Association of hereditary prostate cancer gene polymorphic variants with sporadic aggressive prostate carcinoma

BACKGROUND: ELAC2, MSR1, and RNASEL are candidate genes for hereditary prostate carcinoma (HPC). While, studies have demonstrated that single nucleotide polymorphisms (SNPs) in these genes are associated with sporadic disease as well as HPC, these results are often not replicated in follow-up studies. Given that the majority of patients studied had localized disease and up to 50% of localized prostate cancer is clinically insignificant, the inability to replicate the initial findings may reflect that some subjects had indolent tumors. Herein, we examine patients with metastatic disease to determine if an association exists between HPC SNPs and unambiguously significant prostate cancer. METHODS: We examined polymorphisms within ELAC2 (S217L, A541T, E622V), MSR1 (P275A, R293X, aIVS5-59c), and RNASEL (E265X, R462Q, D541E) in 150 European-Americans with metastatic prostate cancer and 170 prostate cancer-free controls using pyrosequencing assays. RESULTS: Only ELAC2 217L (37% cases vs. 29% controls (P=0.034)) and RNASEL 541E (61% cases vs. 53% controls (P=0.045)) were over-represented. Analysis of genotypes revealed that presence of the leucine ELAC2 allele (OR 1.54: 95% CI=0.99-2.41, SS vs. SL, LL) and homozygosity for the glutamic acid RNASEL allele (OR 1.68: 95% CI=1.04-2.70, EE vs. DE, DD) were associated with increased risk. Patients with both genotypes were of particularly high-risk (OR 2.66: 95% CI=1.36-5.19). CONCLUSIONS: These results suggest that, in a European-American population, ELAC2 217L and RNASEL 541E are associated with metastatic sporadic disease. ELAC2 and RNASEL SNP analysis may prove useful in determining which patients are at risk for developing clinically significant prostate carcinoma.     

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.     

Mutational analysis of PINX1 in hereditary prostate cancer

BACKGROUND: Telomerase activity is increased in most tumors. PinX1 has recently been identified as a critical component in regulating telomerase activity. The PinX1 gene is located within chromosomal region 8p22-23, a region associated with LOH and potentially linked to increased prostate cancer risk. METHODS: PINX1 was re-sequenced in 159 hereditary prostate cancer (HPC) probands. Four non-synonymous coding variants were genotyped in 159 HPC families. RESULTS: Thirty-nine polymorphisms were identified in the HPC screening panel. Ten coding polymorphisms were identified, seven (Gln50His, Leu91Met, Gln206His, Arg215Ile, Thr220Ala, Ser254Cys, and Glu414Ala) of which were non-synonymous. The most common variants Thr220Ala and Ser254Cys were not significantly over-transmitted from affected parent to affected offspring. CONCLUSIONS: Based on these results, we conclude that PINX1 is not a major factor for HPC risk.     

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.     

Histopathological characteristics of radical prostatectomy specimen and long-term PSA changes in men with PSA levels of 4.0 ng/ml or less]

Out of 132 prostate cancer (Pca) patients who underwent radical prostatectomy 31 (mean age 65 +/- 5 years) had prostate specific antigen (PSA) levels of 4.0 ng/ml or less (low PSA group). The average PSA level was 3.3 +/- 0.5 ng/ml in the low PSA group and 8.5 +/- 5.5 ng/ml in patients with a higher PSA (high PSA group). The pT2 ratio of the radical prostatectomy specimens was 74% (23/31) in the low PSA group and 55% (55/101) in the high PSA group, pT3a was 16% (5/31) and 31% (31/101), pT3b was 10% (3/31) and 10% (10/101), pN1 was 0% and 5% (5/101), respectively. The digital rectal examination (DRE) gave a positive result significantly (p = 0.026) less frequently in the low PSA group (6/31 : 20%), than in the high PSA group (44/101 : 44%). However all three pT3b patients with a low PSA were positive in DRE. This suggests the importance of DRE to detect significant Pca with PSA < or = 4.0. PSA was measured at least three times for more than one year in 19 of the 31 patients with a low PSA level before diagnosis. In 14 of these 19 cases (74%), PSA velocity was more than 0.5 ng/ml/ year and PSA doubling time was less than 4 years. Some patients with significant Pca can not be detected with a PSA cutoff level at 4.0 ng/ml. We recommend that individuals have their own PSA levels, and that long-term changes of PSA are sometimes very important to detect cases of Pca with lower PSA.     

NeuroD/BETA2 gene variability and diabetes: no associations to late-onset type 2 diabetes but an A45 allele may represent a susceptibility marker for type 1 diabetes among Danes. Danish Study Group of Diabetes in Childhood, and the Danish IDDM Epidemiology and Genetics Group

Mutations in the NeuroD/BETA2 gene have been shown to associate with type 2 diabetes. In the present study, we examined mutations in the NeuroD/BETA2 gene for association with either type 1 or 2 diabetes. Three variants were identified in patients with type 2 diabetes: Ala45Thr (allelic frequency 0.36, 95% CI 0.31-0.41), Pro197His (0.01), and Ser259Ser (0.01). Ala45Thr and Pro197His were not associated with type 2 diabetes, but the transmission disequilibrium test showed unequal transmission of the A45 allele to offspring with type 1 diabetes (chi2 = 5.90, P < 0.02, odds ratio 1.55, 95% CI 0.91-2.63). This association could not be explained by linkage disequilibrium between the Ala45 allele and IDDM7 (D2S152), which is also located on chromosome 2q32. When tested in vitro, the biological activity of Thr45 (117+/-36% vs. Ala45) and His197 (90+/-28% vs. Pro197) on the regulation of the human insulin gene promoter appeared normal. In conclusion, mutations in the NeuroD/BETA2 gene are not a common cause of late-onset type 2 diabetes among Danes. However, in the type 1 diabetic Danish population, the Ala45Thr variant of NeuroD/BETA2 may represent a susceptibility marker independent of IDDM7 on chromosome 2q32.     

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

Objectives:   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.
Methods:   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.
Results:   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).
Conclusions:   Lys262Arg polymorphism of the CYP2B6 gene may be a genetic marker for evaluating the risk of sporadic prostate cancer in native Japanese men.     

Assessment of matrix Gla protein, Klotho gene polymorphisms, and oxidative stress in chronic kidney disease

Increased vascular calcification and oxidative stress are considered as extra renal risk factors at the pathogenesis cardiovascular events in chronic kidney disease (CKD). We investigated matrix Gla protein (MGP) (T-138C, Glu60X, Thr83Ala) and Klotho (Cys370Ser) gene polymorphisms, serum MGP levels, and oxidative stress status of 84 CKD patients and 37 healthy controls. The MGP gene Glu60X and Thr83Ala polymorphisms were significantly associated with CKD. The correlation between T-138C genotype of MGP gene, Cys370Ser genotype of Klotho gene, and CKD was not significant (p > 0.05). At the haplotype analysis, the combination of the X allele of Glu60X and the Thr allele of Thr83Ala showed a significantly increased risk of CKD (p < 0.05). X allele, Thr allele, and C allele of T-138C were associated with diabetes mellitus and CKD phenotypes occurring concurrently (p < 0.01). Serum zinc levels were significantly low in end-stage renal disease (ESRD) patients (p = 0.0001). The total comet score frequency of ESRD patients was higher than that of control group (p < 0.05). The urinary 8-hydroxy-2'-deoxyguanosine levels were significantly high in CKD patients (p < 0.05). According to this study, analyzing the distribution of MGP gene and oxidative stress status would be very informative in order to detect their role at CKD.     

Structural analysis of the 11beta-hydroxysteroid dehydrogenase type 2 gene in end-stage renal disease

BACKGROUND: Mutations in the 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2) gene cause a rare form of low-renin hypertension leading to end-stage renal disease (ESRD) in some affected subjects. To date, no search for mutations in the HSD11B2 gene was performed in a large population to obtain an estimate its prevalence. METHODS: The HSD11B2 gene was analyzed in 587 subjects, including 260 ESRD patients (either dialysis or transplanted) for mutations in the exons 2 through 5 and corresponding intronic regions by polymerase chain reaction (PCR) using appropriate overlapping primers, gel analysis by single strand conformational polymorphism (SSCP), and sequencing of identified migration variants. RESULTS: The prevalence of single-nucleotide polymorphisms (SNPs) in ESRD patients and controls was 26%. The following genetic variants were found among all subjects investigated: exon 2 T442G (Leu148/Val, N = 70) and C470A (Thr156/Thr, N = 67), exon 3 G534A (Glu178/Glu, N = 69), and exon 5 C1274T (Asp388/Asp, N = 2). Four SNPs were identified in intron 4 only. In the control population, the prevalence of the variants Leu148 and Thr156 was 14% each. Glu178 was 11%, while no variants were found in exon 5. In ESRD patients, the prevalence of the variant Leu148 was 9%, and Thr156 was 8%. Glu178 was 13%, while the Asp388 variant was 0.7%. In patients with a short duration between the time of diagnosis of the renal disease and the onset of ESRD, the prevalence of the Leu148 and Glu178 variants was higher than in subjects with slowly progressing renal disease. The 11betaHSD2 activity of all of these SNPs is predictably unaltered. CONCLUSIONS: There is a high prevalence of SNPs of the HSD11B2 gene, without causing exonic mutations generating a 11betaHSD2 enzyme with altered activity. Based on statistical analyses, the frequency of homozygosity for mutated alleles of the HSD11B2 gene can be derived as <1/250,000 when a Caucasian population is considered.     

Polycomb-group oncogenes EZH2, BMI1, and RING1 are overexpressed in prostate cancer with adverse pathologic and clinical features

OBJECTIVES: Polycomb group (PcG) proteins are involved in maintenance of cell identity and proliferation. The protein EZH2 is overexpressed in disseminated prostate cancer, implicating a role of PcG complexes in tumor progression. In this study, we evaluated the expression of eight members of both PcG complexes in clinicopathologically defined prostate cancer. METHODS: Components of both PcG protein complexes PRC2 (EZH2, EED, YY1) and PRC1 (BMI1, RING1, HPH1, HPC1, HPC2) were immunohistochemically identified in tissue microarrays of 114 prostate cancer patients. Protein expression was semi-quantitatively scored and correlated with pathologic parameters and recurrence of prostate-specific antigen (PSA). RESULTS: Whereas BMI1, RING1, HPC1 and HPH1 were all abundantly present in normal and malignant prostate epithelium, expression of EZH2 occurred in only <10% of cells. Expression of EZH2, BMI1 and RING1 were all significantly enhanced in tumours with Gleason score (GS) > or = 8, extraprostatic extension, positive surgical margins, and PSA recurrence. When only the subgroup of GS < or = 6 was considered, representing the tumour grade in the majority of needle biopsies, EZH2 and BMI1 were also predictive for PSA recurrence. In a multivariable analysis, BMI1 was the only PcG protein with an independent prognostic value. CONCLUSIONS: PcG proteins EZH2, BMI1, and RING1 are associated with adverse pathologic features and clinical PSA recurrence of prostate cancer. Whereas BMI1 and RING1 are abundantly present in prostate cancer, EZH2 is expressed at relatively low levels, making it a less obvious target for therapy.     

Allelic imbalance in hereditary and sporadic prostate cancer

BACKGROUND: In this study, we evaluate the pattern of allelic imbalance (AI) in both sporadic prostate cancer (SPC) and hereditary prostate cancer (HPC) at loci that frequently show allelic imbalance in sporadic prostate cancer, or are believed to have a putative role in the disease. METHODS: DNA obtained from 35 sporadic tumors and 46 hereditary tumors were tested for AI, by using a panel of 35 microsatellite markers. RESULTS: Chromosomal regions that display high frequencies of AI (>or=30%) in HPC include 1q, 5q, 7q, 8p, 13q, 16q, 17q, 18q, and 20q. In SPC, high frequencies of AI were found at 5q, 7q, 8p, 10q, 13q. Main differences (delta >or= 20%) in AI between HPC and SPC were at 1q, 10q, 17q, 18q, and 20q. CONCLUSION: AI at the prostate cancer susceptibility loci HPC1, PCaP, and HPC20 was seen more often in HPC compared with SPC. It appears that there are marked differences in the pattern of AI between sporadic and hereditary PCa.     

Analysis of NPHS2 mutations in Turkish steroid-resistant nephrotic syndrome patients

Mutations in the NPHS2 gene are a frequent cause of familial and sporadic steroid-resistant nephrotic syndrome (SRNS). Inter-ethnic differences have also been suggested to affect the incidence of these mutations. The frequency and spectrum of podocin mutations in the Turkish population have remained largely unknown. As such, the aim of this study was to screen for podocin mutations in Turkish patients with SRNS. Thirty two patients from 30 unrelated families with SRNS were examined. There were seven familial cases from five different families and 25 sporadic cases. PCR-single-strand conformation polymorphism (SSCP) analysis of the NPHS2 gene was followed by direct sequencing. Five different NPHS2 mutations were detected in four of the 30 (13.3%) families studied; five familial patients from three unrelated families (60%) and one sporadic case (4%) were found to carry podocin mutations. The detected mutations included homozygous c. 419delG, compound heterozygous p. [Arg238Ser] + [Pro118Leu], homozygous p. [Pro20Leu; Arg168His] and heterozygous p. Pro20Leu. Two siblings with compound heterozygous mutations had been reported previously by our group. Podocin mutations were found to be responsible for some of the SRNS cases in Turkey, especially when there was more than one affected person in the family. Our results also suggest the presence of a wide range of phenotypic variability between individuals with the same genotype.     

Significance of prostatic specific antigen in the mass screening for prostate cancer]

The significance of prostatic specific antigen (PSA) was investigated in the subjects examined by the mass screening for prostate cancer from 1985 to 1990. All subjects was examined by digital rectal examination (DRE) and with prostatic acid phosphatase (PAP) and the subjects in whom prostate cancer (Pca) was suspected from abnormal DRE and/or elevated PAP were recommended to receive the secondary screening to confirm the presence of Pca. PSA was measured by radioimmunoassay using Ball-Elsa-PSA-kit. 1,600 serum samples were obtained from our serum bank. The relationship among PSA, prostate size estimated by DRE and age was investigated. PSA was increased with age and the prostate size, PSA being more closely related with the latter. Therefore, we estimated that PSA has an ability to detect benign prostatic hypertrophy (BPH) in the mass screening. This estimation should be confirmed by using an ultrasound tomography because the prostate size obtained by DRE is inaccurate as compared with that obtained by ultrasound tomography. The cut off level of PSA was determined by control which was composed from the subjects with normal size prostate and one with BPH. When the cut off level was 8.6 ng/ml, the sensitivity, specificity and efficiency as Pca marker was 73.9%, 97.4% and 97.1%, respectively. PSA was more than 8.6 ng/ml in all of Pca with elevated PAP. PSA was expected to improve the Pca detection rate in our mass screening system.     

How do patients with familial benign prostatic hyperplasia differ clinically from those with sporadic benign prostatic hyperplasia?

INTRODUCTION: The aim of this study was to compare age, prostatic volume, International Prostate Symptom Score (IPSS), maximal flow rate, serum total prostate-specific antigen (PSA), serum free PSA, free/total PSA ratio and PSA density values of familial and sporadic benign prostatic hyperplasia (BPH) patients suffering moderate or severe lower urinary tract symptoms. MATERIALS AND METHODS: Between September 1999 and August 2004, 511 patients with moderate or severe lower urinary tract symptoms (IPSS > or =8) due to BPH were included in the study. Patients with at least 2 first-degree relatives who had undergone surgery or received medication for BPH were classified as having the familial form of the disease, while the remaining patients were taken as sporadic cases. Mean age, prostatic volume, symptom score, maximal flow rate, PSA, free PSA, free/total PSA ratio and PSA density values of the familial and sporadic groups were compared using student's t test. RESULTS: Thirty-eight patients had a positive family history and formed the familial group, while the remaining 473 made up the sporadic group. No significant difference was observed in the parameters studied, except that mean prostate volume of the familial group was found to be greater and the mean age to be lower than those of sporadic patients in accordance with the literature. CONCLUSIONS: Patients with familial BPH need treatment significantly earlier and have larger prostates than those with sporadic BPH.     

Variants of the insulin receptor substrate-1 and fatty acid binding protein 2 genes and the risk of type 2 diabetes, obesity, and hyperinsulinemia in African-Americans: the Atherosclerosis Risk in Communities Study.

We conducted a community-based case-control study of African-American men and women in the Atherosclerosis Risk in Communities Study. The allele frequencies of the Gly972Arg variant of the insulin receptor substrate-1 (IRS-1) gene and the Ala54Thr variant of the fatty acid binding protein 2 (FABP2) gene were compared in 992 normal control subjects and three patient groups: 1) 321 type 2 diabetic individuals, 2) 260 severely obese individuals, and 3) 258 markedly hyperinsulinemic individuals without diabetes. Allele frequencies of Gly972Arg IRS-1 and Ala54Thr FABP2 were 0.07 and 0.22, respectively; there were no differences in allele or genotype frequencies between patients and control subjects for either gene variant. In weighted linear regression of all patients and control subjects, the presence of the IRS-1 gene variant was associated with a 0.85 (0.42) kg/m2 higher BMI (P = 0.04). In addition, individuals with at least one IRS-1 Arg972 allele and two FABP2 Thr54 alleles had a BMI of 33.3 (7.9) kg/m2, compared with 30.0 (6.3) kg/m2 for those with neither allele (P = 0.05). These results suggest that in African-Americans, these variants in the IRS-1 and FABP2 genes are not associated with the risk of type 2 diabetes, severe obesity, or marked hyperinsulinemia, but that their independent and joint effects may be associated with small increases in BMI.     

Novel mutations in thiazide-sensitive Na-Cl cotransporter gene of patients with Gitelman's syndrome

Gitelman's syndrome (GS) is an autosomal recessive disorder characterized by metabolic alkalosis, hypokalemia, hypomagnesemia, and hypocalciuria that has recently been reported to be linked to thiazide-sensitive Na-Cl cotransporter (TSC) gene mutations. In this study, possible mutations in the TSC gene of six Japanese patients clinically diagnosed with GS were investigated. Twenty-six exons encoding TSC were amplified by PCR and then completely sequenced by the direct sequencing method. Patient A showed a missense mutation of Arg 642 to Cys on the paternal allele and a missense mutation of Val 578 to Met and a 2-bp deletion (nucleotide 2543-2544) on the maternal allele. This deletion results in a frameshift that alters codon 837 to encode a stop signal rather than phenylalanine, and it is predicted to lead to loss of the latter half of the intracellular carboxy terminus. In the second family, two affected sisters, patients B and C, had a homozygous missense mutation of Thr 180 to Lys. Both of their parents, who are consanguineously married, have a heterozygous Thr180Lys mutation. Patient D has a homozygous mutation Thr180Lys, which is the same as the second family. Haplotype analysis indicates that patients B and C are not related to patient D. In patients E and F, we could identify only one mutant allele; Ala569Glu and Leu849His, respectively. All of the mutations identified are novel except for the Arg642Cys mutation, which has been found in a Japanese GS patient. Although further in vitro study is required to prove that the mutations are responsible for GS, it is possible that Thr180Lys and Arg642Cys mutations might be common mutations in Japanese GS.     

Assessment of Matrix Gla Protein,Klotho Gene Polymorphisms,and Oxidative Stress in Chronic Kidney Disease

Abstract

Increased vascular calcification and oxidative stress are considered as extra renal risk factors at the pathogenesis cardiovascular events in chronic kidney disease (CKD). We investigated matrix Gla protein (MGP) (T-138C, Glu60X, Thr83Ala) and Klotho (Cys370Ser) gene polymorphisms, serum MGP levels, and oxidative stress status of 84 CKD patients and 37 healthy controls. The MGP gene Glu60X and Thr83Ala polymorphisms were significantly associated with CKD. The correlation between T-138C genotype of MGP gene, Cys370Ser genotype of Klotho gene, and CKD was not significant (p > 0.05). At the haplotype analysis, the combination of the X allele of Glu60X and the Thr allele of Thr83Ala showed a significantly increased risk of CKD (p < 0.05). X allele, Thr allele, and C allele of T-138C were associated with diabetes mellitus and CKD phenotypes occurring concurrently (p < 0.01). Serum zinc levels were significantly low in end-stage renal disease (ESRD) patients (p = 0.0001). The total comet score frequency of ESRD patients was higher than that of control group (p < 0.05). The urinary 8-hydroxy-2′-deoxyguanosine levels were significantly high in CKD patients (p < 0.05). According to this study, analyzing the distribution of MGP gene and oxidative stress status would be very informative in order to detect their role at CKD.     

HGPIN患者血清PSA特征及首次穿刺活检HGPIN阳性针数对再次活检PCa检出率的影响

目的 探讨高级别前列腺上皮内瘤(high grade prostatic intraepithelial neoplasia,HGPIN)患者血清前列腺特异性抗原(prostate specific antigen,PSA)特征及首次穿刺活检HGPIN阳性针数对再次活检前列腺癌(PCa)检测率的影响.方法 选取2013年2月至2015年12月在本院行前列腺穿刺的患者共320例,均行直肠超声引导下前列腺穿刺活检,分析各类患者血清PSA差异,对结果为非PCa患者于6个月后再次穿刺活检.结果 320例患者首次穿刺活检病理结果显示:其中HGPIN患者80例(孤立型51例,多灶型29例),低级别前列腺上皮内瘤(LGPIN)患者45例,前列腺增生(BPH)患者128例,PCa患者67例;其中PCa患者血清PSA为35.20(13.01,60.55) ng/mL,明显高于BPH、LGPIN、孤立型和多灶型HGPIN患者(P＜0.05);多灶型HGPIN血清PSA为12.15(6.82,16.43) ng/mL,明显高于BPH、LGPIN、孤立型HGPIN患者(P＜0.05);BPH、LGPIN、孤立型HGPIN患者血清PSA比较差异无统计学意义(P＞0.05);多灶性HGPIN患者再次穿刺为PCa的比例为38.46％ (10/26),明显高于BPH、LGPIN和孤立型HG-PIN患者(P＜0.05);BPH、LGPIN和孤立型HGPIN再次穿刺为PCa的比例比较差异无统计学意义(P＞0.05).结论 多灶型HGPIN血清PSA水平高于孤立型HGPIN、BPH以及LGPIN,但低于PCa;多灶型HGPIN患者再次活检PCa的检出率显著高于其他患者.     

Serum human glandular kallikrein 2 (hK2) for distinguishing stage and grade of prostate cancer

BACKGROUND: Human glandular kallikrein (hK2) has been shown to add important information regarding the early detection and staging of prostate cancer. Preliminary analysis pointed out that hK2 may discriminate between pT2 and pT3 tumors, and that hK2 may predict Gleason grade 4/5 cancer volume, better than prostate-specific antigen (PSA) or percent free PSA (%fPSA). We investigated the role of hK2 serum values for predicting pathological stage, grade and Gleason score. METHODS: Prostate-specific antigen, free PSA and hK2 were measured on 222 untreated prostate cancer patients who had received radical prostatectomy at the Charité Hospital, Berlin, Germany. Pathological work up revealed pT2-cancer in 111 patients and pT3-cancer in 111 patients. Grade 2 was found in 118 patients whereas grade 3 tumors were found in 104 patients. RESULTS: For pT2 and pT3 patients, the %fPSA (P=0.006), the ratios hK2/fPSA (P=0.08) and hK2xtPSA/fPSA (P=0.002) were all significant different whereas hK2 (P=0.143) and PSA (P=0.1) did not differ. Between grade 2 and grade 3 tumors, the hK2 alone (P=0.27), the %fPSA (P=0.13), the ratios hK2/fPSA (P=0.94) and hK2xtPSA/fPSA (P=0.12) did not separate, whereas PSA (P=0.039) showed a difference. The same relationships were found between the two groups in Gleason score<7 and >or=7. Neither the hK2 ratio, nor % fPSA was different. CONCLUSION: Human glandular kallikrein was not different between pT2 and pT3, nor between G2 versus G3 or Gleason scores<7 and >or=7 prostate cancer. Together with %fPSA, hK2 may only help to distinguish preoperatively between pT2 and pT3 prostate cancer but cannot add further information.     

Evidence of an association between the Arg72 allele of the peptide YY and increased risk of type 2 diabetes

We tested the hypothesis that variants in the gene encoding the prepropeptide YY (PYY) associate with type 2 diabetes and/or obesity. Mutation analyses of DNA from 84 patients with obesity and familial type 2 diabetes identified two polymorphisms, IVS3 + 68C>T and Arg72Thr, and one rare variant, +151C>A of PYY. The common allele of the Arg72Thr variant associated with type 2 diabetes with an allele frequency of the Arg allele of 0.667 (95% CI 0.658-0.677) among 4,639 glucose-tolerant subjects and 0.692 (0.674-0.710) among 1,326 patients with type 2 diabetes (P = 0.005, odds ratio 1.19 [95% CI 1.05-1.35]). The same polymorphism associated with overweight (25 < or = BMI < 30 kg/m2) (P = 0.018, 1.15 [1.02-1.28]). In quantitative trait analyses of a population-based sample of 6,022 subjects, the Arg allele was associated with an increased plasma glucose level 2 h after an oral glucose tolerance test (OGTT) (P = 0.03), an increased area under the curve for the post-OGTT plasma glucose level (P = 0.03), and a lower insulinogenic index (P = 0.01). In conclusion, the common Arg allele of the PYY Arg72Thr variant modestly associates with type 2 diabetes and with type 2 diabetes-related quantitative traits.