Variants in HOXB13, G132E and F127C, Are Associated With Prostate Cancer Risk in Japanese Men.

BACKGROUND/AIM: Several studies have reported on the relationship between HOXB13 variants and an increased prostate cancer (PC) risk. To our knowledge there are not many studies on HOXB13 mutations in Japanese patients with prostate cancer, and there many issues remain uninvestigated. We herein clarified the association between HOXB13 genetic variants and PC risk in a Japanese population. PATIENTS AND METHODS: PC patients were diagnosed at the Gunma University Hospital and affiliated hospitals from 1994 to 2016. Sanger sequencing was performed on the coding regions of the HOXB13 gene in 152 familial PC (FPC) patients. Genotyping was performed on single nucleotide variants (SNVs) found in Sanger sequencing in 230 FPC patients from 152 pedigrees and 197 sporadic PC (SPC) patients and 144 controls. Allelic frequency and clinical data for each variant were studied in cases and controls. RESULTS: G132E and F127C were identified in FPC patients. The frequencies of G132E and F127C were significantly higher compared to the control group (p=0.039). In three families, seven PC patients shared the G132E variant, within second-to-third-degree relatives. It was not possible to clarify to pathogenicity of each SNV alone. CONCLUSION: We found two significant variants of the HOXB13 gene, G132E, F127C by analyzing and comparing gene samples from PC and non-PC patients. Furthermore, the HOXB13 G132E variant was found significantly increased in the FPC group.

Long-term outcome of hypofractionated intensity-modulated radiotherapy using TomoTherapy for localized prostate cancer: A retrospective study.

BACKGROUND: Recently, the clinical outcome of prostate cancer treated by hypofractionated radiation therapy has been reported. However, there are few reports from Japan. In Hidaka Hospital, hypofractionated intensity-modulated radiotherapy (HIMRT) for prostate cancer was initiated in 2007. The purpose of this study is to analyze the long-term outcome. METHODS: Ninety-two patients with localized prostate cancer treated with HIMRT at Hidaka Hospital between 2007 and 2009 were retrospectively analyzed. HIMRT was delivered using TomoTherapy. The prescription dose was 66 Gy at 95% of the PTV in 22 fractions performed 3 days a week over 7 weeks in all patients. The overall survival rate, biochemical relapse-free rate, and acute and late toxicities were evaluated. RESULTS: The median follow-up duration was 78 (range 14-100) months. The median age at the start of the HIMRT was 72 (range 46-84) years. The disease characteristics were as follows: stage T1c, 45; T2a, 20; T2b, 5; T2c, 1; T3a, 13; T3b, 6; T4, 2; Gleason score 6, 13; 7, 44; 8, 20; 9, 15; 10, 0; pretreatment PSA ≤10 ng/mL, 42; 10 to ≤20, 27; and >20, 23. According to the D'Amico classification system, 10, 37, and 45 patients were classified as low-risk, intermediate-risk, and high-risk. The overall survival rate, the cause-specific survival rate, and the biochemical relapse-free rate at 5 years was 94.7%, 100% and 98.9%, respectively. Severe acute toxicity (grade 3 or more) was not observed. The late urinary toxicity was 52.2% in grade 0, 28.3% in grade 1, 19.6% in grade 2, and 2.2% in grade 3. The late rectal toxicity was 78.3% in grade 0, 7.6% in grade 1, 9.8% in grade 2, and 4.3% in grade 3. CONCLUSIONS: The present study demonstrated that HIMRT using TomoTherapy for prostate cancer has a favorable outcome with tolerable toxicity.

Germline Variants of Prostate Cancer in Japanese Families.

Prostate cancer (PC) is the second most common cancer in men. Family history is the major risk factor for PC. Only two susceptibility genes were identified in PC, BRCA2 and HOXB13. A comprehensive search of germline variants for patients with PC has not been reported in Japanese families. In this study, we conducted exome sequencing followed by Sanger sequencing to explore responsible germline variants in 140 Japanese patients with PC from 66 families. In addition to known susceptibility genes, BRCA2 and HOXB13, we identified TRRAP variants in a mutually exclusive manner in seven large PC families (three or four patients per family). We also found shared variants of BRCA2, HOXB13, and TRRAP from 59 additional small PC families (two patients per family). We identified two deleterious HOXB13 variants (F127C and G132E). Further exploration of the shared variants in rest of the families revealed deleterious variants of the so-called cancer genes (ATP1A1, BRIP1, FANCA, FGFR3, FLT3, HOXD11, MUTYH, PDGFRA, SMARCA4, and TCF3). The germline variant profile provides a new insight to clarify the genetic etiology and heterogeneity of PC among Japanese men.

Exendin-4 promotes the membrane trafficking of the AMPA receptor GluR1 subunit and ADAM10 in the mouse neocortex.

Glucagon-like peptide-1 (GLP-1) is a novel treatment modality for type 2 diabetes mellitus. However, GLP-1 has been suggested as a therapeutic target for Alzheimer's disease (AD). In rodent studies, GLP-1 reduces amyloid beta (Aß) and facilitates synaptic plasticity. Therefore, in the present study, we investigated how GLP-1 facilitates synaptic plasticity and reduces the Aß in vivo. Exendin-4, a GLP-1 receptor agonist that can cross the blood brain barrier, was subcutaneously administered to adult mice. We then extracted the total and the plasma membrane proteins from the mouse neocortex. Exendin-4 significantly increased the phosphorylation level of cAMP response element-binding protein (CREB). Consistently, the expression level of brain-derived neurotrophic factor (BDNF), a transcriptional target of CREB, was increased. Furthermore, exendin-4 increased the membrane protein level of the AMPA receptor GluR1 subunit and postsynaptic density protein-95 (PSD-95), whereas GluR2 was unaffected. These exendin-4-dependent increases in membrane GluR1, total PSD-95 and BDNF were abrogated by pretreatment with temozolomide (TMZ), a DNA-alkylating agent, indicating that these alterations were dependent on exendin-4-induced transcriptional activity. In addition, we found that exendin-4 increased the level of the α-C terminal fragment (α-CTF) of amyloid precursor protein (APP). Furthermore, protein levels of both mature and immature ADAM10, the α-secretase of APP in the plasma membrane, were increased, whereas the total mature and immature ADAM10 levels were unchanged. These exendin-4-dependent increases in α-CTF and ADAM10 were not affected by TMZ. These findings suggested that GLP-1 facilitates the GluR1 membrane insertion through CREB activation and increases α-secretase activity through ADAM10 membrane trafficking. Upregulation of GluR1 and ADAM10 at the plasma membrane were also observed in mice with intracerebroventricular administration of Aß oligomer, indicating that a part of benefit of exendin-4 against AD may depend on the GluR1 and ADAM10 membrane trafficking.

[Clinical and basic aspects of familial prostate cancer].

Hereditary and familial prostate cancers respectively account for about 5% and 20% of all prostate cancer in the United States. The most striking characteristic of familial prostate cancer is the early-onset of the disease. In the clinical setting, a family history of prostate cancer is recognized as a high risk for developing prostate cancer, and a risk-based prostate cancer screening program for it has been proposed. Genetic analyses for identifying the susceptible genes have been reported, and it appears that multiple genes are involved in the development of prostate cancer. Recently, genome-wide association studies showed that the single nucleotide polymorphisms located at the 8q24 region had an association with prostate cancer development. Familial prostate cancer, although its incident rate is relatively rare, must be treated as a high-risk group. Further clinical and basic research is warranted to explore the mechanism of prostate cancer development.

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.

[Cae of double cancer involving of the bladder and prostate which was treated by radical cystectomy 8 years after radical prostatectomy].

A 66-year-old man was diagnosed as having prostate cancer (T2aN0M0) and neoadjuvant hormone therapy was started from 17 February 1995. During observation, superficial bladder cancer was incidentally found and the first transurethral resection was carried out on 21 June 1995. Radical prostatectomy was performed on 8 May 1996. Thereafter, bladder cancer demonstrated repeated recurrence. At the time of the third recurrence, malignant trasformation was recognized as TCC G3 T2 or more invasive, and radical cystectomy with ileal conduit was performed on 12 May 2004 when the patient was 74 years old. From the perspective of double cancer, the frequency of diagnosing localized prostate cancer with superficial bladder cancer is expected to increase because PSA screening is being increasingly performed recently. Because of the possibility of malignant transformation in patients with superficial bladder cancer, in cases of coincident of cancers, it remains controversial which treatment should be selected for the previously diagnosed prostate cancer. Here, we report the clinical course and discuss this issue to some extent.

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.

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.

[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.