[Status of occupational exposure limits of air toxic substances in the GESTIS Substances Database].

Objective: In order to understand the current situation of air toxic substances without occupational exposure limits (OELs) in the workplace in the Germany GESTIS Substance Database, and to provide an effective reference for formulating OELs of corresponding toxic substances and improving health standards. Methods: From March 2022 to May 2023, based on the standard of GBZ 2.1-2019 Occupational Exposure Limits for Hazardous Agents in the Workplace-Part 1: Chemical Hazardous Agents, air toxic substances without OELs in the standard of GBZ/T 300.1-2017 Determination of Toxic Substances in Workplace Air-Part 1: General Principles were screened out, then corresponding OELs in other countrie/regions were queried through the Germany GESTIS Substance Database. Results: Among the 333 kinds (classes) of air toxic substances in 160 parts of GBZ/T 300.1-2017 standard, 48 kinds (classes) of air toxic substances were screened out and had not yet been formulated OELs in GBZ 2.1-2019 standard. By querying the Germany GESTIS Substance Database, it was found that among the 48 kinds (classes) of air toxic substances, 35 kinds (classes) of air toxic substances had both 8-hour occupational exposure limit and short-term occupational exposure limit, 4 kinds (classes) of air toxic substances had 8-hour occupational exposure limit but no short-term occupational exposure limit, 9 kinds (classes) of air toxic substances hadn't been retrieved any OELs. In addition, standard test methods of 7 kinds of air toxic substances hadn't been published in the present, including trimethylchlorosilane, trimethylbenzenes, cumene, chloroethane, chloropropane, dibromoethane and acetophenone. Conclusion: In the process of formulating or revising the standards of GBZ 2.1-2019 and GBZ/T 300, the latest published OELs in the Germany GESTIS Substance Database could be used as a reference basis.

[Primary pulmonary NUT carcinoma: a clinicopathological analysis of seven cases].

Objective: To investigate the clinicopathological characteristics of primary pulmonary NUT carcinoma. Methods: A total of 7 cases of primary pulmonary NUT carcinoma were collected from Fujian Provincial Hospital (n=5), Fuzhou Taijiang Hospital (n=1) and Binzhou City People's Hospital of Shandong Province (n=1) from January 2021 to April 2023. The clinical, histopathological, and immunohistochemical features were analyzed, and NUT rearrangement were detected by fluorescence in situ hybridization (FISH) with break-apart probes. Results: Seven cases were all male with age ranging from 32 to 73 years. The main clinical manifestations were cough, expectoration and chest tightness. Microscopically, NUT carcinoma was composed of monotonous proliferation of primitive-appearing small-to-medium round cells, with few eosinophilic cytoplasm, arranged in solid sheets, nests or clusters. Abrupt keratinization was typically observed in 4 cases (4/7), with high mitotic activities and necrosis. Immunohistochemistry (IHC) showed that the tumors were positive for NUT (7/7), CK7 (4/4), CK5/6 (5/6), p40 (6/7). Ki-67 index were 30%-80%. NUT gene segregation (7/7) was detected by FISH break probes. Conclusions: Primary pulmonary NUT carcinoma is rare and highly malignant. Diagnosis depends on histopathology and IHC, with molecular detection as an adjunct for diagnosis. Pathologists should be aware of the clinicopathological characteristics to avoid misdiagnosis.

Identification of fifty-seven novel loci for abdominal wall hernia development and their biological and clinical implications: results from the UK Biobank.

PURPOSE: Familial aggregation is known for both hernia development and recurrence. To date, only one genome-wide association study (GWAS) limited to inguinal hernia has been reported that identified four risk-associated loci. We aim to investigate polygenic architecture of abdominal wall hernia development and recurrence. METHODS: A GWAS was performed in 367,394 subjects from the UK Biobank to investigate the polygenic architecture of abdominal wall hernia subtypes (inguinal, femoral, umbilical, ventral) and identify specific single nucleotide polymorphisms (SNPs) that are associated with their risk. Expression quantitative trait loci (eQTL) analysis was performed to identify genes whose expression levels are associated with these SNPs. A genetic risk score (GRS) was used to assess the cumulative effect of multiple independent risk-associated SNPs on hernia development and recurrence in independent subjects (n = 82,064). RESULTS: Heritability (h2) was 0.12, 0.06, 0.16, and 0.07 for inguinal, femoral, umbilical, and ventral hernias, respectively. A high-level of genetic correlation (rg) was found among these subtypes of hernia. We confirmed the aforementioned four loci and identified 57 novel loci (P < 5 × 10-8), including 55, 3, 5, and 3 loci for inguinal, femoral, umbilical, and ventral hernias, respectively. Significantly different expression levels between risk/reference alleles of SNPs were found for 145 genes, including TGF-ß2 and AIG1 for inguinal hernia risk and CALD1 for umbilical hernia risk. Finally, higher GRS deciles were significantly associated with increased risk for hernia development (Ptrend = 3.33 × 10-38) and recurrent hernia repair surgery (Ptrend = 3.64 × 10-14). CONCLUSION: These novel results have potential biological and clinical implications for hernia management in high-risk patients.

[The expression of KLK7 in pancreatic cancer and the effects on the biological behavior of pancreatic cancer cells].

Objective: To investigate the expression of KLK7 in pancreatic cancer and its clinical significance. Methods: Immunohistochemistry was used to detect the expression of KLK7 protein in pancreatic cancer tissue microarray with 92 samples. Statistical analysis of the relationship between KLK7 and clinicopathological characteristics was finished. Pancreatic cancer cell lines were infected with lentiviuses in order to get cells with KLK7 stable overexpression.KLK7-siRNA was transfected into pancreatic cancer cells to knock down KLK7.Cell proliferation and chemosensitivity were detected by CCK-8 assay; Cell invasion and migration abilities were detected by Transwell assay. At the same time, subcutaneous xenograft tumor models were established in nude mice to observe the effect of KLK7 on tumor growth in nude mice. Data were statistically analyzed by rank sum test, χ(2) test and Logistic regression analysis. Results: The expression level of KLK7 in pancreatic cancer tissues was higher than that in paired adjacent tissues (P<0.05). KLK7 expression was correlated with vascular invasion(χ(2)=7.535, P<0.05). Further univariate and multivariate analysis showed that KLK7 expression was an independent risk factor for vascular invasion of pancreatic cancer(χ(2)=7.535, P<0.05). The overexpression of KLK7 in pancreatic cancer cell lines BxPC-3 and CFPAC can increase their proliferation abilities, reduce the chemosensitivity and promote their migration and invasion behaviour; The results of in vivo experiments showed that the volume of subcutaneously transplanted tumors in the overexpressing KLK7 group was significantly larger than that in the control group (t=4.479, P<0.05). The group of overexpressing KLK7 showed greater tumor weight than the control group(t=2.831, P<0.05). Conclusions: The expression level of KLK7 in pancreatic ductal adenocarcinoma was higher than that in paired adjacent tissues and it is an independent risk factor for vascular invasion of pancreatic cancer.KLK7 can promote the proliferation of pancreatic cancer cells, reduce the chemosensitivity and increase the invasion and migration of pancreatic cancer cells.

Ginsenoside Rg1 protects human renal tubular epithelial cells from lipopolysaccharide-induced apoptosis and inflammation damage

Ginsenoside Rg1, one of the most notable active components of Panax ginseng, has been widely reported to exert anti-inflammatory actions. This study aimed to reveal whether ginsenoside Rg1 also exhibits beneficial roles against lipopolysaccharide (LPS)-induced apoptosis and inflammation in human renal tubular epithelial cells, and to evaluate the potential role of the component on tubulointerstitial nephritis treatment. HK-2 cells were treated with various doses of ginsenoside Rg1 (0, 50, 100, 150, and 200 μM) in the absence or presence of 5 μg/mL LPS. Thereafter, CCK-8 assay, flow cytometry, western blot, migration assay, reactive oxygen species (ROS) assay, and ELISA were carried out to respectively assess cell viability, apoptosis, migration, ROS activity, and the release of inflammatory cytokines. As a result, ginsenoside Rg1 protected HK-2 cells from LPS-induced injury, as cell viability was increased, cell apoptosis was decreased, and the release of MCP-1, IL-1β, IL-6, and TNF-α was reduced. Ginsenoside Rg1 functioned to HK-2 cells in a dose-dependent manner, and the 150 μM dose exhibited the most protective functions. Ginsenoside Rg1 had no significant impact on cell migration and ROS activity, while it alleviated LPS-induced ROS release and migration impairment. Furthermore, the down-regulations of p-PI3K, p-AKT, and up-regulations of PTEN, p-IκBα, p-p65, Bcl-3 induced by LPS were recovered to some extent after ginsenoside Rg1 treatment. In conclusion, ginsenoside Rg1 protects HK-2 cells against LPS-induced inflammation and apoptosis via activation of the PI3K/AKT pathway and suppression of NF-κB pathway.

Ginsenoside Rg1 protects human renal tubular epithelial cells from lipopolysaccharide-induced apoptosis and inflammation damage.

Ginsenoside Rg1, one of the most notable active components of Panax ginseng, has been widely reported to exert anti-inflammatory actions. This study aimed to reveal whether ginsenoside Rg1 also exhibits beneficial roles against lipopolysaccharide (LPS)-induced apoptosis and inflammation in human renal tubular epithelial cells, and to evaluate the potential role of the component on tubulointerstitial nephritis treatment. HK-2 cells were treated with various doses of ginsenoside Rg1 (0, 50, 100, 150, and 200 µM) in the absence or presence of 5 µg/mL LPS. Thereafter, CCK-8 assay, flow cytometry, western blot, migration assay, reactive oxygen species (ROS) assay, and ELISA were carried out to respectively assess cell viability, apoptosis, migration, ROS activity, and the release of inflammatory cytokines. As a result, ginsenoside Rg1 protected HK-2 cells from LPS-induced injury, as cell viability was increased, cell apoptosis was decreased, and the release of MCP-1, IL-1ß, IL-6, and TNF-α was reduced. Ginsenoside Rg1 functioned to HK-2 cells in a dose-dependent manner, and the 150 µM dose exhibited the most protective functions. Ginsenoside Rg1 had no significant impact on cell migration and ROS activity, while it alleviated LPS-induced ROS release and migration impairment. Furthermore, the down-regulations of p-PI3K, p-AKT, and up-regulations of PTEN, p-IκBα, p-p65, Bcl-3 induced by LPS were recovered to some extent after ginsenoside Rg1 treatment. In conclusion, ginsenoside Rg1 protects HK-2 cells against LPS-induced inflammation and apoptosis via activation of the PI3K/AKT pathway and suppression of NF-κB pathway.

[Correlation between miR-1178 expression and clinicopathological significance in human pancreatic cancer].

Objective: To test the expression of miR-1178 in pancreatic cancer and study its clinicopathological significance and mechanism. Methods: The expression of miR-1178 in 87 paired paraffin pancreatic ductal adenocarcinoma specimens and adjacent non- cancerous pancreatic tissue diagnosed by Pathology Department of Peking Union Medical College Hospital was detected by hybridization in situ. The relationship between the expression of miR-1178 and clinicopathological characters was analyzed.miR-1178 mimics and inhibitor were used to further detect the close relationship among miR-1178 and cancer invasion. Establish a nude mice subcutaneously transplanted tumor model, 4 weeks after vaccination for tumor volume and weight measurement.Student t-test, rank sum test, and χ(2) test was used respectively to compare the data between two groups. Cox regression was adopted to improve the single factor and multiple factors analysis. Results: The results of hybridization in situ showed the expression of miR-1178 was increased in 72 cases with pancreatic cancer compared to that in paired normal pancreatic tissues (50/72 vs. 11/72, χ(2)=43.26, P<0.05). miR-1178 expression was positively associated with tumor lymph node stage (χ(2)=4.189, P=0.041). Univariate and multivariate analysis revealed that miR-1178 was an independent adverse prognostic indicator for patients with pancreatic cancer (HR=2.364, 95%CI: 1.114-5.019, P=0.025). Transwell assay indicated the over-expression of miR-1178 increased the number of AsPC-1 cells that penetrated the ECM-coated membrane (177.0±19.8 vs. 119.7±15.9)(χ(2)=8.21, P<0.05). For the in vivo experiment, overexpression of miR-1178 significantly promoted tumor growth, compared with control group (tumor volume: (5 122.4±760.2)mm(3) vs. (1 976.8±601.8)mm(3), t=2.413, P<0.05; tumor weight: (1.55±0.21)g vs. (0.67±0.17)g, t=2.960, P<0.05). Over-expression of miR-1178 down-regulated the expression of Stub1 and elevated the expression of FAK/MMP-9 signal pathway(P<0.05). Conclusions: MiR-1178 is overexpressed in pancreatic cancer, and is effective for predicting patients' prognosis. MiR-1178 regulate Stub1/FAK/MMP-9 signal pathway and promote the invasion of AsPC-1 cells.

Comparison of the antiplatelet effect of clopidogrel benzene sulfonate and clopidogrel hydrogen sulfate in stable coronary heart disease.

Clopidogrel hydrogen sulfate (CHS) is a thienopyridine, which can be used to prevent cardiovascular complications alone or in combination with acetyl salicylic acid as an important antiplatelet agent. Clopidogrel benzene sulfonate (CB) is a special clopidogrel salt that can be used as a conventional drug for antiplatelet effects, but the mechanism is still unknown. This study aimed to compare the antiplatelet effects of CHS and CB in stable coronary artery disease patients. Stable coronary artery disease patients (N = 119) were randomly divided into two groups receiving CHS (N = 67) or CB (N = 52). The patients were administered the drugs (600 mg dosage) and monitored for 12 to 14 h to detect antiplatelet effects. Antiplatelet response was evaluated by the P2Y12 response unit (PRU) and P2Y12 suppression percentage. In addition, all patients' CYP2C19*2, CYP2C19*3, and CYP3A5 polymorphisms were studied. Similar clinical manifestations were observed in the two groups. No obvious difference was detected in the platelet levels of patients given CHS or CB. The antiplatelet response (PRU and P2Y12 evaluation) of the patients using CHS and CB was not significantly different. In the two groups, the CYP2C19*2 polymorphic heterozygote number and antiplatelet response were similar. CB and CHS presented similar antiplatelet effects in stable coronary artery disease patients, and there was no difference in the CYP2C19*2 heterozygous polymorphism.

Nimodipine improves regional cerebral blood flow and suppresses inflammatory factors in the hippocampus of rats with vascular dementia.

OBJECTIVE: To study the effect of nimodipine on hippocampal regional cerebral blood flow (rCBF) and proinflammatory cytokines in rats with experimental vascular dementia. METHODS: Male Sprague Dawley rats were randomly divided into four groups (n = 15/group): sham operated controls (group A); focal cerebral ischaemia (group B); vascular dementia (group C); and vascular dementia treated with 20 mg/kg nimodipine daily (group D). The Morris water maze test evaluated learning and memory, and magnetic resonance perfusion-weighted imaging was used to measure rCBF. Hippocampal levels of nuclear factor-κB (NF-κB), tumour necrosis factor-α (TNF-α) and interleukin 1ß (IL-1ß) were measured. RESULTS: Compared with group C, rats in group D demonstrated significantly improved learning ability and significantly increased hippocampal rCBF. The levels of NF-κB, TNF-α and IL-1ß were significantly lower in group D than in group C. Hippocampal nerve cell morphology was abnormal in group C but near normal in group D. CONCLUSIONS: Nimodipine improved the symptoms of cognitive impairment, increased rCBF, reduced hippocampal cytokine levels and alleviated neuronal injury in the hippocampus of rats with experimental vascular dementia.

Identification of novel CHD1-associated collaborative alterations of genomic structure and functional assessment of CHD1 in prostate cancer.

A clearer definition of the molecular determinants that drive the development and progression of prostate cancer (PCa) is urgently needed. Efforts to map recurrent somatic deletions in the tumor genome, especially homozygous deletions (HODs), have provided important positional information in the search for cancer-causing genes. Analyzing HODs in the tumors of 244 patients from two independent cohorts and 22 PCa xenografts using high-resolution single-nucleotide polymorphism arrays, herein we report the identification of CHD1, a chromatin remodeler, as one of the most frequently homozygously deleted genes in PCa, second only to PTEN in this regard. The HODs observed in CHD1, including deletions affecting only internal exons of CHD1, were found to completely extinguish the expression of mRNA of this gene in PCa xenografts. Loss of this chromatin remodeler in clinical specimens is significantly associated with an increased number of additional chromosomal deletions, both hemi- and homozygous, especially on 2q, 5q and 6q. Together with the deletions observed in HEK293 cells stably transfected with CHD1 small hairpin RNA, these data suggest a causal relationship. Downregulation of Chd1 in mouse prostate epithelial cells caused dramatic morphological changes indicative of increased invasiveness, but did not result in transformation. Indicating a new role of CHD1, these findings collectively suggest that distinct CHD1-associated alterations of genomic structure evolve during and are required for the development of PCa.

Thalidomide attenuates graft arteriosclerosis of aortic transplant in a rat model.

OBJECTIVE: The purpose of the current study was to evaluate the effects of thalidomide on graft arteriosclerosis. MATERIALS AND METHODS: Male Lewis rats received abdominal aorta grafts from male Brown-Norway rats. The animals were divided into 4 groups: no treatment controls, a low-dose group that received thalidomide (50 mg/kg per day), a middle dose group that received thalidomide (100 mg/kg per day), and a high-dose group that received thalidomide (200 mg/kg per day) by daily intragastric administration. Rats were humanely killed at 60 days after surgery. The grafted aortas were analyzed by histology, immunohistochemistry, and Western blot analysis. The serum was analyzed by an enzyme-linked immunosorbent assay (ELISA). RESULTS: The neointimal thickness of the thalidomide treated aortas was significantly thinner compared with that of no treatment aortas (P < .05). Vascular endothelial growth factor (VEGF), platelet-derived growth factor, and intracellular adhesian molecule (ICAM-1) protein expression in the treatment group were significantly lower than those in the control group (P < .05). Moreover, thalidomide significantly inhibited the production of VEGF and ICAM-1 in serum (P < .05). CONCLUSION: Our data suggested that thalidomide can attenuate graft arteriosclerosis so as to protect aortic grafts.

Genetic variation in the COX-2 gene and the association with prostate cancer risk.

COX-2 is a key enzyme in the conversion of arachidonic acid to prostaglandins. The prostaglandins produced by COX-2 are involved in inflammation and pain response in different tissues in the body. Accumulating evidence from epidemiologic studies, chemical carcinogen-induced rodent models and clinical trials indicate that COX-2 plays a role in human carcinogenesis and is overexpressed in prostate cancer tissue. We examined whether sequence variants in the COX-2 gene are associated with prostate cancer risk. We analyzed a large population-based case-control study, cancer prostate in Sweden (CAPS) consisting of 1,378 cases and 782 controls. We evaluated 16 single nucleotide polymorphisms (SNPs) spanning the entire COX-2 gene in 94 subjects of the control group. Five SNPs had a minor allele frequency of more than 5% in our study population and these were genotyped in all case patients and control subjects and gene-specific haplotypes were constructed. A statistically significant difference in allele frequency between cases and controls was observed for 2 of the SNPs (+3100 T/G and +8365 C/T), with an odds ratio of 0.78 (95% CI=0.64-0.96) and 0.65 (95% CI=0.45-0.94) respectively. In the haplotype analysis, 1 haplotype carrying the variant allele from both +3100 T/G and +8365 C/T, with a population frequency of 3%, was also significantly associated with decreased risk of prostate cancer (p=0.036, global simulated p-value=0.046). This study supports the hypothesis that inflammation is involved in prostate carcinogenesis and that sequence variation within the COX-2 gene influence the risk of prostate cancer.

Interleukin-1 receptor antagonist haplotype associated with prostate cancer risk.

IL1-RN is an important anti-inflammatory cytokine that modulate the inflammation response by binding to IL1 receptors, and as a consequence inhibits the action of proinflammatory cytokines IL1alpha and IL1beta. In this study, we hypothesise that sequence variants in the IL1-RN gene are associated with prostate cancer risk. The study population, a population-based case-control study in Sweden, consisted of 1383 prostate cancer case patients and 779 control subjects. We first selected 18 sequence variants covering the IL1-RN gene and genotyped these single-nucleotide polymorphisms (SNPs) in 96 control subjects. Gene-specific haplotypes of IL1-RN were constructed and four haplotype-tagging single-nucleotide polymorphisms (htSNPs) were identified (rs878972, rs315934, rs3087263 and rs315951) that could uniquely describe >95% of the haplotypes. All study subjects were genotyped for the four htSNPs. No significant difference in genotype frequencies between cases and controls were observed for any of the four SNPs based on a multiplicative genetic model. Overall there was no significant difference in haplotype frequencies between cases and controls; however, the prevalence of the most common haplotype (ATGC) was significantly higher among cases (38.7%) compared to controls (33.5%) (haplotype-specific P = 0.009). Evaluation of the prostate cancer risk associated with carrying the 'ATGC' haplotype revealed that homozygous carriers were at significantly increased risk (odds ratio (OR) = 1.6, 95% confidence interval (CI) = 1.2-2.2), compared to noncarriers, while no significant association was found among subjects heterozygous for the haplotype (OR = 1.0, 95% CI = 0.8-1.2). Restricting analyses to advanced prostate cancer strengthened the association between the 'ATGC' haplotype and disease risk (OR for homozygous carriers vs noncarriers 1.8, 95% CI = 1.3-2.5). In conclusion, the results from this study support the hypothesis that inflammation has a role of in the development of prostate cancer, but further studies are needed to identify the causal variants in this region and to elucidate the biological mechanism for this association.

Hereditary prostate cancer in African American families: linkage analysis using markers that map to five candidate susceptibility loci.

African American men have the highest incidence of prostate cancer in the world. Despite this statistic, linkage studies designed to localise prostate cancer susceptibility alleles have included primarily men of Caucasian descent. In this report, we performed a linkage analysis using 33 African American prostate cancer families from two independent research groups. In total, 126 individuals (including 89 men with prostate cancer) were genotyped using markers that map to five prostate cancer susceptibility loci, namely HPC1 at 1q24-25, PCAP at 1q42.2-43, CAPB at 1p36, HPC20 on chromosome 20, and HPCX at Xq27-28. Multipoint mode-of-inheritance-free linkage analyses were performed using the GENEHUNTER software. Some evidence of prostate cancer was detected to HPC1 using all families with a maximum NPL Z score of 1.12 near marker D1S413 (P=0.13). Increased evidence of linkage was observed in the 24 families with prostate cancer diagnosis prior to age 65 years and in the 20 families with male-to-male transmission. Some evidence of prostate cancer linkage was also detected at markers mapping to PCAP, HPC20, and HPCX. Continued collection and analysis of African American prostate cancer families will lead to an improved understanding of inherited susceptibility in this high-risk group.

Polymorphisms in the CYP1B1 gene are associated with increased risk of prostate cancer.

CYP1B1 has been evaluated as a candidate gene for various cancers because of its function in activating environmental procarcinogens and catalysing the conversion of oestrogens to genotoxic catechol oestrogens. To test the hypothesis that genetic polymorphisms in the CYP1B1 gene may associate with the risk for prostate cancer (CaP), we compared the allele, genotype, and haplotype frequencies of 13 single nucleotide polymorphisms (SNPs) of CYP1B1 among 159 hereditary prostate cancer (HPC) probands, 245 sporadic CaP cases, and 222 unaffected men. When each of the SNPs was analysed separately, marginally significant differences were observed for allele frequencies between sporadic cases and controls for three consecutive SNPs (-1001C/T, -263G/A, and -13C/T, P=0.04-0.07). Similarly, marginally significant differences between sporadic cases and controls in the frequency of variant allele carriers were observed for five consecutive SNPs (-1001C/T, -263G/A, -13C/T, +142C/G, and +355G/T, P=0.02-0.08). Interestingly, when the combination of these five SNPs was analysed using a haplotype approach, a larger difference was found (P=0.009). One frequent haplotype (C-G-C-C-G of -1001C/T, -263G/A, -13C/T, +142C/G, and +355G/T) was associated with an increased risk for CaP, while the other frequent haplotype (T-A-T-G-T) was associated with a decreased risk for CaP. These findings suggest that genetic polymorphisms in CYP1B1 may modify the risk for CaP.

Linkage and association of CYP17 gene in hereditary and sporadic prostate cancer.

Androgens are essential for prostate development, growth and maintenance and the association between androgen levels and prostate cancer is well established. Since the CYP17 gene encodes the enzyme cytochrome P450c17alpha, which mediates 17alpha-hydroxylase and 17,20-lyase activities in the androgen biosynthesis pathway, sequence variations in the gene and association with increased risk to prostate cancer has been studied. In particular, several groups have studied the association between a polymorphism in the 5' promoter region and prostate cancer using a population-based association approach. However, the results from these studies were inconclusive. To further study this polymorphism and its possible role in hereditary prostate cancer (HPC), we performed a genetic linkage analysis and family-based association analysis in 159 families, each of which contains at least 3 first-degree relatives with prostate cancer. In addition, we performed a population-based association analysis to compare the risk of this polymorphism to hereditary and sporadic prostate cancer in 159 HPC probands, 249 sporadic prostate cancer patients and 211 unaffected control subjects. Evidence for linkage at the CYP17 gene region was found in the total 159 HPC families (LOD = 1.3, p = 0.01, at marker D10S222). However, family-based association tests did not provide evidence for overtransmission of either allele of the CYP17 polymorphism to affected individuals in the HPC families. The allele and genotype frequencies of the polymorphism were not statistically different among the HPC probands, sporadic cases and unaffected control subjects. In conclusion, our results suggest that the CYP17 gene or other genes in the region may increase the susceptibility to prostate cancer in men; however, the polymorphism in the 5' promoter region has a minor role if any in increasing prostate cancer susceptibility in our study sample.

Linkage and association studies of prostate cancer susceptibility: evidence for linkage at 8p22-23.

Multiple lines of evidence have implicated the short arm of chromosome 8 as harboring genes important in prostate carcinogenesis. Although most of this evidence comes from the identification of frequent somatic alterations of 8p loci in prostate cancer cells (e.g., loss of heterozygosity), studies have also suggested a role for 8p genes in mediation of inherited susceptibility to prostate cancer. To further examine this latter possibility, we performed linkage analyses, in 159 pedigrees affected by hereditary prostate cancer (HPC), using 24 markers on the short arm of chromosome 8. In the complete set of families, evidence for prostate cancer linkage was found at 8p22-23, with a peak HLOD of 1.84 (P=.004), and an estimate of the proportion of families linked (alpha) of 0.14, at D8S1130. In the 79 families with average age at diagnosis >65 years, an allele-sharing LOD score of 2.64 (P=.0005) was observed, and six markers spanning a distance of 10 cM had LOD scores >2.0. Interestingly, the small number of Ashkenazi Jewish pedigrees (n=11) analyzed in this study contributed disproportionately to this linkage. Mutation screening in HPC probands and association analyses in case subjects (a group that includes HPC probands and unrelated case subjects) and unaffected control subjects were carried out for the putative prostate cancer-susceptibility gene, PG1, previously localized to the 8p22-23 region. No statistical differences in the allele, genotype, or haplotype frequencies of the SNPs or other sequence variants in the PG1 gene were observed between case and control subjects. However, case subjects demonstrated a trend toward higher homozygous rates of less-frequent alleles in all three PG1 SNPs, and overtransmission of a PG1 variant to case subjects was observed. In summary, these results provide evidence for the existence of a prostate cancer-susceptibility gene at 8p22-23. Evaluation of the PG1 gene and other candidate genes in this area appears warranted.

Evidence for a prostate cancer linkage to chromosome 20 in 159 hereditary prostate cancer families.

Prostate cancer is the most common malignancy diagnosed in men in the US. Genetic susceptibility to prostate cancer has been well documented. A region at chromosome 20q13 (HPC20) has been reported to be linked to a prostate cancer susceptibility gene. To confirm this finding, we genotyped 16 markers spanning approximately 95 cM on chromosome 20 in 159 hereditary prostate cancer (HPC) families. Positive (but not statistically significant) linkage scores were observed from 20pter to 20q11, with the highest non-parametric linkage (NPL) score for the complete dataset of 1.02 (P=0.15) being observed at D20S195 at 20q11. Evidence for linkage from parametric analyses with a dominant or a recessive model was weak. Interestingly, consistent with the original findings of linkage to 20 g higher linkage scores were observed in the subsets of families with a later age at diagnosis (> or =65 years; n=80, NPL=1.94, P=0.029 at D20S186), fewer than five affected family members (n=69, NPL=1.74, P=0.037 at D20S889), or without male-to-male disease transmission (n=60, NPL=1.01, P=0.15 at D20S117). The region with positive linkage scores spanned approximately 60 cM from 20pter to 20q11 in these subsets of families. Our results are consistent with a prostate cancer susceptibility locus on chromosome 20.