Identification and replication of the interplay of four genetic high risk variants for urinary bladder cancer

Little is known whether genetic variants identified in genome-wide association studies interact to increase bladder cancer risk. Recently, we identified two- and three-variant combinations associated with a particular increase of bladder cancer risk in a urinary bladder cancer case-control series (IfADo, 1501 cases, 1565 controls). In an independent case-control series (Nijmegen Bladder Cancer Study, NBCS, 1468 cases, 1720 controls) we confirmed these two- and three-variant combinations. Pooled analysis of the two studies as discovery group (IfADo-NBCS) resulted in sufficient statistical power to test up to four-variant combinations by a logistic regression approach. The New England and Spanish Bladder Cancer Studies (2080 cases and 2167 controls) were used as a replication series. Twelve previously identified risk variants were considered.The strongest four-variant combination was obtained in never smokers. The combination of rs1014971[AA] near APOBEC3A and CBX6, SLC14A1 exon SNP rs1058396[AG,GG], UGT1A intron SNP rs11892031[AA], and rs8102137[CC,CT] near CCNE resulted in an unadjusted odds ratio of 2.59 (95% CI = 1.93-3.47; P = 1.87x10-10), while the individual variant odds ratios ranged only between 1.11-1.30. The combination replicated in the New England and Spanish bladder Cancer Studies (ORunadjusted=1.60, 95% CI = 1.10-2.33; P = 0.013). The four-variant combination is relatively frequent, with 25% in never smoking cases and 11% in never smoking controls (total study group: 19% cases, 14% controls). In conclusion, we show that four high risk variants can statistically interact to confer increased bladder cancer risk particularly in never smokers

Identification of a novel susceptibility locus at 13q34 and refinement of the 20p12.2 region as a multi-signal locus associated with bladder cancer risk in individuals of european ancestry

Candidate gene and genome-wide association studies (GWAS) have identified 15 independent genomic regions associated with bladder cancer risk. In search for additional susceptibility variants, we followed up on four promising single-nucleotide polymorphisms (SNPs) that had not achieved genome-wide significance in 6911 cases and 11 814 controls (rs6104690, rs4510656, rs5003154 and rs4907479, P < 1 7 10(-6)), using additional data from existing GWAS datasets and targeted genotyping for studies that did not have GWAS data. In a combined analysis, which included data on up to 15 058 cases and 286 270 controls, two SNPs achieved genome-wide statistical significance: rs6104690 in a gene desert at 20p12.2 (P = 2.19 7 10(-11)) and rs4907479 within the MCF2L gene at 13q34 (P = 3.3 7 10(-10)). Imputation and fine-mapping analyses were performed in these two regions for a subset of 5551 bladder cancer cases and 10 242 controls. Analyses at the 13q34 region suggest a single signal marked by rs4907479. In contrast, we detected two signals in the 20p12.2 region-the first signal is marked by rs6104690, and the second signal is marked by two moderately correlated SNPs (r(2) = 0.53), rs6108803 and the previously reported rs62185668. The second 20p12.2 signal is more strongly associated with the risk of muscle-invasive (T2-T4 stage) compared with non-muscle-invasive (Ta, T1 stage) bladder cancer (case-case P 64 0.02 for both rs62185668 and rs6108803). Functional analyses are needed to explore the biological mechanisms underlying these novel genetic associations with risk for bladder cancer

Polymorphe Enzyme, Harnblasenkarzinom und Strukturwandel in der Montanregion im Großraum Dortmund

Es konnte in einer Fall-Kontroll-Studie mit 196 Fällen mit histologisch gesichertem Harnblasenkarzinom und 235 Kontrollen ohne anamnestische Hinweise auf einen Tumor aus der gleichen Klinik in Dortmund-Hörde, die im Zeitraum Juli 2009 bis Dezember 2010 untersucht worden waren, gezeigt werden, dass der Anteil der Glutathion-S-Transferase M1 (GSTM1)-negativen Harnblasenkarzinompatienten sowohl bei den Fällen als auch bei den Kontrollen 52% betrug und somit im Bereich der mitteleuropäischen Normalbevölkerung liegt. In einer Studie in den frühen 1990er Jahren betrug der Anteil des GSTM1-negativen Genotyps bei Harnblasenkarzinom-Patienten in Dortmund 70 % und bei den Kontrollen 54 %. Die Normalisierung des ehemals stark erhöhten Anteils der GSTM1-negativen Harnblasenkarzinompatienten im Großraum Dortmund wird auf den Jahrzehnte währenden Niedergang der Montanindustrie und letztendlich deren Schließung in den 1990er Jahren und der damit verbundenen Verringerung der Exposition zurückgeführt

Identification and replication of the interplay of four genetic high risk variants for urinary bladder cancer

Little is known whether genetic variants identified in genome-wide association studies interact to increase bladder cancer risk. Recently, we identified two- and three-variant combinations associated with a particular increase of bladder cancer risk in a urinary bladder cancer case-control series (IfADo, 1501 cases, 1565 controls). In an independent case-control series (Nijmegen Bladder Cancer Study, NBCS, 1468 cases, 1720 controls) we confirmed these two- and three-variant combinations. Pooled analysis of the two studies as discovery group (IfADo-NBCS) resulted in sufficient statistical power to test up to four-variant combinations by a logistic regression approach. The New England and Spanish Bladder Cancer Studies (2080 cases and 2167 controls) were used as a replication series. Twelve previously identified risk variants were considered.The strongest four-variant combination was obtained in never smokers. The combination of rs1014971[AA] near APOBEC3A and CBX6, SLC14A1 exon SNP rs1058396[AG,GG], UGT1A intron SNP rs11892031[AA], and rs8102137[CC,CT] near CCNE resulted in an unadjusted odds ratio of 2.59 (95% CI = 1.93-3.47; P = 1.87x10-10), while the individual variant odds ratios ranged only between 1.11-1.30. The combination replicated in the New England and Spanish bladder Cancer Studies (ORunadjusted=1.60, 95% CI = 1.10-2.33; P = 0.013). The four-variant combination is relatively frequent, with 25% in never smoking cases and 11% in never smoking controls (total study group: 19% cases, 14% controls). In conclusion, we show that four high risk variants can statistically interact to confer increased bladder cancer risk particularly in never smokers

Genome-wide association study yields variants at 20p12.2 that associate with urinary bladder cancer

Genome-wide association studies (GWAS) of urinary bladder cancer (UBC) have yielded common variants at 12 loci that associate with risk of the disease. We report here the results of a GWAS of UBC including 1670 UBC cases and 90 180 controls, followed by replication analysis in additional 5266 UBC cases and 10 456 controls. We tested a dataset containing 34.2 million variants, generated by imputation based on whole-genome sequencing of 2230 Icelanders. Several correlated variants at 20p12, represented by rs62185668, show genome-wide significant association with UBC after combining discovery and replication results (OR = 1.19, P = 1.5 × 10(-11) for rs62185668-A, minor allele frequency = 23.6%). The variants are located in a non-coding region approximately 300 kb upstream from the JAG1 gene, an important component of the Notch signaling pathways that may be oncogenic or tumor suppressive in several forms of cancer. Our results add to the growing number of UBC risk variants discovered through GWAS

European genome-wide association study identifies SLC14A1 as a new urinary bladder cancer susceptibility gene

Contains fulltext : 97884.pdf (publisher's version ) (Closed access)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 x 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