| 1. |
- Kiemeney, Lambertus A, et al.
(författare)
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A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer.
- 2010
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 42:5, s. 415-9
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Tidskriftsartikel (refereegranskat)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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| 2. |
- Rafnar, Thorunn, et al.
(författare)
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European genome-wide association study identifies SLC14A1 as a new urinary bladder cancer susceptibility gene.
- 2011
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Ingår i: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 0964-6906. ; 20:21, s. 4268-81
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Tidskriftsartikel (refereegranskat)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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| 3. |
- Rothman, Nathaniel, et al.
(författare)
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A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 978-984
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Tidskriftsartikel (refereegranskat)abstract
- We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis.
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| 4. |
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| 5. |
- Gontero, Paolo, et al.
(författare)
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Prognostic Factors and Risk Groups in T1G3 Non-Muscle-invasive Bladder Cancer Patients Initially Treated with Bacillus Calmette-Guerin : Results of a Retrospective Multicenter Study of 2451 Patients
- 2015
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Ingår i: European Urology. - : Elsevier BV. - 0302-2838 .- 1873-7560. ; 67:1, s. 74-82
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Tidskriftsartikel (refereegranskat)abstract
- Background: The impact of prognostic factors in T1G3 non-muscle-invasive bladder cancer (BCa) patients is critical for proper treatment decision making. Objective: To assess prognostic factors in patients who received bacillus Calmette Guerin (BCG) as initial intravesical treatment of T1G3 tumors and to identify a subgroup of high-risk patients who should be considered for more aggressive treatment. Design, setting, and participants: Individual patient data were collected for 2451 T1G3 patients from 23 centers who received BCG between 1990 and 2011. Outcome measurements and statistical analysis: Using Cox multivariable regression, the prognostic importance of several clinical variables was assessed for time to recurrence, progression, BCa-specific survival, and overall survival (OS). Results and limitations: With a median follow-up of 5.2 yr, 465 patients (19%) progressed, 509 (21%) underwent cystectomy, and 221 (9%) died because of BCa. In multivariable analyses, the most important prognostic factors for progression were age, tumor size, and concomitant carcinoma in situ (CIS); the most important prognostic factors for BCa-specific survival and OS were age and tumor size. Patients were divided into four risk groups for progression according to the number of adverse factors among age >= 70 yr, size >= 3 cm, and presence of CIS. Progression rates at 10 yr ranged from 17% to 52%. BCa-specific death rates at 10 yr were 32% in patients >= 70 yr with tumor size >= 3 cm and 13% otherwise. Conclusions: T1G3 patients >= 70 yr with tumors >= 3 cm and concomitant CIS should be treated more aggressively because of the high risk of progression. Patient summary: Although the majority of T1G3 patients can be safely treated with intravesical bacillus Calmette-Guerin, there is a subgroup of T1G3 patients with age >= 70 yr, tumor size >= 3 cm, and concomitant CIS who have a high risk of progression and thus require aggressive treatment.
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| 6. |
- Schultz, Iman J, et al.
(författare)
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Gene expression analysis for the prediction of recurrence in patients with primary Ta urothelial cell carcinoma
- 2007
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Ingår i: European Urology. - : Elsevier BV. - 0302-2838 .- 1873-7560. ; 51:2, s. 416-423
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Tidskriftsartikel (refereegranskat)abstract
- Objectives The individual recurrence-free period after primary surgery of patients with Ta urothelial cell carcinoma (UCC) cannot be predicted accurately. This study aims at discriminating between patients with primary Ta UCC and long or short recurrence-free periods. Methods We investigated mRNA expression of 23 genes in 44 primary Ta tumours (23 and 21 tumours were from patients with long [≥4 yr] or short [≤2 yr] recurrence-free periods, respectively), using real-time quantitative polymerase chain reaction. The genes were selected from previously published studies and showed a relationship with tumour recurrence in patients with UCC. Results Differential mRNA expression between the two patient groups indicated statistical significance only for the gene survivin (p = 0.0011). Its recurrence predictive value could not be increased by a combination with any of the other genes. Comparison of the receiver operating characteristic curves for survivin expression between patients with long or short recurrence-free intervals revealed an area under the curve of 0.79 (95%CI, 0.65–0.92). Using the median expression (0.84) as cut-off level, survivin identified 71.4% (95%CI, 47.8–88.7) and 69.6% (95%CI, 47.1–86.8) of the patients with long or short recurrence-free periods, respectively. Conclusions Our study identifies survivin as the most promising candidate to distinguish between patients with primary Ta UCC and long or short recurrence-free intervals. Therefore, survivin mRNA expression analysis might help the urologist to individualise patient treatment and prevent unnecessary cystoscopies in a subgroup of these patients.
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| 7. |
- Schultz, Iman J., et al.
(författare)
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Prediction of recurrence in Ta urothelial cell carcinoma by real-time quantitative PCR analysis : a microarray validation study
- 2006
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 119:8, s. 1915-1919
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Tidskriftsartikel (refereegranskat)abstract
- Accurate prediction of tumor recurrence in patients with superficial urothelial cell carcinoma (UCC) might result in a significant reduction of invasive follow-up cystoscopies. A recent study identified a panel of 26 genes from a large cDNA microarray analysis of bladder tumors that discriminated between early- and late-recurring patients with superficial Ta tumors (Dyrskjot et al., Nat Genet 2003;33:90-6). We aimed to validate this panel of genes in 44 primary Ta UCCs (23 and 21 tumors from patients with short or prolonged recurrence-free periods, respectively), by real-time quantitative PCR. Statistical analysis showed marginal significant different mRNA expression levels between the 2 patient groups. To evaluate a supplementary effect of genes for the identification of patients with short or prolonged recurrence-free intervals, forward logistic regression analysis was applied. This revealed that a combination of the expression profiles of the genes HNRPK, LTB4DH and ANP32B resulted in the best performance, although the combination only marginally increased the predictive value of HNRPK alone. Comparing the receiver-operating-characteristic curves for HNRPK expression among patients with short or prolonged recurrence-free periods, revealed an area under the curve of 0.696 (95% CI, 0.537-0.855). Using the median HNRPK expression level as cut-off, a sensitivity of 69.6% and a specificity of 71.4% were obtained for the identification of patients with short or prolonged recurrence-free periods, respectively. In conclusion, we were not able to confirm the microarray gene expression pattern of the 26 genes shown by Dyrskjot et al. The discovery of accurate recurrence predictive markers, therefore, remains a challenge.
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| 8. |
- Schultz, Iman J., et al.
(författare)
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The Prognostic Role of the STK15 T91A Polymorphism and of STK15 mRNA Expression in Patients with Urothelial Cell Carcinoma
- 2007
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Ingår i: Anticancer Research. - 0250-7005 .- 1791-7530. ; 27:2, s. 1025-1030
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Tidskriftsartikel (refereegranskat)abstract
- Background: The prognostic role of the STK15 T91A polymorphism and of STK15 mRNA expression was investigated in patients with urothelial cell carcinoma (UCC). Materials and Methods: The STK15 genotype with respect to the T91A polymorphism was assessed by restriction fragment length polymorphism in 135 patients. STK15 mRNA expression was measured in tumor tissues of 103 patients, using real-time quantitative PCR. Results: The T91A polymorphism lacked any prognostic information in our patient cohort. Interestingly though, STK15 mRNA expression was increased in invasive and high-grade tumors (p-values of 0.009 and 0.0001, respectively). Additionally, patients with superficial UCC (n=82) who had a tumor recurrence in the first year after surgery displayed elevated STK15 mRNA expression levels (p=0.009). Kaplan-Meier survival analysis revealed an increased risk of tumor progression for patients with Ta tumors (n=62) and high STK15 expression (log-rank p=0.04). Furthermore, a decreased overall (log-rank p=0.006) and UCC-specific survival (log-rank p=0.001) were shown for patients with elevated STK15 mRNA levels. Conclusion: Patients with UCC and elevated levels of STK15 mRNA generally showed a more adverse disease course than patients with low levels. This may help in identifying patients in need of more aggressive treatment.
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| 9. |
- Westhoff, Ellen, et al.
(författare)
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Body Mass Index, Diet-Related Factors, and Bladder Cancer Prognosis: A Systematic Review and Meta-Analysis.
- 2018
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Ingår i: Bladder cancer (Amsterdam, Netherlands). - 2352-3727. ; 4:1, s. 91-112
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Tidskriftsartikel (refereegranskat)abstract
- Urologists are frequently confronted with questions of urinary bladder cancer (UBC) patients about what they can do to improve their prognosis. Unfortunately, it is largely unknown which lifestyle factors can influence prognosis.To systematically review the available evidence on the association between body mass index (BMI), diet, dietary supplements, and physical activity and UBC prognosis.We searched PubMed and Embase up to May 2017. We included thirty-one articles reporting on observational and randomized controlled trials investigating BMI, diet and dietary supplements in relation to recurrence, progression, cancer-specific or all-cause mortality in UBC patients.In non-muscle invasive bladder cancer (NMIBC) patients, both overweight (3 studies, pooled hazard ratio (HR) 1.29, 95% CI 1.05-1.58, I2 = 0%) as well as obesity (3 studies, pooled HR 1.82, 95% CI 1.12-2.95, I2 = 79%) were associated with increased risk of recurrence when compared to normal weight. No association of BMI with risk of progression was found. Results for BMI and prognosis in muscle-invasive or in all stages series were inconsistent. Observational studies on diet and randomized controlled trials with dietary supplements showed inconsistent results. No studies on physical activity and UBC prognosis have been published to date.Evidence for an association of lifestyle factors with UBC prognosis is limited, with some evidence for an association of BMI with risk of recurrence in NMIBC. Well-designed, prospective studies are needed to develop evidence-based guidelines on this topic.
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| 10. |
- Wu, Xifeng, et al.
(författare)
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Genetic variation in the prostate stem cell antigen gene PSCA confers susceptibility to urinary bladder cancer.
- 2009
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 41:9, s. 991-5
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Tidskriftsartikel (refereegranskat)abstract
- We conducted a genome-wide association study on 969 bladder cancer cases and 957 controls from Texas. For fast-track validation, we evaluated 60 SNPs in three additional US populations and validated the top SNP in nine European populations. A missense variant (rs2294008) in the PSCA gene showed consistent association with bladder cancer in US and European populations. Combining all subjects (6,667 cases, 39,590 controls), the overall P-value was 2.14 x 10(-10) and the allelic odds ratio was 1.15 (95% confidence interval 1.10-1.20). rs2294008 alters the start codon and is predicted to cause truncation of nine amino acids from the N-terminal signal sequence of the primary PSCA translation product. In vitro reporter gene assay showed that the variant allele significantly reduced promoter activity. Resequencing of the PSCA genomic region showed that rs2294008 is the only common missense SNP in PSCA. Our data identify rs2294008 as a new bladder cancer susceptibility locus.
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