| 1. |
- Hosen, Ismail, et al.
(author)
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Mutations in TERT promoter and FGFR3 and telomere length in bladder cancer
- 2015
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In: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 137:7, s. 1621-1629
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Journal article (peer-reviewed)abstract
- Mutations in the promoter of the telomerase reverse transcriptase (TERT) and fibroblast growth factor receptor 3 (FGFR3) genes constitute the most recurrent somatic alterations in urothelial carcinoma of bladder. In this study, we screened DNA from 327 urothelial bladder carcinomas from well-documented patients, with different stages and grades and known TERT promoter mutational status, for FGFR3 alterations and measured relative telomere length (RTL). Although, the frequency of the TERT promoter mutations was higher than those in FGFR3; however, the alterations at the two loci occurred together more frequently than per chance [Odds ratio (OR)=4.93, 95% CI=2.72-8.92, p<0.0001]. While tumors with TERT promoter and FGFR3 mutations had shorter RTL than those without mutations (p<0.0001), the TERT promoter mutations in conjunction with the common allele of the rs2853669 polymorphism defined sub-group of patients with an observed decreased overall survival (OR=2.15, 95% CI=1.00-4.61) and increased recurrence in patients with TaG1+TaG2 disease categories (OR=3.68, 95%CI=1.12-12.05). The finding of shorter telomeres in tumors with TERT promoter and/or FGFR3 mutations than without mutations implies mechanistic relevance of telomere biology in cancer progression. The observed association with recurrence and survival shows that the TERT promoter mutations can potentially be used as markers to refine selection of patients for different treatments. The overwhelming frequency of the TERT promoter mutations also represents a case for development of an eventual therapeutic target. What's New? The identification of recurrent somatic mutations in bladder cancer opens the door to the development of new prognostic and therapeutic tools. Here, the TERT promoter mutations in conjunction with a common variant, rs2853669, define a subset of patients with increased risk of recurrence and poor survival. Mutations in FGFR3, in contrast, were not independently associated with either disease recurrence or overall survival. Tumors with mutations in FGFR3 or the TERT promoter carried shorter telomeres than those without mutations. The findings highlight the prognostic potential of TERT mutations and reveal a possible etiological role for telomere biology in bladder cancer.
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| 2. |
- Kiemeney, Lambertus A, et al.
(author)
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A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer.
- 2010
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In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 42:5, s. 415-9
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Journal article (peer-reviewed)abstract
- Previously, we reported germline DNA variants associated with risk of urinary bladder cancer (UBC) in Dutch and Icelandic subjects. Here we expanded the Icelandic sample set and tested the top 20 markers from the combined analysis in several European case-control sample sets, with a total of 4,739 cases and 45,549 controls. The T allele of rs798766 on 4p16.3 was found to associate with UBC (odds ratio = 1.24, P = 9.9 x 10(-12)). rs798766 is located in an intron of TACC3, 70 kb from FGFR3, which often harbors activating somatic mutations in low-grade, noninvasive UBC. Notably, rs798766[T] shows stronger association with low-grade and low-stage UBC than with more aggressive forms of the disease and is associated with higher risk of recurrence in low-grade stage Ta tumors. The frequency of rs798766[T] is higher in Ta tumors that carry an activating mutation in FGFR3 than in Ta tumors with wild-type FGFR3. Our results show a link between germline variants, somatic mutations of FGFR3 and risk of UBC.
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| 3. |
- Littorin, Margareta, et al.
(author)
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Influence of polymorphic metabolic enzymes on biotransformation and effects of diphenylmethane diisocyanate.
- 2008
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In: International Archives of Occupational and Environmental Health. - : Springer Science and Business Media LLC. - 1432-1246 .- 0340-0131. ; 81:4, s. 429-441
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Journal article (peer-reviewed)abstract
- Objectives To identify effect modification produced by genetic traits found in metabolic enzymes, to investigate how these affect the levels of different biomarkers of sprayed and thermo-degraded polyurethane (PUR) based on 4,4′-diphenylmethane diisocyanate (MDI) and to determine how associated respiratory disorders are affected. Methods Two partly overlapping groups of 141 and 158 factory employees exposed to sprayed or heated MDI-PUR glue were examined in years 0 and 2, respectively, for occurrence of polymorphisms in five genes (N-acetyltransferase NAT2 and the glutathione S-transferases GSTM1, GSTM3, GSTP1 [codon 105 and 114] and GSTT1) on the basis of the polymerase chain reaction, exposure biomarkers in plasma and urine (P- and U-MDX), by means of gas chromatography-mass spectrometry, specific serum IgG antibodies against MDI (S-IgG-MDI) by means of ELISA, total S-IgE, symptoms in the eyes, nose and lower airways as assessed by questionnaire and interview, and lung function as measured by spirometry. Results Both the GSTP1 105 isoleucine/isoleucine and GSTP1 114 alanine/alanine genotypes showed higher levels of U-MDX than the other genotypes and the GSTP1 114 genotype modified the P-MDX/U-MDX relationship. GSTP1 105 isoleucine/isoleucine was found to be associated with lower levels of S-IgG-MDI and fewer eye symptoms, but with an increased risk of symptoms in the airways, as well as with atopy. Presence of the GSTT1 gene resulted in somewhat lower lung function levels than did the null genotype. A slow NAT2 acetylating capacity was associated with lower P- and U-MDX and S-IgG-MDI levels, and better lung function, but a higher risk of eye and airway symptoms. Analysing the effects of combinations of the different genes provided no further information. Conclusions Although our study has clear limitations, it reveals various effect modifications produced by the GST and NAT2 genotypes. Gene-environment interactions are highly complex. Further research is needed to obtain a more comprehensive understanding of them.
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| 4. |
- Rachakonda, P. Sivaramakrishna, et al.
(author)
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TERT promoter mutations in bladder cancer affect patient survival and disease recurrence through modification by a common polymorphism
- 2013
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In: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 110:43, s. 17426-17431
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Journal article (peer-reviewed)abstract
- The telomerase reverse transcriptase (TERT) promoter, an important element of telomerase expression, has emerged as a target of cancer-specific mutations. Originally described in melanoma, the mutations in TERT promoter have been shown to be common in certain other tumor types that include glioblastoma, hepatocellular carcinoma, and bladder cancer. To fully define the occurrence and effect of the TERT promoter mutations, we investigated tumors from a well-characterized series of 327 patients with urothelial cell carcinoma of bladder. The somatic mutations, mainly at positions - 124 and - 146 bp from ATG start site that create binding motifs for E-twenty six/ternary complex factors (Ets/TCF), affected 65.4% of the tumors, with even distribution across different stages and grades. Our data showed that a common polymorphism rs2853669, within a preexisting Ets2 binding site in the TERT promoter, acts as a modifier of the effect of the mutations on survival and tumor recurrence. The patients with the mutations showed poor survival in the absence [hazard ratio (HR) 2.19, 95% confidence interval (CI) 1.02-4.70] but not in the presence (HR 0.42, 95% CI 0.18-1.01) of the variant allele of the polymorphism. The mutations in the absence of the variant allele were highly associated with the disease recurrence in patients with Tis, Ta, and T1 tumors (HR 1.85, 95% CI 1.11-3.08). The TERT promoter mutations are the most common somatic lesions in bladder cancer with clinical implications. The association of the mutations with patient survival and disease recurrence, subject to modification by a common polymorphism, can be a unique putative marker with individualized prognostic potential.
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| 5. |
- Rafnar, Thorunn, et al.
(author)
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European genome-wide association study identifies SLC14A1 as a new urinary bladder cancer susceptibility gene.
- 2011
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In: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 0964-6906. ; 20:21, s. 4268-81
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Journal article (peer-reviewed)abstract
- Three genome-wide association studies in Europe and the USA have reported eight urinary bladder cancer (UBC) susceptibility loci. Using extended case and control series and 1000 Genomes imputations of 5 340 737 single-nucleotide polymorphisms (SNPs), we searched for additional loci in the European GWAS. The discovery sample set consisted of 1631 cases and 3822 controls from the Netherlands and 603 cases and 37 781 controls from Iceland. For follow-up, we used 3790 cases and 7507 controls from 13 sample sets of European and Iranian ancestry. Based on the discovery analysis, we followed up signals in the urea transporter (UT) gene SLC14A. The strongest signal at this locus was represented by a SNP in intron 3, rs17674580, that reached genome-wide significance in the overall analysis of the discovery and follow-up groups: odds ratio = 1.17, P = 7.6 × 10(-11). SLC14A1 codes for UTs that define the Kidd blood group and are crucial for the maintenance of a constant urea concentration gradient in the renal medulla and, through this, the kidney's ability to concentrate urine. It is speculated that rs17674580, or other sequence variants in LD with it, indirectly modifies UBC risk by affecting urine production. If confirmed, this would support the 'urogenous contact hypothesis' that urine production and voiding frequency modify the risk of UBC.
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| 6. |
- Ryk, Charlotta
(author)
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Influence of genetic polymorphisms on DNA repair, p53 mutations and cancer risk
- 2006
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Doctoral thesis (other academic/artistic)abstract
- Individuals have different susceptibility towards environmental exposures that may cause or contribute to disease. This inter-individual variation is partly due to genetic polymorphisms in genes involved in DNA repair and metabolism, which have potential to modulate the function of the encoded proteins. This thesis is a contribution to the knowledge about the importance of polymorphisms, and how they might interfere with health. More specifically, the aims have been to investigate (1) if and how the mutational spectra of the tumour suppressor gene p53 in lung and bladder tumours is affected by genetic polymorphisms, (2) if polymorphisms can influence lung cancer risk in a study population with a high frequency of women and non-smokers, and (3) to develop a method to study the functionality of DNA repair polymorphisms in vitro. Papers I-II are based on a lung cancer case-control study population, with approximately 50 % nonsmokers and 70 % women. Papers III-IV are based on a bladder cancer cohort that includes all bladder cancer cases in the Stockholm county between 1995-1996. In paper V, lymphocytes from healthy nonsmoking volunteers were collected to study the functionality of DNA repair polymorphisms, using the Comet assay. PCR-RFLP and Taq-Man allelic discrimination were used for genotyping, SSCP and sequencing for identification of p53 mutations in tumours. The impact of genetic polymorphisms on the p53 gene was investigated in study I, III and IV. In study I we observed an association between the XPD 751G1n allele and an increased frequency of p53 transversion mutations in lung tumours, especially among smokers, suggesting that XPD 751G1n carriers have a reduced DNA repair proficiency. In study III we found that p53 transversion mutations were more common in bladder tumours of GSTM1 null individuals, and also the GSTP1 105Val allele was associated with a higher frequency of p53 transversion mutations than the wild type allele. GSTP1 105 Val was also associated with a higher frequency of p53 transitions at CpG sites. These results indicated that an impaired glutathione conjugation might affect the p53 mutational spectrum. In study IV, the cyclin D1 variant allele homozygotes and the XRCC3 241 Met homozygotes were associated with an increased p53 mutation frequency, while the NQ01 187Ser and 139Trp alleles and the XPC 939GIn allele were associated with an increased frequency of p53 transversion mutations. Thus, in general, these polymorphisms seem to have an impact on the type of mutations in the p53 gene in lung- and bladdertumours, while their impact on the frequency of mutation is small. This increased risk for specific types of mutations probably reflects a higher susceptibility to environmental exposures following the impaired metabolism (glutathione conjugation), or less efficient DNA repair, among carriers of the susceptible alleles. The influence of polymorphisms on lung cancer risk was investigated in study II, where the XRCC1 399GIn and the XRCC3 241 Met alleles were found to be associated with decreased risk for lung cancer among non-smoking- and smoking- women respectively. The NBS1 185GIn allele was associated with an increased risk among non-smoking and low-dose smoking women. The effects of the two HR-proteins, XRCC3 and NBS1 enhanced each other. Our results suggest that these polymorphisms influence the cancer risk through their effect on the repair capacity, which may alter the risk of having mutations fixed in the genome. In study V, we used a modified comet assay to study the influence of DNA repair polymorphisms on repair of MMS-induced DNA damage in peripheral blood lymphocytes in vitro. The investigated APEX1 Asp 148Glu, XRCC3 Thr241Met and NBS1 Glu 185Gln polymorphisms were shown to have effect on the early stages of DNA repair, and were associated with the rate of transitions of cells from a more damaged to a less damaged state. This type of functional study of DNA repair enzyme polymorphisms will contribute to a better understanding of the significance of gene association studies in cancer research.
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| 7. |
- Ryk, Charlotta, et al.
(author)
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The (CCTTT)n microsatellite polymorphism in the nitric oxide synthase 2 gene may influence bladder cancer pathogenesis.
- 2010
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In: The Journal of urology. - : Ovid Technologies (Wolters Kluwer Health). - 1527-3792 .- 0022-5347. ; 184:5, s. 2150-2157
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Journal article (peer-reviewed)abstract
- Purpose: We analyzed whether the NOS2 promoter microsatellite (CCTTT)n polymorphism influences bladder cancer pathogenesis. Materials and Methods: We genotyped 359 patients with bladder cancer in a population based cohort and 164 population controls by DNA fragment analysis and sequencing. Genotypes were combined with information on tumor stage, grade and stage, grade progression and cancer specific death. Clinical followup was 5 years. Results: We divided (CCTTT)n alleles into short—10 or fewer, intermediate—11 or 12 and long—13 or greater repeats. Patients homozygous for 13 or longer (CCTTT)n repeats were at decreased odds ratio for bladder cancer (p = 0.010). However, after illness developed they were at 3-fold increased hazard ratio for stage progression (p = 0.062) and 4-fold increased hazard ratio for death from bladder cancer (p = 0.056). We discovered what is to our knowledge a previously undescribed polymorphism at position 23105343 (C/T). There was no difference in frequency between bladder cancer cases and population controls for this polymorphism. No associations were found between tumor stage, grade or stage and grade progression. However, patients with bladder cancer with the heterozygous CT genotype were at 3-fold increased hazard ratio of death from cancer (p = 0.011). Conclusions: Nitric oxide can induce proliferation or apoptosis depending on the cellular context. Results suggest that the (CCTTT)n NOS2 microsatellite may influence bladder cancer risk and aggressiveness. This polymorphism may have an impact on disease pathogenesis, possibly by affecting intracellular nitric oxide levels.
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| 8. |
- Thiel, Tomas, et al.
(author)
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Secondary stimulation from Bacillus Calmette-Guerin induced macrophages induce nitric oxide independent cell-death in bladder cancer cells
- 2014
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In: Cancer Letters. - : Elsevier BV. - 0304-3835 .- 1872-7980. ; 348:1-2, s. 119-125
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Journal article (peer-reviewed)abstract
- The anti-tumour mechanisms following Bacillus Calmette-Guerin (BCG) treatment of bladder-cancer remain largely unknown. Previous studies have shown involvement of nitric-oxide (NO) formation in the BCG-mediated effect. We analyzed the effects of macrophage secreted factors (MSFs) from BCG-stimulated RAW264.7 cells on the bladder-cancer cell line MBT2. Direct treatment with BCG did not induce NO in MBT2-cells whereas supernatant from BCG-stimulated macrophages increased NOS2 mRNA and protein expression, NO concentrations and cell-death. Blocking NO-synthesis with the NOS-inhibitor L-NAME did not affect levels of cell-death suggesting cytotoxic pathways involving other signalling molecules than NO. Several such candidate genes were identified in a microarray.
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| 9. |
- Thiel, Tomas, et al.
(author)
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Secondary stimulation from Bacillus Calmette-Guérin induced macrophages upregulatesNOS2 protein in bladder cancer cells
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Other publication (other academic/artistic)abstract
- Treatment with Bacillus Calmette-Guérin (BCG) bladder instillations is an established treatment modality for superficial urinary bladder cancer and carcinoma in situ (CIS), but the anti-tumor mechanisms following BCG-instillations remain largely unknown. Previous data show increased nitric oxide (NO) concentrations in the urinary bladder from patients treated with BCG suggesting that NO-formation may be involved in the BCG-mediated effect. Using immunohistochemistry we have previously shown nitric oxide synthase 2 (NOS2/iNOS) protein expression in both immune cells and in urothelial cells in bladder cancer patient biopsies. In this study we analysed the influence of macrophage- (RAW 264.7) secreted factors on NO production by stimulating urothelial carcinoma cells (MBT2) with supernatant from BCG-treated macrophages as well as supernatant from untreated macrophages. Using real-time PCR, western blot and chemiluminescence, we found no effect of BCG when added straight to the culture medium of urothelial carcinoma cells. However, when 40% of the culture medium of the bladder cancer cells was substituted with supernatant from BCGstimulated macrophages, we found increased NOS2 mRNA and protein expression as well as increased levels of NO. In addition we found increased cell death only in bladder cancer cells stimulated with supernatant from BCG-treated macrophages, as visualized by cell cycle analysis and PARP cleavage. These results suggest that simultaneous targeting of the microenvironment and subsequent stimulation of adaptive responses can improve conventional BCG-therapy.
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