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- Figueroa, Jonine D., et al.
(författare)
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Genome-wide association study identifies multiple loci associated with bladder cancer risk
- 2014
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Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 23:5, s. 1387-1398
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Tidskriftsartikel (refereegranskat)abstract
- andidate gene and genome-wide association studies (GWAS) have identified 11 independent susceptibility loci associated with bladder cancer risk. To discover additional risk variants, we conducted a new GWAS of 2422 bladder cancer cases and 5751 controls, followed by a meta-analysis with two independently published bladder cancer GWAS, resulting in a combined analysis of 6911 cases and 11 814 controls of European descent. TaqMan genotyping of 13 promising single nucleotide polymorphisms with P < 1 × 10−5 was pursued in a follow-up set of 801 cases and 1307 controls. Two new loci achieved genome-wide statistical significance: rs10936599 on 3q26.2 (P = 4.53 × 10−9) and rs907611 on 11p15.5 (P = 4.11 × 10−8). Two notable loci were also identified that approached genome-wide statistical significance: rs6104690 on 20p12.2 (P = 7.13 × 10−7) and rs4510656 on 6p22.3 (P = 6.98 × 10−7); these require further studies for confirmation. In conclusion, our study has identified new susceptibility alleles for bladder cancer risk that require fine-mapping and laboratory investigation, which could further understanding into the biological underpinnings of bladder carcinogenesis.
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| 2. |
- Fu, Yi-Ping, et al.
(författare)
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The 19q12 Bladder Cancer GWAS Signal : Association with Cyclin E Function and Aggressive Disease
- 2014
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 74:20, s. 5808-5818
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Tidskriftsartikel (refereegranskat)abstract
- A genome-wide association study (GWAS) of bladder cancer identified a genetic marker rs8102137 within the 19q12 region as a novel susceptibility variant. This marker is located upstream of the CCNE1 gene, which encodes cyclin E, a cell-cycle protein. We performed genetic fine-mapping analysis of the CCNE1 region using data from two bladder cancer GWAS (5,942 cases and 10,857 controls). We found that the original GWAS marker rs8102137 represents a group of 47 linked SNPs (with r(2) >= 0.7) associated with increased bladder cancer risk. From this group, we selected a functional promoter variant rs7257330, which showed strong allele-specific binding of nuclear proteins in several cell lines. In both GWASs, rs7257330 was associated only with aggressive bladder cancer, with a combined per-allele OR = 1.18 [95% confidence interval (CI), 1.09-1.27, P = 4.67 x 10(-5)] versus OR = 1.01 (95% CI, 0.93-1.10, P = 0.79) for nonaggressive disease, with P = 0.0015 for case-only analysis. Cyclin E protein expression analyzed in 265 bladder tumors was increased in aggressive tumors (P = 0.013) and, independently, with each rs7257330-A risk allele (P-trend = 0.024). Overexpression of recombinant cyclin E in cell lines caused significant acceleration of cell cycle. In conclusion, we defined the 19q12 signal as the first GWAS signal specific for aggressive bladder cancer. Molecular mechanisms of this genetic association may be related to cyclin E overexpression and alteration of cell cycle in carriers of CCNE1 risk variants. In combination with established bladder cancer risk factors and other somatic and germline genetic markers, the CCNE1 variants could be useful for inclusion into bladder cancer risk prediction models.
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| 3. |
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| 4. |
- Figueroa, Jonine D., et al.
(författare)
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Genome-wide interaction study of smoking and bladder cancer risk
- 2014
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Ingår i: Carcinogenesis. - : Oxford University Press. - 0143-3334 .- 1460-2180. ; 35:8, s. 1737-1744
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Tidskriftsartikel (refereegranskat)abstract
- Bladder cancer is a complex disease with known environmental and genetic risk factors. We performed a genome-wide interaction study (GWAS) of smoking and bladder cancer risk based on primary scan data from 3002 cases and 4411 controls from the National Cancer Institute Bladder Cancer GWAS. Alternative methods were used to evaluate both additive and multiplicative interactions between individual single nucleotide polymorphisms (SNPs) and smoking exposure. SNPs with interaction P values < 5 x 10(-5) were evaluated further in an independent dataset of 2422 bladder cancer cases and 5751 controls. We identified 10 SNPs that showed association in a consistent manner with the initial dataset and in the combined dataset, providing evidence of interaction with tobacco use. Further, two of these novel SNPs showed strong evidence of association with bladder cancer in tobacco use subgroups that approached genome-wide significance. Specifically, rs1711973 (FOXF2) on 6p25.3 was a susceptibility SNP for never smokers [combined odds ratio (OR) = 1.34, 95% confidence interval (CI) = 1.20-1.50, P value = 5.18 x 10(-7)]; and rs12216499 (RSPH3-TAGAP-EZR) on 6q25.3 was a susceptibility SNP for ever smokers (combined OR = 0.75, 95% CI = 0.67-0.84, P value = 6.35 x 10-7). In our analysis of smoking and bladder cancer, the tests for multiplicative interaction seemed to more commonly identify susceptibility loci with associations in never smokers, whereas the additive interaction analysis identified more loci with associations among smokers-including the known smoking and NAT2 acetylation interaction. Our findings provide additional evidence of gene-environment interactions for tobacco and bladder cancer.
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| 5. |
- Pignot, G., et al.
(författare)
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L’Ischémie n’est pas un facteur d’insuffisance rénale chronique après néphrectomie partielle sur rein unique
- 2014
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Ingår i: Progrès en urologie (Paris). - : Elsevier. - 1166-7087. ; 24:13, s. 822-822
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Tidskriftsartikel (refereegranskat)abstract
- Objectifs Déterminer l‘influence du clampage pédiculaire et de sa durée sur la fonction rénale à long terme après néphrectomie partielle (NP) pour cancer sur rein unique.Méthodes L’étude a inclus rétrospectivement 259 patients opérés par NP entre 1979 et 2010 dans 13 centres. L’utilisation d’un clampage, son type (pédiculaire ou parenchymateux), sa durée ainsi que les données pré-, intra- et postopératoires ont été recueillies. Les valeurs de débit de filtration glomérulaire (DFG) préopératoire et au dernier suivi ont été comparés. Une analyse multivariée selon le modèle de Cox a été réalisée afin de déterminer l’impact de l’ischémie sur le risque d’insuffisance rénale (IR) chronique postopératoire.Résultats La taille moyenne des tumeurs était de 4,0±2,3cm et le DFG préopératoire moyen de 60,8±18,9ml/min. Au total, 106 patients ont été opérés en ischémie chaude (40,9 %) et 53 en ischémie froide (20,5 %). Trente patients (11,6 %) ont évolué vers l’insuffisance rénale chronique. En analyse multivariée, ni le clampage pédiculaire (p=0,44), ni la durée d’ischémie chaude (p=0,1) n’étaient associés à une évolution vers l’insuffisance rénale. Les facteurs indépendants d’insuffisance rénale à long terme étaient le DFG préopératoire (p<0,0001) et les pertes sanguines (p=0,02).Conclusion La fonction rénale après NP sur rein unique apparaît principalement liée à des facteurs non modifiables et notamment le DFG préopératoire. Ce travail relativise l’importance du clampage pédiculaire et du temps d’ischémie qui n’étaient pas significativement liés au risque d’IR dans notre étude.
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| 7. |
- Verhoest, G, et al.
(författare)
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Predictive factors of chronic kidney disease stage V after partial nephrectomy in a solitary kidney : a multi-institutional study
- 2014
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Ingår i: Urologic Oncology. - : Elsevier. - 1078-1439 .- 1873-2496. ; 32:1, s. 28.e21-28.e26
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Partial Nephrectomy (PN) in a solitary kidney is at risk of chronic kidney disease (CKD) stage V and/or haemodialysis (HD). Our objective was to determine predictive factors of CKD stage V in this population. MATERIAL & METHODS: Data from 300 patients were retrospectively collected from 16 tertiary centres. Clinical and operative parameters, tumor characteristics and renal function before surgery were analyzed. Patients with and without CKD stage V (defined as MDRD<15ml/min) were compared using χ2 and Student-t tests for qualitative and quantitative variables, respectively. Predictive factors of CKD stage V were evaluated with a multivariable analysis using a Cox regression model. RESULTS: Median age and BMI were 63 years old and 26kg/m², respectively. Most of the patients (65%) were male with an anatomic solitary kidney (88.3%). Median tumor size was 4cm and 98% were malignant tumors. Median operative time, blood loss and clamping time were 180min, 350ml and 20min respectively. Renal cooling was used in 19.3% and clamping of the pedicle was performed in 61.6%. Twenty five patients (8.5%) presented post operative CKD stage V at last follow-up and 18 underwent HD (6%) post-operatively because of acute renal insufficiency. There was no difference between CKD stage V and non CKD stage V patients concerning Charlson index, operative time (180min vs 179min, p= 0.39), blood loss (475ml vs 350ml, p= 0.51), use of renal cooling and type of clamping. Patients with CKD stage V were older (70 vs 63 years old, p= 0.005), had a lower baseline renal function (clearance MDRD 41 vs. 62ml/min, p<0.0001) and an increased tumor size (p= 0.02). Complications occurred in 91 patients (30%) with 16% of minor (Clavien 1-2) and 14% of major (Clavien>2) complications, respectively. In multivariable analysis, baseline MDRD, BMI, and the occurrence of a minor complication were independent predictive factors of post operative CKD stage V. CONCLUSION: PN in a solitary kidney is at risk of post-operative CKD stage V and HD. Pre-operative altered renal function and post operative complications are the main predictive factors of permanent CKD stage V.
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