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

Associations between pancreatic expression quantitative traits and risk of pancreatic ductal adenocarcinoma

none57siPancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers. Its poor prognosis is predominantly due to the fact that most patients remain asymptomatic until the disease reaches an advanced stage, alongside the lack of early markers and screening strategies. A better understanding of PDAC risk factors is essential for the identification of groups at high risk in the population. Genome-wide association studies (GWAS) have been a powerful tool for detecting genetic variants associated with complex traits, including pancreatic cancer. By exploiting functional and GWAS data, we investigated the associations between polymorphisms affecting gene function in the pancreas (expression quantitative trait loci, eQTLs) and PDAC risk. In a two-phase approach, we analysed 13 713 PDAC cases and 43 784 controls and identified a genome-wide significant association between the A allele of the rs2035875 polymorphism and increased PDAC risk (P=7.14×10 -10). This allele is known to be associated with increased expression in the pancreas of the keratin genes KRT8 and KRT18, whose increased levels have been reported to correlate with various tumor cell characteristics. Additionally, the A allele of the rs789744 variant was associated with decreased risk of developing PDAC (P=3.56×10 -6). This SNP is situated in the SRGAP1 gene and the A allele is associated with higher expression of the gene, which in turn inactivates the cyclin-dependent protein 42 (CDC42) gene expression, thus decreasing the risk of PDAC. In conclusion, we present here a functional-based novel PDAC risk locus and an additional strong candidate supported by significant associations and plausible biological mechanisms.restrictedPistoni, Laura; Gentiluomo, Manuel; Lu, Ye; López de Maturana, Evangelina; Hlavac, Viktor; Vanella, Giuseppe; Darvasi, Erika; Milanetto, Anna Caterina; Oliverius, Martin; Vashist, Yogesh; Di Leo, Milena; Mohelnikova-Duchonova, Beatrice; Talar-Wojnarowska, Renata; Gheorghe, Cristian; Petrone, Maria Chiara; Strobel, Oliver; Arcidiacono, Paolo Giorgio; Vodickova, Ludmila; Szentesi, Andrea; Capurso, Gabriele; Gajdán, László; Malleo, Giuseppe; Theodoropoulos, George E; Basso, Daniela; Soucek, Pavel; Brenner, Hermann; Lawlor, Rita T; Morelli, Luca; Ivanauskas, Audrius; Kauffmann, Emanuele Federico; Macauda, Angelica; Gazouli, Maria; Archibugi, Livia; Nentwich, Michael; Loveček, Martin; Cavestro, Giulia Martina; Vodicka, Pavel; Landi, Stefano; Tavano, Francesca; Sperti, Cosimo; Hackert, Thilo; Kupcinskas, Juozas; Pezzilli, Raffaele; Andriulli, Angelo; Pollina, Luca; Kreivenaite, Edita; Gioffreda, Domenica; Jamroziak, Krzysztof; Hegyi, Péter; Izbicki, Jakob R; Testoni, Sabrina Gloria Giulia; Zuppardo, Raffaella Alessia; Bozzato, Dania; Neoptolemos, John P; Malats, Núria; Canzian, Federico; Campa, DanielePistoni, Laura; Gentiluomo, Manuel; Lu, Ye; López de Maturana, Evangelina; Hlavac, Viktor; Vanella, Giuseppe; Darvasi, Erika; Milanetto, Anna Caterina; Oliverius, Martin; Vashist, Yogesh; Di Leo, Milena; Mohelnikova-Duchonova, Beatrice; Talar-Wojnarowska, Renata; Gheorghe, Cristian; Petrone, Maria Chiara; Strobel, Oliver; Arcidiacono, Paolo Giorgio; Vodickova, Ludmila; Szentesi, Andrea; Capurso, Gabriele; Gajdán, László; Malleo, Giuseppe; Theodoropoulos, George E; Basso, Daniela; Soucek, Pavel; Brenner, Hermann; Lawlor, Rita T; Morelli, Luca; Ivanauskas, Audrius; Kauffmann, Emanuele Federico; Macauda, Angelica; Gazouli, Maria; Archibugi, Livia; Nentwich, Michael; Loveček, Martin; Cavestro, Giulia Martina; Vodicka, Pavel; Landi, Stefano; Tavano, Francesca; Sperti, Cosimo; Hackert, Thilo; Kupcinskas, Juozas; Pezzilli, Raffaele; Andriulli, Angelo; Pollina, Luca; Kreivenaite, Edita; Gioffreda, Domenica; Jamroziak, Krzysztof; Hegyi, Péter; Izbicki, Jakob R; Testoni, Sabrina Gloria Giulia; Zuppardo, Raffaella Alessia; Bozzato, Dania; Neoptolemos, John P; Malats, Núria; Canzian, Federico; Campa, Daniel