α was a risk factor for PCa development.

Correction: Polymorphisms in the mTOR Gene and Risk of Sporadic Prostate Cancer in an Eastern Chinese Population

Affiliations numbers 1 and 3 for multiple authors are incorrect. The correct affiliation number 1 is: Cancer Institute, Fudan University Cancer Center, Shanghai, China. The correct affiliation number 3 is: Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.

G84E mutation in HOXB13 is firmly associated with prostate cancer risk: a meta-analysis

The rare but recurrent germline G84E mutation in HOXB13 was recently found to be associated with a significantly increased risk of familial prostate cancer (PCa). However, epidemiologic findings have been inconsistent. In an attempt to confirm and expand the findings that the PCa risk increased in men carrying G84E, we therefore performed a meta-analysis to clarify the association between the germline G84E mutation and PCa risk. We also aim to verify the increased PCa risk with respect to diagnostic age, family history, and disease aggressiveness. Comprehensive search of databases was carried out, and other relevant articles were also identified. Then, the meta-analyses were conducted according to the standard guidelines. A total of 11 studies with 120,167 participants were included on the basis of inclusion criteria. The G84E allele carrier frequencies ranged from 0.1 to 4.9 % in the patients with PCa, as compared with 0 to 1.4 % in control subjects. Men with the HOXB13 G84E variant had a 4.51-fold higher relative risk of PCa compared with non-carriers (95 % CI 3.28-6.20). The much higher risks were observed in individuals with early onset (odds ratio (OR) = 9.73, 95 % confidence interval (CI) 6.57-14.39), more than two affected relatives (OR = 7.27, 95 % CI 4.02-13.15), and highly aggressive disease (OR = 5.81, 95 % CI 3.72-9.08). Our findings provide further evidences that the rare mutation in HOXB13 contributes to both hereditary and sporadic PCa risk. Despite the low G84E carrier rate, biological and clinical implications of the mutation in subjects with early onset, more than two affected relatives, and highly aggressive disease remain important in continued investigation.

Polymorphisms in the mTOR Gene and Risk of Sporadic Prostate Cancer in an Eastern Chinese Population

BackgroundThe mTOR gene regulates cell growth by controlling mRNA translation, ribosome biogenesis, autophagy, and metabolism. Abnormally increased expression of mTOR was associated with carcinogenesis, and its functional single nucleotide polymorphisms (SNPs) may regulate the expression of mTOR and thus contribute to cancer risk.Methodology/Principal FindingsIn a hospital-based case-control study of 1004 prostate cancer (PCa) cases and 1051 cancer-free controls, we genotyped six potentially functional SNPs of mTOR (rs2536 T>C, rs1883965 G>A, rs1034528 G>C, rs17036508 T>C, rs3806317 A>G, and rs2295080 T>G) and assessed their associations with risk of PCa by using logistic regression analysis.Conclusions/SignificancesIn the single-locus analysis, we found a significantly increased risk of PCa associated with mTOR rs2536 CT/CC and rs1034528 CG/CC genotypes [adjusted OR = 1.42 (1.13–1.78), P = 0.003 and 1.29 (1.07–1.55), P = 0.007), respectively], compared with their common homozygous genotypes, whereas mTOR rs2295080 GT/GG genotypes were associated with a decreased risk of PCa [adjusted OR = 0.76 (0.64–0.92), P = 0.003], compared with wild-type TT genotypes. In the combined analysis of the six SNPs, we found that individuals carrying two or more adverse genotypes had an increased risk of PCa [adjusted OR = 1.24 (1.04–1.47), P = 0.016], compared with individuals carrying less than two adverse genotypes. In the multiple dimension reduction analysis, body mass index (BMI) was the best one-factor model with the highest CVC (100%) and the lowest prediction error (42.7%) among all seven factors. The model including an interaction among BMI, rs17036508, and rs2536 was the best three-factor model with the highest CVC (100%) and the lowest prediction error of 41.9%. These findings suggested that mTOR SNPs may contribute to the risk of PCa in Eastern Chinese men, but the effect was weak and needs further validation by larger population-based studies.

Genetic Variations ofα-Methylacyl-CoA Racemase Are Associated with Sporadic Prostate Cancer Risk in Ethnically Homogenous Koreans

Background. To assess if the variants of (R)-alpha-methyl-CoA racemase (AMACR) gene would be associated with the risk of sporadic prostate cancer in ethnically homogenous Koreans. Materials and Methods. We enrolled 194 patients with prostate cancer and 169 healthy controls. A total of 17 single nucleotide polymorphisms of the AMACR gene were selected. The distribution of each genotype and haplotype was analyzed and their association with the incidence of prostate cancer was evaluated. Further, we detected AMACR expression in tumor with immunohistochemistry and analyzed its association with genotype regarding prostate cancer risk. Results. AG or GG genotype of rs2278008 (E277K) tended to lower prostate cancer risk. The minor G allele was found to be a significant allele that decreased the risk of prostate cancer (adjusted OR, 0.57; 95% CI, 0.35–0.93, P value = 0.025). In patients expression AMACR, AG or GG genotype was also significant genotype in terms of prostate cancer risk (adjusted OR, 0.47; 95% CI, 0.26–0.87, P value = 0.017). Further, [GGCGG] haplotype consisted of five coding SNPs of rs2278008, rs34677, rs2287939, rs10941112, and rs3195676 which decreased the risk of prostate cancer (P value = 0.047). Conclusions. Genetic variations of AMACR are associated with the risk of sporadic prostate cancer that underwent radical prostatectomy in Koreans.

Steroid 5-alpha-reductase type 2 (SRD5A2) V89L and A49T polymorphisms and sporadic prostate cancer risk: a meta-analysis

Steroid 5-α-reductase type 2 (SRD5A2) V89L and A49T polymorphisms are thought to play a crucial role in the androgen synthesis and metabolic pathway, but their associations with prostate cancer risk remain controversial. To provide a more precise estimation of the associations between V89L and A49T polymorphisms and prostate cancer risk, we performed a meta-analysis using all published case-control studies of prostate cancer since January 1995. We used odds ratio (OR) and its 95% confidence interval (CI) to assess the strength of the association under various genetic models in both overall and stratified analyses. We also calculated the false-positive report probability, the power of the current study, and the observed P value for significant findings. This analysis included 45 eligible studies of a total of 15,562 cases and 15,385 controls, in which no significant associations were found for the V89L polymorphisms under all genetic models. However, small excess prostate cancer risk was associated with the 49T allele in mixed populations compared with the 49A allele (OR = 1.24, 95% CI = 1.02-1.50), and similar results were observed in Caucasians (OR = 1.24, 95% CI = 1.01-1.53). The sensitivity analysis further strengthened the validity of these findings without publication bias. Although there was no overall association between V89L and prostate cancer risk, A49T might play a role in the etiology of prostate cancer among Caucasians. Additional large and well-designed studies are warranted to validate these findings.

Association of chromosome 8q24 variants with prostate cancer risk in the Siberian region of Russia and meta-analysis

Compelling evidence demonstrates chromosome 8q24 as a prostate cancer susceptibility locus. In present work we studied whether the common variants of 8q24 region, rs6983267 and rs1447295, were associated with the sporadic prostate cancer risk in the Russian population. Polymorphisms were genotyped in 393 case and 384 control Russian Caucasian men from Siberia region. The A allele of rs1447295 was significantly associated with the risk of prostate cancer (OR[CI 95%] = 1.74 [1.26-2.4], p = 7.8 x 10(-4)). A common G-A haplotype for rs6983267 - rs1447295 also showed an association with prostate cancer risk in Russian population (OR[CI 95%] = 2.03 [1.1 - 3.75], p = 0.02). We performed a meta-analysis combining our results with previous studies to evaluate the association between studied SNPs and prostate cancer risk. Meta-analysis has strongly supported the association for these SNPs (p < 10(-6)). Accordingly our study confirms the association between chromosome 8q24 and prostate cancer risk.

8q24 and prostate cancer: Association with the risk of disease and meta-analysis.

e15180 Background: Genome-wide association studies and subsequent replication studies have shown that single nucleotide polymorphisms (SNPs) in the chromosomal region 8q24 are associated with prostate cancer (PC) susceptibility. We examined the residents of the West Siberian Region of Russia to assess the contribution of SNPs rs6983267 and rs1447295 in the risk of sporadic PC. The group consisted of 393 Caucasian men with sporadic PC (mean aged 69.1 = 8.5 years). The group was selected from patients of the Altai Affiliated Department of N.N.Blokhin Cancer Research Center, Altai Regional Oncological Center and Krasnoyarsk Regional Oncologic Centre. Control group consisted of 384 Caucasian men (mean aged 61.3 = 16.6 years) without a history of cancer. All participants included in this study provided written informed consent. Methods: Genotyping was carried out by real-time PCR using competitive TaqMan probes. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% C.I.). We considered p-value below 0.05 to indicate statistical significance. We also performed a meta-analysis combining our result with 21 previous studies evaluating the association between rs1447295 and PC risk. The inclusion criteria were: (a) case–control studies evaluating studied SNPs and sporadic PC risk; (b) sufficient data for estimating an OR with 95%C.I. and (c) enough ethnicity information for subgroup analysis. OR and its 95%C.I. were used to evaluate the size effect. Results: The frequencies of genotypes in control DNA samples and in samples from patients with sporadic PC corresponded to the Hardy-Weinberg distribution in both groups. No significant association of rs6983267 polymorphic loci and PC development was detected (OR = 1.04; p=0.68). We observed association with PC for SNP rs1447295: the A-allele was associated with the risk of PC (OR(C.I.95%) = 1.74 (1.26-2.4), p = 0.00078) among men of the West Siberian Region. Meta-analysis of our result with previously reported studies of PC strongly support the association for this SNP (combined OR for rs1447295=1.37, 95%C.I. 1.32-1.43, p<10-6). Conclusions: Our study confirms the association between SNP rs1447295 on chromosome 8q24 and PC risk.

EphB2 SNPs and Sporadic Prostate Cancer Risk in African American Men

The EphB2 gene has been implicated as a tumor suppressor gene somatically altered in both prostate cancer (PC) and colorectal cancer. We have previously shown an association between an EphB2 germline nonsense variant and risk of familial prostate cancer among African American Men (AAM). Here we set out to test the hypothesis that common variation within the EphB2 locus is associated with increased risk of sporadic PC in AAM. We genotyped a set of 341 single nucleotide polymorphisms (SNPs) encompassing the EphB2 locus, including known and novel coding and noncoding variants, in 490 AA sporadic PC cases and 567 matched controls. Single marker-based logistical regression analyses revealed seven EphB2 SNPs showing statistically significant association with prostate cancer risk in our population. The most significant association was achieved for a novel synonymous coding SNP, TGen-624, (Odds Ratio (OR) = 0.22; 95% Confidence Interval (CI) 0.08–0.66, p = 1×10−5). Two other SNPs also show significant associations toward a protective effect rs10465543 and rs12090415 (p = 1×10−4), OR = 0.49 and 0.7, respectively. Two additional SNPs revealed trends towards an increase in risk of prostate cancer, rs4612601 and rs4263970 (p = 0.001), OR = 1.35 and 1.31, respectively. Furthermore, haplotype analysis revealed low levels of linkage disequilibrium within the region, with two blocks being associated with prostate cancer risk among our population. These data suggest that genetic variation at the EphB2 locus may increase risk of sporadic PC among AAM.

Genetic susceptibility to prostate cancer in residents of the west Siberian region.

e12036 Background: Prostate cancer (PC) is becoming one of the most common cancers in males all over the World including Russia. PC incidence rates increased by 60% per year from 2002 to 2007 in Russia. Screening for prostate cancer aims to advance the time of diagnosis (lead time) and detect cancers that would not have been found without screening. We examined the residents of the West Siberian region in order to clear out the impact of a single nucleotide polymorphisms (SNPs) in the c-MYC gene (rs6983267), in the CASP8 gene (rs3834129) and CYP1B1 gene (rs1056836) in the risk of sporadic PC. Methods: The group consisted of 285 Caucasian men with sporadic PC (mean aged 69 years). Control group consisted of 198 Caucasian men (mean aged 62 years) without a history of cancer. The group was selected from patients of the Altai Affiliated Department of N. N. Blokhin Cancer Research Center and Altai Regional Oncological Center. Genotyping was carried out by real-time PCR using competitive TaqMan probes. Results: The incidence of polymorphic loci in control DNA samples and in samples from patients with sporadic PC corresponded to the Hardy-Weinberg distribution in both groups. No significant associations of rs6983267 and rs3834129 polymorphic loci and PC development were detected (OR = 1.27; p = 0.230 and OR = 1.0; p = 0.87, respectively). CYP1B1 is involved in the activation of many procarcinogens and the hydroxylation of testosterone. Conclusions: In our study rs1056836 G-allele of CYP1B1 gene was significantly associated with decreased risk for PC (OR = 0.713; C.I.= [0.547-0.930]; p = 0.012) among men of the West Siberian Region. Further studies with a larger sample size are needed to confirm our results. No significant financial relationships to disclose.

Significance of common variants on human chromosome 8q24 in relation to the risk of prostate cancer in native Japanese men

BackgroundCommon variants on human chromosome 8q24, rs1447295 (C/A) and rs6983267 (T/G), have been recently linked to the prevalence of prostate cancer in European and American populations. Here, we evaluated whether the single-nucleotide polymorphisms rs1447295 and rs6983267 were associated with the risk of sporadic prostate cancer as well as latent prostate cancer in a native Japanese population.ResultsWe analyzed genomic DNA samples from 391 sporadic prostate cancer patients, 323 controls who had died from causes unrelated to cancer and 112 Japanese men who were diagnosed as having latent prostate cancer based on autopsy results. The polymorphisms were determined by allelic discrimination using a fluorescent-based TaqMan assay. The A allele of rs1447295 was significantly associated with the risk of sporadic prostate cancer (p = 0.04; age-adjusted OR, 1.34), while the G allele of rs6983267 showed a trend towards being a high-risk allele (p = 0.06; age-adjusted OR, 1.27). No significant difference between these two polymorphisms and the risk of latent prostate cancer was observed in the present Japanese population.ConclusionKnown variants on human chromosome 8q24 may be risk factors for sporadic prostate cancer in native Japanese men.

CYP1A1 polymorphisms and risk of prostate cancer: a meta-analysis.

Two common polymorphisms in cytochrome P450; family 1, subfamily A, polypeptide 1 (CYP1A1); have been implicated as a risk factor of prostate cancer, but individual studies have been inconclusive or controversial. We reviewed studies on CYP1A1 polymorphisms in patients with prostate cancer. The strategy searching in the PubMed was based on combinations of prostate cancer, CYP1A1, CYP1A1 gene polymorphism, and genetic susceptibility. The last search update was May 2008. The retrieved articles and their bibliographies of were evaluated and reviewed independently by 2 experts. We shortlisted 19 studies, of which 14 on sporadic prostate cancer were analyzed. Overall, 2573 patients with prostate cancer and 2576 controls were analyzed. The random effects odds ratio was 1.350 (95% confidence interval, 1.110 to 1.641; P = .003) for T/C polymorphism and 1.085 (95% confidence interval, 0.863 to 1.364; P = .49) for A/G polymorphism. The A/G polymorphism was not associated with increased risk of prostate cancer. However, the T/C polymorphism showed conflicting results in different studies, while overall, this polymorphism showed significant effects on the susceptibility to prostate cancer. There was no significant between-study heterogeneity for both polymorphisms with respect to distribution of alleles. This meta-analysis suggests that while the CYP1A1 T/C polymorphism is likely to considerably increase the risk of sporadic prostate cancer on a wide population basis, the A/G polymorphism may not influence this risk. However, the association of polymorphisms may be significant with respect to smoking history, diet habits, ethnicity, and race.

Polymorphism of cytochrome P450 2B6 and prostate cancer risk: A significant association in a Japanese population

To explore whether Lys262Arg polymorphism of the Cytochrome P450 2B6 (CYP2B6) gene could act as a genetic marker for prostate cancer risk among Japanese men. A total of 350 patients with sporadic prostate cancer and 328 controls were examined. A single nucleotide polymorphism with non-synonymous amino acid change located at Lys262Arg of the CYP2B6 gene was genotyped using a TaqMan assay. The frequency of the Arg/Arg genotype among prostate cancer patients was significantly higher than that among the controls (P = 0.027). The frequency of the G allele of the Lys262Arg polymorphism was also significantly higher in prostate cancer patients than in the controls (30.4% vs 24.8%, P = 0.025). Patients with the Lys/Arg plus Arg/Arg genotypes carried a low Gleason score more frequently than those with the Lys/Lys genotype (P = 0.042). The frequency of the G allele of the Lys262Arg polymorphism was significantly higher in the low Gleason score group than that in the high Gleason score group (34.3% vs 26.8%, P = 0.038). Lys262Arg polymorphism of the CYP2B6 gene may be a genetic marker for evaluating the risk of sporadic prostate cancer in native Japanese men.

Chromosome 8q24 markers: Risk of early‐onset and familial prostate cancer

Recent admixture mapping and linkage/association studies have implicated an approximately 1 Mb region on chromosome 8q24 in prostate cancer susceptibility. In a subsequent follow-up investigation, Haiman et al. (Nat Genet 2007;39:638-44) observed significant, independent associations between 7 markers within this region and sporadic prostate cancer risk in a multi-ethnic sample. To clarify the risk associated with hereditary prostate cancer, we tested for prostate cancer association with 6 of these 7 markers in a sample of 1,015 non-Hispanic white men with and without prostate cancer from 403 familial and early-onset prostate cancer families. Single nucleotide polymorphisms (SNPs) rs6983561 and rs6983267 showed the strongest evidence of prostate cancer association. Using a family-based association test, the minor ("C") allele of rs6983561 and the major ("G") allele of rs6983267 were preferentially transmitted to affected men (p < 0.05), with estimated odds ratios (ORs) of 2.26 (95% confidence interval of 1.06-4.83) and 1.30 (95% confidence interval of 0.99-1.71), respectively, for an additive model. Notably, rs6983561 was significantly associated with prostate cancer among men diagnosed at an early (<50 years) but not later age (p = 0.03 versus p = 0.21). Similarly, the association with rs6983267 was (not) statistically significant among men with(out) clinically aggressive disease (p = 0.007 versus p = 0.34). Our results confirm the association of prostate cancer with several of the SNPs on chromosome 8q24 initially reported by Haiman et al. In addition, our results suggest that the increased risk associated with these SNPs is approximately doubled in individuals predisposed to develop early onset or clinically aggressive disease.

Mismatch Repair Gene MSH3 Polymorphism is Associated With the Risk of Sporadic Prostate Cancer

The mismatch repair system is a DNA repair mechanism that corrects mispaired bases during DNA replication errors. Cancer cells deficient in MMR proteins have a 10(2) to 10(3)-fold increase in the mutation rate. Single nucleotide polymorphisms of mismatch repair genes have been shown to cause a decrease in DNA repair activity. We hypothesized that mismatch repair gene polymorphism could be a risk factor for prostate cancer and p53 Pro/Pro genotype carriers could influence MSH3 and MSH6 polymorphisms. DNA samples from 110 patients with prostate cancer and 110 healthy controls were analyzed by single strand conformational polymorphism and polymerase chain reaction-restriction fragment length polymorphism to determine the genotypic frequency of 5 polymorphic loci on 2 MMR genes (MSH3 and MSH6) and p53 codon72. The chi-square test was applied to compare genotype frequency between patients and controls. A significant increase in the G/A+A/A genotype of MSH3 Pro222Pro was observed in patients compared to controls (OR 1.87, 95% CI 1.0-3.5). The frequency of A/G + G/G genotypes of MSH3 exon23 Thr1036Ala also tended to increase in patients (OR 1.57, 95% CI 0.92-2.72). In p53 codon72 Arg/Pro + Pro/Pro carriers the frequency of the AG + GG genotype of MSH3 exon23 was significantly increased in patients compared to controls (OR 2.1, 95% CI 1.05-4.34). To our knowledge this is the first report of the association of MSH3 gene polymorphisms in prostate cancer. These results suggest that the MSH3 polymorphism may be a risk factor for prostate cancer.

Truncating Variants in p53AIP1 Disrupting DNA Damage–Induced Apoptosis Are Associated with Prostate Cancer Risk

Germ line mutations in several genes (BRCA1, BRCA2, and CHEK2) whose products are involved in the DNA damage-signaling pathway have been implicated in prostate cancer risk. To identify additional genes in this pathway that might confer susceptibility to this cancer, we analyzed a recently identified DNA damage-response gene, p53AIP1 (a gene encoding for p53-regulated apoptosis-inducing protein 1), for genetic variants in prostate cancer. Five novel germ line variants were identified. The two truncating variants (Ser(32)Stop and Arg(21)insG) were found in 3% (4 of 132) of unselected prostate tumor samples. Genotyping of the two variants in an additional 393 men with sporadic prostate cancer showed a frequency of 3.1% (12 of 393) in contrast to 0.6% (2 of 327) in 327 unaffected men (Fisher's exact test, P = 0.018), with an odds ratio (OR) of 5.1 [95% confidence interval (95% CI), 1.1-23.0]. In addition, two of six tumors carrying the truncating variants were associated with loss of heterozygosity of the wild-type alleles, suggesting that p53AIP1 may act as a tumor suppressor. We also showed that the truncated p53AIP1 was unable to induce apoptosis and suppress cell growth in HeLa and COS-7 cells. These results suggest that loss-of-function variants in p53AIP1 associated with the risk of sporadic prostate cancer and further support the concept that the genetic defects in the DNA damage-response genes play an important role in the development of prostate cancer.

HER‐2 gene polymorphism at codon 655 in familial prostate cancer in a Japanese population

AbstractBackground: The Ile to Val polymorphism at codon 655 of HER‐2 was reported to be associated with a risk of sporadic prostate cancer and breast cancer. In this study, we examined the association of the HER‐2 polymorphism with familial prostate cancer in a Japanese population.Materials and methods: We performed a case‐control study consisting of 144 familial prostate cancer cases and 119 normal control subjects. The genetic polymorphism was analyzed by the restriction fragment length polymorphism method.Results: There was no significant difference between the case group and the control group for the allele or genotype distribution.Conclusion: In the present study, we could not confirm any significant association between the HER‐2 polymorphism with familial prostate cancer risk in a Japanese population. Further large‐scale studies are warranted to confirm the association of the HER‐2 polymorphism with the risk of development of prostate cancer.

Genetic Analysis of the RNASEL Gene in Hereditary, Familial, and Sporadic Prostate Cancer

The RNASEL gene has been proposed as a candidate gene for the HPC1 locus through a positional cloning and candidate gene approach. Cosegregation between the truncating mutation E265X and disease in a hereditary prostate cancer (HPC) family and association between prostate cancer risk and the common missense variant R462Q has been reported. To additionally evaluate the possible role of RNASEL in susceptibility to prostate cancer risk, we performed a comprehensive genetic analysis of sequence variants in RNASEL in the Swedish population. Using 1624 prostate cancer cases and 801 unaffected controls, the truncating mutation E265X and five common sequence variants, including the two missense mutations R462Q and D541E, were evaluated for association between genotypes/haplotypes and prostate cancer risk. The prevalence of E265X carriers among unaffected controls and prostate cancer patients was almost identical (1.9 and 1.8% in controls and cases, respectively), and evidence for segregation of E265X with disease was not observed within any HPC family. Overall, the analyses of common sequence variants provided limited evidence for association with prostate cancer risk. We found a marginally significant inverse association between the missense mutation D541E and sporadic prostate cancer risk (odds ratio, 0.77; 95% confidence interval, 0.59-1.00) and reduced risk of prostate cancer in carriers of two different haplotypes being completely discordant. Considering the high quality in genotyping and the size of this study, these results provide solid evidence against a major role of RNASEL in prostate cancer etiology in Sweden.

H6D polymorphism in macrophage-inhibitory cytokine-1 gene associated with prostate cancer.

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. 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). 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. 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.