| 1. |
- Sanyal, S., et al.
(författare)
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Polymorphisms in DNA repair and metabolic genes in bladder cancer
- 2004
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Ingår i: Carcinogenesis. - 0143-3334. ; 25:5, s. 729-34
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Tidskriftsartikel (refereegranskat)abstract
- We investigated the association of urinary bladder cancer with genetic polymorphisms in the xeroderma pigmentosum complementation group C (XPC), group D (XPD) and group G (XPG), X-ray repair cross-complementing group 1 (XRCC1) and group 3 (XRCC3), Nijmegen breakage syndrome 1 (NBS1), cyclin D1, methylene-tetrahydrofolate reductase (MTHFR), NAD(P)H dehydrogenase quinone 1 (NQO1), H-ras and glutathione S-transferase theta 1 (GSTT1) genes. Bladder cancer patients from the different hospitals in Stockholm County Council area and matching controls were genotyped for different polymorphisms. The frequency of the variant allele for A/C polymorphism in exon 15 of the XPC gene was significantly higher in the bladder cancer cases than in the controls (OR 1.49, 95% CI 1.16-1.92, P = 0.001). The variant allele homozygote genotype for the T/C polymorphism in exon 1 of the H-ras gene was associated with a decreased risk for bladder cancer (OR 0.12, 95% CI 0.02-0.67, P = 0.006). The variant allele genotypes for the single nucleotide polymorphisms (SNPs) in DNA repair genes, XPG and NBS1, showed a marginal association with the occurrence of bladder cancer (OR 0.38, 95% CI 0.15-0.94, P = 0.03 and OR 1.64, 95% CI 0.92-2.90, P = 0.09, respectively). We also report a positive correlation between the null homozygote of GSTT1 with the risk of bladder cancer (OR 2.54, 95% CI 1.32-4.98, P = 0.003). For other polymorphisms included in this study, NBS1 Glu185Gln, XPD Lys751Gln, XPG Asp1104His, XRCC1 Arg399Gln, XRCC3 Thr241Met, cyclin D1 Pro242Pro, MTHFR Ala222Val and Glu429Ala, NQO1 Arg139Trp and Pro187Ser, no significant differences for genotype distributions and allele frequencies between the bladder cancer cases and the controls were observed in the present study.
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| 2. |
- Hemminki, K., et al.
(författare)
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Molecular epidemiology of VHL gene mutations in renal cell carcinoma patients : relation to dietary and other factors
- 2002
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Ingår i: Carcinogenesis. - Oxford, United Kingdom : Oxford University Press. - 0143-3334 .- 1460-2180. ; 23:5, s. 809-815
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Tidskriftsartikel (refereegranskat)abstract
- Carcinogenic chemicals act through DNA damage and mitogenic effects. No established mechanism explains the cancer preventive effects, if any, of food items, such as vegetables and fruit. If such data were available, preferably on tumor-initiating genes, the evidence for the protective effects would become stronger. The von Hipple-Lindau (VHL) gene is the tumor suppressor gene predisposing to both sporadic renal cell carcinoma (RCC) and von Hippel-Lindau disease. We have earlier analyzed VHL mutations in RCCs from 102 Swedish patients identified in a case-control study and here examine associations between patient characteristics, including dietary habits and mutations, considering the type of mutation. The results are given as odds ratios (OR), separately for smokers and all patients. In univariate analysis, consumption of vegetables and citrus fruit decreased the frequency of VHL mutations among smokers and citrus fruit among all patients. In multivariate analysis of smokers' characteristics, welding fumes showed a risk of 5.63 for multiple VHL mutations. In smokers, citrus fruit decreased the OR of GC to AT mutations to 0.13 and that of multiple mutations to 0.17; vegetables decreased the OR for single mutations to 0.22. Among all subjects, welding fumes were a risk factor and citrus fruit a protective factor. Additionally, an intake of selenium protected against multiple mutations. The present results provide evidence that the intake of vegetables, selenium and particularly of citrus fruit protects the renal VHL gene from mutational insults that may be endogenous or common in a population. Even though most of the associations are biologically plausible, and vegetables and fruit were an a priori hypothesis, fortuitous results cannot be ruled out in this relatively small study.
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| 3. |
- Ma, X., et al.
(författare)
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VHL gene alterations in renal cell carcinoma patients : novel hotspot or founder mutations and linkage disequilibrium
- 2001
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Ingår i: Oncogene. - Hampshire, United Kingdom : Nature Publishing Group. - 0950-9232 .- 1476-5594. ; 20:38, s. 5393-5400
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in the von Hippel-Lindau (VHL) gene are frequently detected in human sporadic renal cell carcinoma (RCC). We analysed 102 Swedish RCCs for VHL mutations by PCR-SSCP and sequencing. In 47 patients (46.1%), 70 different mutations were found, and most of them represented novel variations of the VHL gene. Mutations in the VHL gene were found in 54% of clear cell renal cell carcinomas (CCRCC) and in 18% of chromophilic cancers but in no chromophobe cancers or oncocytomas (P=0.016). Three novel hotspot or founder mutations were detected in our study: four CCRCCs carried a missense mutation (glutamic acid to lysine) at codon 160 which is critical in the stabilization of the H1 helix of the alpha domain and the alpha-beta domain interface in the VHL protein. Five CCRCCs and one chromophilic RCC harbored a 15-nucleotide in-frame deletion (codons 41-45) at a duplex tandem repeat sequence site. Moreover, this deletion was in linkage disequilibrium with a C-->T transition in the promoter region. The frequency of linkage was 17 times more common than chance. Five patients with this linked mutation resided in the same hospital district and at least three of them showed the two sequence variants in the tumor-adjacent tissue. In 5/6 patients the wild-type allele was lost in the tumor samples, suggesting a causal role for the mutations in RCC. These linked mutations might be novel polymorphisms maintained in a relative isolated population. Multiple mutations in VHL were found in 17 tumors out of 47 tumors with the VHL mutation. A higher multiple mutation detected rate (33%) was observed in grade 3 CCRCCs than those in grade 1 (22%) and grade 2 (9%) (P=0.04). This is evidence on the association between VHL mutation and extent of nuclear atypia.
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| 4. |
- Shiao, Y. H., et al.
(författare)
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VHL down-regulation and differential localization as mechanisms in tumorigenesis
- 2003
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Ingår i: Kidney International. - Malden, USA : Blackwell Publishing. - 0085-2538 .- 1523-1755. ; 64:5, s. 1671-1674
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Tidskriftsartikel (refereegranskat)abstract
- Background: The von Hippel-Lindau (VHL) gene has been widely analyzed in many tumors. Early studies in animal tumors suggest that changes in VHL protein level and localization may be also important in tumorigenesis. In this study, we determined the role of VHL protein in human renal cell carcinomas. METHODS: Seventy-five human renal cell carcinomas, predominantly of clear cell type (60 of 75), were examined for VHL protein by immunohistochemistry. The level and pattern of protein expression were then compared to VHL mutations and tumor characteristics.Results: An apparent decline of VHL level (positive in <50% of tumor cells) was observed in 49 (65%) tumors, a change more frequent than VHL mutations (28 of 75) (37%). In tumors, VHL was localized to the cytoplasm and/or the cell membrane. The occurrence of a predominantly membranous signal was significantly associated with missense mutations (9 of 14 tumors with missense mutations versus 14 of 61 tumors with no or nonmissense mutations, P = 0.0025) and tumor stage (23 of 60 tumors with stage TI versus 0 of 15 tumors with TII and TIII, P = 0.0034).Conclusion: This study provides the first evidence of the role of VHL protein level and intracellular localization in tumorigenesis in humans.
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