Association of SNP rs1447295 and microsatellite marker DG8S737 with familial prostate cancer and high grade disease.

PURPOSE: Several prior studies show a relationship between genetic markers at chromosome 8q24 and an increased prostate cancer risk. We confirmed the association of 8q24 markers with prostate cancer in the Japanese population and the association of these genetic variants with clinical characteristics. MATERIALS AND METHODS: Included in this study were 134 patients with familial prostate cancer, 158 with sporadic prostate cancer and 119 controls. All were Japanese. We genotyped the 2, 8q24 markers SNP rs1447295 and microsatellite marker DG8S737 using real-time polymerase chain reaction and polymerase chain reaction based assay with fluorescence labeled primers. RESULTS: There was a significant positive association between the DG8S737 -12 allele and familial prostate cancer risk (OR 1.86, 95% CI 1.11-3.00, p = 0.02) and a significant association of risk with the rs1447295 A allele (OR 2.36, 95% CI 1.41-3.94, p = 0.002). Significant associations were noted for each marker in men with a high Gleason score. CONCLUSIONS: Two alleles at 8q24 are genetic risk factors for familial prostate cancer and high grade disease.

[Prognostic factors for estrogen therapy of relapsed prostate cancer after maximal androgen blockade (MAB)].

PURPOSE: Advanced prostate cancer responds well to endocrine therapy initially, but soon becomes refractory and has a poor prognosis. We analyzed the prognostic factors of prostate cancer responding well initially to maximal androgen blockade (MAB) but later showing PSA relapse and treated with estrogen. MATERIALS AND METHODS: In prostate cancer patients newly diagnosed from January 1992 to December 2008 at our institution, there were 85 patients in that the PSA level dropped below 10 ng/ml by MAB, but showed PSA relapse thereafter and treated with estrogen. We investigated the relationship between age at diagnosis, clinical stage, pathological differentiation, initial PSA, the value of PSA nadir, duration between diagnosis and initiation of estrogen therapy, duration between PSA failure and initiation of estrogen therapy, the value of PSA at estrogen therapy, PSA doubling time (PSA-DT) at estrogen therapy, PSA response three months after initiation of estrogen therapy, use of diethylstilbestrol diphosphate (DES-P) at the initial stage of therapy, local radiotherapy to prostate, type of estrogen and prognosis after estrogen therapy. RESULTS: In Kaplan-Meier method, factors which showed poorer prognosis were stage B and D, poorly differentiated, PSA 11.9 ng/ml or higher at estrogen therapy, PSA-DT shorter than 2.3 months before estrogen therapy and PSA response without CR three months after initiation of estrogen therapy. In multivariate analysis, the factor that most significantly affected prognosis after estrogen therapy was PSA response three months after initiation of estrogen therapy (hazard ratio: 12.61), followed by PSA-DT at estrogen therapy (hazard ratio: 2.59). CONCLUSION: We investigated the prognostic factors refractory to MAB and treated with estrogen. These results are useful in planning the therapy, and in explaining the status or future prospective of the disease to families and patients.

Further evidence for null association of phenol sulfotransferase SULT1A1 polymorphism with prostate cancer risk: a case-control study of familial prostate cancer in a Japanese population.

Sulfation is a key pathway in xenobiotic metabolism and chemical defense, and phenol sulfotransferase SULT1A1 plays a central role in this reaction. Genetic polymorphism of the SULT1A1 gene, SULT1A1, was reported to be associated with risks of several cancers; however, one study showed no significant relation between SULT1A1 genotype with prostate cancer risk. The present study was conducted to confirm the association of a G638A polymorphism, Arg213His, in SULT1A1 with familial prostate cancer risk in a Japanese population. A case-control study consisting of 126 cases and 119 controls was performed. In controls, GG, GA, and AA genotypes were observed in 85 (71.4%), 32 (26.9%), and 2 (1.7%), respectively; whereas, GG, GA, and AA genotypes were observed in 94 (74.6%), 32 (25.4%), and 0 cases, respectively. No significant differences were found in genotypic frequencies among cases and controls. Furthermore, stratification of cases according to clinical stages (localized or metastatic), pathological grades (Gleason score <7, or >7), age at diagnosis (<70 years or >70) and the number of affected relatives (2 or >2) did not show any significant differences among categories. These findings suggested that genetic polymorphism of SULT1A1 might not be involved in genetic susceptibility to prostate cancer.

[Clinical study on poor PSA response to initial endocrine therapy with MAB or estrogenic drugs for treatment of prostate cancer].

PURPOSE: The prostate specific antigen (PSA) level usually is lowered in response to initial endocrine therapy even in advanced cases of prostate cancer, but in some cases, it is not. We examined the cases in which the PSA level was not sufficiently lowered by initial endocrine therapy with maximal androgen blockade (MAB) or estrogenic drugs. MATERIALS AND METHODS: The subjects were 20 patients with prostate cancer diagnosed between January 1992 and December 2005 whose PSA level was not lowered below 10 ng/ml after initial endocrine therapy with MAB or estrogenic drugs. We investigated the frequency of cases, pretreatment PSA levels, PSA nadir levels after initial endocrine therapy and throughout the therapy, PSA response to second line therapy, and the prognosis. RESULTS: The PSA level was not lowered below 10 ng/ml after initial endocrine therapy with MAB or estrogenic drugs in 4.9% of the cases. Cancer-specific survival rates in all cases were extremely poor, 75.0% at 1 year and 14.7% at 3 years. Prognosis tended to be worse in patients with a higher PSA nadir level throughout the therapy and on whom second therapy was not effective, although the difference was not statistically significant. CONCLUSION: The patients whose PSA levels were not lowered sufficiently by MAB or estrogenic drugs had an extremely poor prognosis. These results are useful in planning the therapy, and in explaining the status or future prospective of the disease to patients and their families.

[A case of combination with proliferative cystitis and pelvic lipomatosis causing bilateral hydronephrosis].

A 70-year-old man consulted our hospital complaining of gross hematuria and bilateral hydronephrosis. Cystoscopic findings suggested non-papillary sessile tumor at the bladder neck. CT findings revealed bilateral hydronephrosis caused by the stricture of lower ureters. Tumorous structure existed between bladder and prostate. Abundant fatty tissue was observed around bladder and rectum, the shape of the bladder was distorted to inverted tear-drop and the bladder was transferred anteriorly, showing findings of pelvic lipomatosis. Urethrocystography revealed elongation of prostatic urethra and anterior displacement of the bladder. Transurethral tumor resection was performed under spinal anesthesia. Pathological diagnosis was proliferative cystitis and no malignant cells were observed. Transperineal tumor biopsy also revealed no malignant cells. The patient was followed under administration of "Saireitou" (chinese medicine) and cetirizine hydrochloride, followed by antibiotics and anti-inflammatory enzyme preparations.

Association of the polymorphisms of genes involved in androgen metabolism and signaling pathways with familial prostate cancer risk in a Japanese population.

BACKGROUND: Androgen plays a central role in the normal and malignant development of prostate glands. Genetic polymorphisms of genes involved in androgen metabolism and signaling might be associated with the risk of prostate cancer. METHODS: One hundred and two patients with prostate cancer with a family history and 117 healthy age- and residence-matched male controls were enrolled. Genotypes of the CAG repeat length of androgen receptor (AR), CYP17, 5alpha-reductase type II (SRD5A2), UDG-glucuronosyltransferase (UGT) 2B15, PSA promoter genes were analyzed. RESULTS: For single polymorphisms, the presence of Y alleles showed a significantly lower risk of prostate cancer in comparison with the D/D genotype in UGT2B15 (odds ratio [OR]=0.41, 95% confidence interval [CI]=1.40-4.28, p=0.0015), and the presence of A2 alleles showed a weak tendency to decrease prostate cancer risk in comparison with the A1/A1 genotype in CYP17 (OR=0.69, 95% CI=0.39-1.23, p=0.21). The stratification of cases according to clinical stage and pathological grade showed that the A2/A2 genotype was significantly associated with localized stage cancer in comparison with metastatic stage cancer (OR=5.18, 95% CI=1.49-17.95, p=0.007). The combination of UGT2B15 and CYP17 genotypes could identify higher risk subjects even in subjects with low-risk UGT2B15 genotypes, i.e., Y/Y+D/Y genotypes (OR=1.97, 95% CI=0.92-4.22, p=0.079). CONCLUSION: Genetic polymorphisms of the genes involved in androgen metabolism and signaling were significantly associated with familial prostate cancer risk. Single nucleotide polymorphisms of low-penetrance genes could be targets to understand genetic susceptibility to familial prostate cancer.

[Prognostic factors for PSA relapse of prostate cancer after endocrine therapy].

PURPOSE: Advanced prostate cancer responds well to endocrine therapy initially, but soon becomes refractory and has a poor prognosis. We analyzed the prognostic factors of prostate cancer responding well initially to endocrine therapy with lowering of serum prostate specific antigen (PSA) level but later showing PSA relapse. MATERIALS AND METHODS: In prostate cancer patients newly diagnosed from January 1992 to December 2004 at our institution, there were 93 patients in that the PSA level of 10 ng/ml or more before therapy initially dropped below 10 ng/ml by endocrine therapy, but showed PSA relapse thereafter. We investigated the relationship between clinical stage, pathological differentiation, initial PSA, duration between initiation of therapy and PSA nadir, the value of PSA nadir, duration between initiation of therapy and PSA relapse, PSA doubling time (PSA-DT) at relapse, PSA response three months after initiation of second line therapy and prognosis after PSA relapse. RESULTS: In Kaplan-Meier method, between all or some categories investigated showed significant difference in prognosis after PSA relapse. In multivariate analysis, the factors that significantly affected prognosis after PSA relapse were clinical stage, pathological differentiation, PSA nadir value, duration between initiation of therapy and PSA relapse and PSA response three months after initiation of second line therapy. CONCLUSION: We investigated the prognostic factors refractory to endocrine therapy. These results are useful in planning the therapy, and in explaining the status or future prospective of the disease to patients and families.

[A case of prostate cancer diagnosed pathologically by bone metastatic site biopsy].

A 61-year-old man consulted our hospital complaining of high prostate specific antigen (PSA) value and difficulty to urinate. Prostate biopsy had been performed at another hospital, but did not reveal cancer. PSA was 18.5 ng/ml. Transrectal ultrasound-guided prostate biopsy was performed, but cancer was not detected. Later, PSA rose rapidly, and findings suggesting bone metastasis at right pubic bone and left sacro-ilial joint were found on computed tomography (CT), bone scintigraphy and magnetic resonance imaging (MRI). A repeat prostate biopsy was performed, but cancer was not detected from the prostate. On right pubic bone biopsy, poorly to moderately differentiated adenocarcinoma was detected. PSA immunohistochemical staining was positive, and the diagnosis was bone metastasis from prostate cancer. After endocrine therapy was started, PSA declined and bone metastasis disappeared on bone scintigraphy.

[Prognostic factors of superficial bladder cancer recurring after initial transurethral resection].

About 70% of bladder cancers are superficial at the initial state. If diagnosed at an early stage, the tumor may be resected completely and easily. However, recurrence is seen in many cases. Prognostic factors of recurrence were investigated in 55 cases of bladder cancer newly diagnosed (excluding carcinoma in situ) between 1995 and 2003, and in which complete resection by transurethral resection (TUR) was possible at first recurrence after initial TUR. One- and three-year postoperative non-recurrence rates were 51.9% and 36.3%, respectively. None of the factors studied, i.e., stage, grade, tumor multiplicity (at initial and at first recurrence), change of stage and grade at first recurrence compared with that of initial TUR, duration to recurrence and adjuvant therapy after TUR, were found to influence the prognosis after recurrence. Similar results were obtained for third TUR. Recurred pTa, grade 1 or solitary cancer at initial or at recurrence had the same prognosis as pT1, grade 2-3 or multiple cancers, and careful follow-up is needed.

[Chronological changes of incidence rates, clinical stages and pathological differentiation of prostate cancer in Gunma Prefecture, Japan].

Prostate cancer is the most common urogenital cancer, and is increasing rapidly. We performed an epidemiological study on prostate cancer in Gunma Prefecture, Japan. Registration of prostate cancer patients diagnosed at clinics and hospitals in and around Gunma Prefecture was started at Gunma University in 1985. The epidemiological characteristics of prostate cancer patients in Gunma Prefecture were analyzed by these data. The incidence and crude incidence rates have increased five-fold, from 114 and 12.0 in 1985 to 539 and 53.9 in 2000, respectively. The age-adjusted incidence rate (adjusted to the world population) was increased three-fold, from 8.3 in 1985 to 24.2 in 2000. The age-specific incidence rate showed an increase with age. The cancers in clinical stages A and D decreased, while those in stages B and C increased. No change in distribution was observed in pathological differentiation. Prostate cancer has increased rapidly during these 16 years in Gunma Prefecture. It is important to perform PSA testing aggressively in males age 50 or older, and detect prostate cancer in an early stage.

Genomewide linkage analysis of familial prostate cancer in the Japanese population.

Prostate cancer (PC) is one of the most common causes of cancer mortality in Western countries, and familial aggregation of PC is well known. Multiple PC susceptibility loci have been reported in Western countries, but attempts to confirm the loci in independent data sets have proven to be inconsistent. We performed a genomewide linkage analysis with 53 affected sib pairs to identify genetic loci related to PC in a Japanese population. Two linkage analyses, GENEHUNTER-PLUS and SIBPAL, were applied and detected nominal statistical significance of linkage to PC at chromosome 1p and 8p, which were reported as being loci for PC in Caucasians. The best evidence of linkage was detected near D8S550 on 8p23 (maximum Zlr=2.25, P=0.037), and the second-best evidence of linkage was observed near D1S2667 on 1p36 (maximum Zlr=2.24, P=0.034). This is the first genetic mapping of PC in Japanese, and the results suggest that susceptibilities to PC lie close to D8S550 on 8p23 and D1S2667 on 1p36.

Genetic polymorphisms of estrogen receptor alpha, CYP19, catechol-O-methyltransferase are associated with familial prostate carcinoma risk in a Japanese population.

BACKGROUND: Estrogen is one of the crucial hormones participating in the proliferation and carcinogenesis of the prostate glands. Genetic polymorphisms in the estrogen metabolism pathway might be involved in the risk of prostate carcinoma development. The authors evaluated the association between genetic polymorphisms in estrogen-related enzymes and receptors and the risk of developing familial prostate carcinoma. METHODS: In the current study, 101 cases with prostate carcinoma whose first-degree relatives had prostate carcinoma and 114 healthy age and residence-matched male controls were enrolled. The genotypes of estrogen receptor (ER) alpha, aromatase (CYP19), and catechol-O-methyltransferase (COMT) genes were analyzed. RESULTS: For single polymorphisms, a significant association of the T/T genotype of the PvuII site in the ER alpha gene (odds ratio [OR], 3.44; 95% confidence interval [CI], 1.97-5.99; P = 0.0028), and the C/T and T/T genotypes of the CYP19 gene (OR, 1.77; 95% CI, 1.02-3.09; P = 0.037) with prostate carcinoma risk, was observed. The G/A genotype of the COMT gene showed a weak tendency toward increased risk (OR, 1.48; 95% CI, 0.85-2.57; P = 0.18). Stratification of cases according to clinical stage and pathologic grade showed that the C/T and T/T genotypes of the CYP19 gene were associated significantly with high-grade carcinoma (OR, 2.59; 95% CI, 1.47-4.46; P = 0.048). The number of high-risk genotypes (the T/T in ER alpha, the C/T and T/T in CYP19, and the G/A in COMT) significantly increased the risk of developing prostate carcinoma (2 genotypes: OR, 3.00; 95% CI, 1.72-5.23; P = 0.008; 3 genotypes: OR, 6.30; 95% CI, 3.61-10.99; P = 0.002). CONCLUSIONS: Genetic polymorphisms of genes in the estrogen metabolism pathway were associated significantly with familial prostate carcinoma risk. Single nucleotide polymorphisms of low-penetrance genes are targets for understanding the genetic susceptibility of familial prostate carcinoma.

Association of genetic polymorphisms of glutathione-S-transferase genes (GSTM1, GSTT1 and GSTP1) with familial prostate cancer risk in a Japanese population.

BACKGROUND: Glutathione-S-transferases (GSTs) are active in the detoxification of a wide variety of toxins and carcinogens. The genetic polymorphisms of GSTM1, GSTT1 and GSTP1 genes have been studied to estimate the relative risk of various cancers. In the current study, we examined the association of the GST gene polymorphisms with familial prostate cancer in a Japanese population by performing a case-control study consisting of 81 familial prostate cancer cases and 105 normal controls. MATERIALS AND METHODS: No significant association of the GSTM1 and GSTT1 gene polymorphisms with familial prostate cancer risk was found; however, the Val/Val genotype of the GSTP1 gene significantly increased risk (OR = 9.31, 95% CI = 0.47-184, p = 0.030). The combination analysis of genotypes of the three genes showed that presence of two high-risk genotypes, i.e., null genotype of the GSTM1 or GSTT1 gene, or any Val genotypes of the GSP1 gene, significantly increased the risk of prostate cancer (OR = 2.67, 95% CI = 1.08-6.59, p = 0.03). Stratification of cases according to the pathological grade or the clinical stage showed no significant differences among categories. CONCLUSION: In the present study, we found that genotypes of GSTs, especially the Val-allele of the GSTP1 gene and the combination of three genotypes, were associated with familial prostate cancer risk.

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.

Association of the genetic polymorphism in cytochrome P450 (CYP) 1A1 with risk of familial prostate cancer in a Japanese population: a case-control study.

Association between genetic polymorphisms of CYP1A1 and familial prostate cancer risk was examined by a case-control study of 185 individuals. Although the individual analysis of m1 or m2 genotype of CYP1A1 showed no significant association with prostate cancer risk, the presence of any mutated alleles significantly increased prostate cancer risk in comparison with wild-type genotypes by combination analysis (odds ratio [OR]=2.38; 95% confidence interval [CI]=1.72-3.29; P=0.0069). Furthermore, metastatic cancer had a significant association with mutated alleles of m1 and m2. These finding suggested that CYP1A1 polymorphisms has an association with prostate cancer risk, especially with progression of prostate cancer.

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.

Association of the genetic polymorphism of the CYP19 intron 4[TTTA]n repeat with familial prostate cancer risk in a Japanese population.

BACKGROUND: Estrogen is crucial for development of benign prostate hyperplasia and prostate cancer. Aromatase (CYP19) is a key enzyme for estrogen synthesis in males. The genetic polymorphism of the CYP19 intron 4 [TTTA]n tetranucleotide has been studied in relation to breast cancer susceptibility. MATERIALS AND METHODS: We examined the association of the tetranucleotide repeat polymorphism of the CYP19 gene with familial prostate cancer risk in a Japanese population by performing a case-control study consisting of 99 familial prostate cancer cases and 116 normal controls. RESULTS: [TTTA] repeats ranged from 7 to 13 and were designated as A1 to A7 according to the repeat number. We did not observe any A3 allele among cases and controls, nor A7 among cases. Short repeat alleles, A1 and A2, had a tendency to be frequently observed in cases (odds ratio [OR] = 1.43, 95% confidence interval [CI] = 0.96-2.14, p = 0.080). Analysis of polymorphic genotypes showed that short genotypes, i.e., A1A1, A1A2 and A2A2, significantly increased prostate cancer risk in comparison with other longer genotypes (OR = 1.80, 95% CI = 1.04-3.11, p = 0.035). Stratification of cases according to the pathological grade or the clinical stage showed no significant differences among categories. CONCLUSIONS: In the present study, we found that short polymorphic genotypes of [TTTA]n repeats of the CYP19 gene were associated with familial prostate cancer risk.

Cyclin D1 gene polymorphism and familial prostate cancer: the AA genotype of A870G polymorphism is associated with prostate cancer risk in men aged 70 years or older and metastatic stage.

BACKGROUND: Cyclin D1 is a key protein involved in cell cycle regulation. A common A870G single nucleotide polymorphism in exon 4 of the cyclin D1 gene (CCND1) has an effect on the transcription of two different cyclin D1 mRNAs. Association of the genetic polymorphism of A870G of CCND1 with several cancer risks has been reported. MATERIALS AND METHODS: We performed a case-control study consisting of 99 familial prostate cancer cases and 115 noncancer controls to examine the genotypic frequency of the CCND1 polymorphism. RESULTS: We did not observe a significant association of the genotypic frequency of CCND1 with overall cases and controls. However, the AA genotype of CCND1 showed a tendency to increase prostate cancer risk in subjects aged 70 years or older (odds ratio [OR] = 2.14, 95% confidence interval [CI] = 0.86-5.27, p = 0.096). Stratification of cases according to clinical stages showed that the AA genotype was significantly frequently observed in metastatic cancer in comparison with GG + AG genotypes (OR = 3.03, 95% CI = 1.11-8.23, p = 0.026). CONCLUSION: The present study suggested that the genetic polymorphism might be associated with familial prostate cancer risk in a Japanese population.