Association of HER-2 polymorphism with Japanese sporadic prostate cancer susceptibility

BACKGROUND: Genetic polymorphisms may affect the development of prostate cancer (Pca). HER-2 is a proto-oncogene that has an important role in many human cancers, including Pca. To determine the association of the HER-2 gene with Japanese sporadic Pca, we analyzed the frequency of codon 655 (A/G, isoleucine, or valine) in case and control group. METHODS: We genotyped Ile 655 Val in Pca patients (n = 285) and in matched controls (n = 233). Statistical analyses were performed by Fisher's exact test and logistic regression analysis. RESULTS: We observed a significantly lower frequency of the Val655 allele in the Pca patients (14.7%) compared to the control group (26.2%) (P = 0.0025, odds ratio (OR) = 0.476, 95% CI = 0.306-0.740). This SNP was not found to be correlated with clinical stage, PSA level, Gleason score of biopsies or age at diagnosis. CONCLUSIONS: Our results indicate that the frequency of Val655 in HER-2 was significantly lower in Japanese Pca patients, however, it was recently reported that Val655 was significant higher in breast cancer patients. This contradictory observation in prostate and breast cancer patients is interesting considering the opposite hormonal sensitivity of these two cancers.     

Low-activity V89L variant in SRD5A2 is associated with aggressive prostate cancer risk: an explanation for the adverse effects observed in chemoprevention trials using 5-alpha-reductase inhibitors

OBJECTIVE: The 5-alpha-reductase type 2 (5A2) enzyme catalyses the irreversible conversion of testosterone to dihydrotestosterone, the most active androgen in the prostate. This key enzyme in prostate gland physiopathology has recently been targeted by using inhibitors for chemoprevention of prostate cancer. However, some controversies have arisen by the observation of greater than expected high-grade tumours in men diagnosed with prostate cancer in the finasteride chemoprevention trial. To help understand the impact of prolonged exposure to low 5A2 activity on prostate cancer risk, we analysed the rather common genetic V89L polymorphism, which has previously been well characterised functionally for determining low enzymatic activities. METHODS: The study was performed on 1605 white Caucasian French men categorised in 803 patients with prostate adenocarcinoma and 802 matched healthy male controls. The different alleles and genotypes were analysed according to case-control status and the aggressiveness pattern of the tumours. RESULTS: The V89L amino acid substitution leading to the homozygous genotype LL increased the risk of clinically significant disease (odds ratio [OR]=1.89, 95% confidence interval (%95 CI), 1.07-2.74; p=0.0017) and was also associated with the most aggressive patterns of the disease (OR=2.56, 95%CI, 1.41-4.63; p=0.002). CONCLUSIONS: Our data confirm in a large and homogeneous Caucasian French population that the low-activity V89L variant is associated with an increased risk of aggressive prostate cancer. These results corroborate that long-term exposure to 5A2 inhibitors (chemoprevention) must be evaluated in terms of risk of prostate cancer adverse effects.     

Association between FAS polymorphism and prostate cancer development

The role of FAS polymorphisms in prostate cancer has not been studied. Using the PCR-based restriction fragment-length polymorphism methodology, we evaluated FAS gene locus -670 genotypes in DNA from 904 men: 657 prostate cancer patients and 247 healthy controls. We found that carriers of AG or GG genotypes have a statistically significant protection (odds ratio (OR)=0.30; confidence interval (CI): 0.20-0.44 and OR=0.22; CI: 0.12-0.74, respectively) for disease with extra-capsular invasion. Taken together, a 72% protection was found for G allele carriers (OR=0.28; CI: 0.19-0.41). Fas exist as membrane-bound and soluble forms and with opposite roles. They derive from the same gene by alternative splicing. Membrane Fas receptors trigger apoptosis whereas, on the other hand, soluble Fas (sFas) bind to Fas ligand antagonizing Fas-Fas ligand apoptotic pathway. Our results suggest that G allele may reduce sFas levels preventing the apoptotic inhibition caused by the soluble form.     

Vitamin D receptor gene polymorphism in familial prostate cancer in a Japanese population

AIM: Vitamin D acts as an antiproliferative agent against prostate cells. Epidemiological study has shown that a low level of serum vitamin D concentration is a risk factor for prostate cancer. Vitamin D acts via vitamin D receptor (VDR), and an association of genetic polymorphisms of the VDR gene has been reported. In the current study, we examined the association of VDR gene polymorphisms with familial prostate cancer in a Japanese population. METHODS: We performed a case-control study consisting of 81 familial prostate cancer cases and 105 normal control subjects. Three genetic polymorphisms (BsmI, ApaI and TaqI) in the VDR gene were examined by the restriction fragment restriction length polymorphism method. RESULTS: Overall, there was no significant association of the VDR gene polymorphisms with familial prostate cancer risk in the cases and control subjects. However, a weak association between BsmI or TaqI genotypes and cancer risk was observed in subjects under 70 years of age. Stratification of cases by clinical stage or pathological grade did not show significant association between the VDR gene polymorphisms and prostate cancer risk. CONCLUSION: In the present study, we could not confirm any significant association between VDR gene polymorphisms with familial prostate cancer risk in a Japanese population. Further large-scale case-control studies are warranted to confirm the importance of VDR gene polymorphisms in familial prostate cancer.     

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

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

HPC2/ELAC2 polymorphism associated with Japanese sporadic prostate cancer

BACKGROUND: HPC2/ELAC2 gene was identified by linkage analysis from familial prostate cancer (Pca) patients in USA. To determine the association of HPC2/ELAC2 gene with Japanese sporadic Pca, we performed a case-control study focused on two missense polymorphisms. METHODS: We genotyped the two polymorphic sites of Ser217Leu and Ala541Thr in sporadic Japanese Pca patients (n = 285) and matched controls (n = 233). Controls were unrelated Japanese outpatients who had no history of any cancer and normal PSA level (less than 4.0 ng/ml). Statistical analyses were performed by Mann-Whitney's U-test, Fisher's exact test, and logistic regression analysis. RESULTS: We observed a significantly higher frequency of the Thr allele at 541 polymorphic site in Pca patients (8.4%) compared to the control group (2.1%) (P = 0.0030, Odds Ratio (OR) = 4.02, 95% CI = 1.50-10.8). However, this SNP does not correlate with clinical stage, PSA level, Gleason score of biopsies or age at diagnosis. No association was identified at Ser217Leu polymorphic site. CONCLUSIONS: Our results indicate that Thr allele at 541 in HPC2/ELAC2 has strong significance in the predisposition of sporadic Pca in Japan. This polymorphism can be useful to predict the personal Pca risk, which lead the effective screening of Pca.     

前列腺癌发生风险与CYP3A5基因多态性的关系

目的 探讨CYP3A5基因多态性与前列腺癌发生风险和病理特点的关系。方法 采用限制性片段多态性分析法对356例前列腺癌患者和306个男性对照中CYP3A5基因第3内含子多态性进行了研究。结果 在前列腺癌和对照组之间CYP3A5基因型分布差异无显著性(P=0．063)，但两组间CYP3A5*1等位基因的分布差异存在显著性(P=0．025)；与携带CYP3A5*3*3基因型者相比，携带CYP3A5*1等位基因的男性患前列腺癌的风险降低了30％(P=0．026)。在不同分期和分级的前列腺癌患者之间CYP3A5基因型分布差异无显著性(P=0．904和0．986)。结论 CYP3A5基因中的CYP3A5*1等位基因可能与前列腺癌的患病风险降低有关。     

Evaluation of SRD5A2 sequence variants in susceptibility to hereditary and sporadic prostate cancer

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.     

Association of the ABCG2 C421A polymorphism with prostate cancer risk and survival

OBJECTIVE

To determine if the C421A single nucleotide polymorphism (SNP) in the ATP‐binding cassette transporter ABCG2 increases prostate cancer risk or affects survival.

PATIENTS, SUBJECTS AND METHODS

Numerous studies have suggested that dietary, hormonal and environmental factors all play a role in the initiation in prostate cancer; among these, the carcinogenic heterocyclic amine 2‐amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine (PhIP), a known substrate of the ABCG2. A SNP of ABCG2, C421A, resulting in a glutamine to lysine change at amino acid 141, has been shown to result in decreased function of the protein. Due to the expression of ABCG2 in the prostate, together with the purported role of dietary carcinogens and steroids in the development and progression of prostate cancer, 311 individuals were genotyped for the ABCG2 C421A SNP, 170 patients with androgen‐independent prostate cancer (AIPC) and 141 ‘healthy’ controls. We also evaluated the effect of this SNP on the intracellular accumulation of PhIP and testosterone in vitro.

RESULTS

There were no significant differences in the prevalence of prostate cancer based on ABCG2 genetic variation in this population. However, survival was significantly longer for individuals with wild‐type ABCG2, as compared with those hetero‐ or homozygous for the C421A SNP (7.4 years vs 5.3 years, P = 0.044). Intracellular accumulation of PhIP was 80% higher in HEK293 cells transfected with Q141K ABCG2 than in wild‐type cells, confirming that this SNP decreases transport of PhIP. In contrast, testosterone was not transported by either wild‐type or variant transfected cells, nor did it act as in inhibitor of ABCG2 in subsequent transport assays.

CONCLUSION

Increased exposure to PhIP may decrease survival, but the ABCG2 C421A polymorphism does not appear to increase the risk of prostate cancer.     

Somatic mutations at the SRD5A2 locus encoding prostatic steroid 5alpha-reductase during prostate cancer progression

Prostate cancer is a serious public health problem in many industrialized countries. Androgens appear to play a critical role in its etiology. Specifically, the active androgen in the prostate, dihydrotestosterone (DHT) which is synthesized by the enzyme steroid 5alpha-reductase from testosterone (T), acts as a mitogen. Hence androgen-deprivation is commonly used during prostate cancer therapy. Two isozymes for steroid 5alpha-reductase have been reported. The type II enzyme is prostate-specific and encoded by the SRD5A2 gene. We have investigated a polymorphic (TA)n dinucleotide repeat in the 3' UTR (untranslated region) of the SRD5A2 gene in 30 matched samples of constitutional ("germline") DNA from peripheral blood lymphocytes and microdissected, pure tumor DNA. We report here 8 LOH (loss of heterozygosity) events and 9 cases of microsatellite instability at this marker. Therefore, almost 57% of the samples examined showed evidence of somatic mutations at the 3' UTR of the SRD5A2 locus. Our data suggest that the SRD5A2 gene may be involved in prostate cancer progression and that this may have relevance for treatment of the disease.     

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

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

N-acetyltransferase-2 gene polymorphism as a possible biomarker for prostate cancer in Japanese men

BACKGROUND: The purpose of this study was to determine the frequency of a polymorphism of the candidate metabolic enzyme N-acetyltransferase-2 (NAT2) in Japanese prostate cancer patients and Japanese non-cancer controls, in order to determine if an association exists between NAT2 genotype and the occurrence, clinical stage and grade of prostate cancer. METHODS: In the present case-control study, 111 patients with prostate cancer and 152 controls were genotyped for the NAT2 polymorphism using the polymerase chain reaction-based restriction fragment length polymorphism method. The NAT2 genotypes (slow or rapid acetylator genotype) were determined by the combination of three known NAT2 mutant alleles (M1, M2, M3) and the wild-type allele. RESULTS: The NAT2 slow acetylator genotype was statistically higher among prostate cancer patients (17.1%) compared with controls (8.6%) (Odds ration (OR) = 2.21; 95% confidence interval (CI), 1.04-4.69; P = 0.0289). In addition, there was a statistically increased risk of prostate cancer among smokers with the NAT2 slow genotype (OR = 3.78: 95% CI, 1.48-9.66; P = 0.0041). Furthermore, the NAT2 slow acetylator genotype was significantly higher among prostate cancer patients with locally advanced and metastatic disease (22.7%) compared with controls (8.6%) (OR = 3.14; 95% CI, 1.40-7.06; P = 0.0051). Lastly, the NAT2 slow acetylator genotype was significantly higher among prostate cancer patients with high-grade tumors (31.4%) compared with controls (8.6%) (OR = 4.90; 95% CI, 1.97-12.20; P = 0.0010). CONCLUSION: These data demonstrate that the NAT2 slow acetylator genotype plays an important role in determining the risk of developing prostate cancer in Japanese men and is also associated with more clinically advanced and pathologically aggressive disease. Furthermore, a possible interaction between the NAT2 slow acetylator genotype and smoking status was suggested.     

A novel SRD5A2 mutation in an Iranian family with sex development disorder

Disorders of sex development (DSD) are different types of conditions that their accurate diagnosis by using conventional phenotypic and biochemical approaches is a challenging issue. Precise determination of DSD is critical due to the detection of possible life-threatening associated disorders. It may also assist parents in choosing the most suitable management for their affected child. In this study, two affected kids born from consanguineous families who were clinically diagnosed for sex development disorder were investigated for the main cause of the disease. Biochemical analysis failed to make an accurate diagnosis. Karyotype analysis showed an abnormal sex chromosome pattern. Whole exome sequencing was sequentially applied to precisely ascertain the genetic cause of the disease. A novel deletion, g.40936_53878del12943insTG (NG_008365.1), and one known mutation, c.586G>A (p.Gly196Ser), were detected in SRD5A2 gene in case I and case II respectively. Further analysis was performed using polymerase chain reaction, primer walking and Sanger sequencing to detect the nucleotides changes accurately. Segregation analysis in the families confirmed 13kb novel homozygous deletion of SRD5A2 in case I and c.586G>A in case II. The present study confirms the diagnostic value of whole exome sequencing in the detection of DSD aetiology, especially when several differential diagnoses are possible.     

Findings from a prostate cancer screening program in a Japanese population

Although Asia has a very low incidence of prostate cancer in comparison with other Asian countries, Japan has one of the highest incidence （30.4 per 100 000） and mortality rates （5 per 100 000） from prostate cancer, according to the 2012 GLOBOCAN estimates. Kitagawa et al. conducted a retrospective analysis of the populationbased trends of prostate-specific antigen （PSA） screening conducted in men, between the ages of 54 and 69 years in Kanazawa city, which comprises of about a third of the Japanese population. In this annual screening program, they demonstrated a decreasing trend in the median serum PSA levels in men diagnosed with prostate cancer,