Large-Scale Genome-Wide Association Study Identifies Multiple Novel Germline Susceptibility Variants Associated With Bladder Cancer Risk.

Abstract Background: Genomic regions that confer susceptibility for bladder cancer have provided important insights into the mechanisms of this disease. Sixteen genomic regions harboring bladder cancer susceptibility loci have been reported to date. To identify additional loci associated with bladder cancer risk, we conducted a meta-analysis including data from previously published genome-wide association studies as well as unpublished data. Methods: Data from 32 studies including 13,790 bladder cancer cases and 343,502 controls of European ancestry were included. Stratified analyses by sex and smoking status, as well as heterogeneity in risk by muscle-invasiveness, were also conducted. We tested for multiplicative and additive interactions between cigarette smoking and susceptibility loci that achieved genome-wide significance. After genotyping, quality control, and imputation log-additive effects were calculated by study/array group using regression models adjusting for age and significant eigenvectors. Results were combined by meta-analysis using a fixed-effects model. Results: We report strengthened or independent signals in several previously published regions at 4p16.3 (TACC3, FGFR3), 5p15.33 (CLPTM1L, TERT) and 11p15.5 (TNNT3, LSP1), as well as nine novel loci. In addition, we observed the first evidence of effect modification by sex at the FGFR3 locus, with a stronger risk observed in women (pmultiplicative-interaction=0.002). Further, we confirmed an interaction between smoking and a susceptibility locus at 8p22 (NAT2), indicating an increased risk of bladder cancer among smokers with the NAT2 slow acetylation genotype/phenotype (pmultiplicative-interaction=0.001). We also identified additional multiplicative, as well as additive, interactions between several novel loci and cigarette smoking status. In addition, we are currently building a risk stratification model using the combined effects of smoking and genetic susceptibility to identify subgroups of individuals at higher and lower absolute risk of bladder cancer. Conclusions: This meta-analysis identified 3 novel loci in previously reported regions and 9 novel bladder cancer susceptibility loci in new regions. These results add to our knowledge of the genetic architecture of bladder cancer. In addition, observed gene-smoking interactions suggest that risk stratification models may have translational implications, informing future disease screening efforts. Citation Format: Stella Koutros, Lambertus A. Kiemeney, Roger L. Milne, Yuanqing Ye, Vijai Joseph, Jonine Figueroa, Nilanjan Chatterjee, Graham G. Giles, Michelle A. Hildebrandt, Lars Dyrskjot, Kenneth Offit, Manolis Kogevinas, Elisabete Weiderpass, Marjorie L. McCullough, Neal D. Freedman, Demetrius Albanes, Charles Kooperberg, Victoria Cortessis, Margaret R. Karagas, Dalsu Baris, Alison Johnson, Molly R. Schwenn, Helena Furberg, Dean F. Bajorin, Parichoy Pal Choudhury, Oscar Florez-Vargas, Olivier Cussenot, Geraldine Cancel-Tassin, Simone Benhamou, Peter Kraft, Stefano Porru, Mark P. Purdue, Katherine A. McGlynn, Cari M. Kitahara, Christopher A. Haiman, Mark H. Greene, Thorunn Rafnar, Stephen J. Chanock, Xifeng Wu, Francisco X. Real, Debra T. Silverman, Montserrat Garcia-Closas, Kari Stefansson, Ludmila Prokunina-Olsson, Nuria Malats, Nathaniel Rothman. Large-scale genome-wide association study identifies multiple novel germline susceptibility variants associated with bladder cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 826.