Patients with non-muscle invasive bladder cancer (NMIBC) frequently experience recurrence and may progress to muscle-invasive disease. Although several common germline variants associated with bladder cancer risk have been identified, their prognostic value in NMIBC remains unclear. We performed an updated genome-wide association study (GWAS), incorporating additional cohorts and analysing multiple NMIBC recurrences, to identify germline genetic variants associated with recurrence and progression.
We analysed eight cohorts (N = 5009) from the Netherlands, UK, Canada, and Spain. Cohort-specific GWAS were conducted using Cox regression for recurrence-free survival (RFS) and progression-free survival (PFS), including recurrent-event analysis and gene-based analyses. Analyses included chromosome X and were stratified by sex and Bacillus Calmette-Guérin (BCG) treatment. Previously reported variants for bladder cancer risk and prognosis were also evaluated.
We observed 4237 recurrences, of which 2145 were first recurrences, and 742 cases of progression in stage and/or grade. No genome-wide significant associations were identified in the overall population, chromosome X, or sex-stratified analyses. In BCG-treated patients, two loci reached genome-wide significance for RFS, with the strongest signal for rs72744118, an intron variant in DISP-1 (HR = 0.43; 95% CI (0.32, 0.56), p = 5.8 × 10-10). Gene prioritization identified 101 candidate genes from SNP associations (p < 1 × 10-6) and colocalization analyses, of which 16 genes showed nominally significant association between gene expression and NMIBC outcome in UROMOL.
In the largest GWAS of NMIBC prognosis to date, we prioritized a set of 16 genes. Future research should independently validate the prognostic and functional roles of identified genes.
Cancer genetics. 2026 Jun 13 [Epub ahead of print]
Jasper P Hof, Tessel E Galesloot, Katja K H Aben, Richard T Bryan, James W F Catto, Kar K Cheng, Samantha Conroy, Neil E Fleshner, Antoine G van der Heijden, Nicholas D James, Lourdes Mengual, Florine M Uunk, Gerald Verhaegh, Alina Vrieling, Maurice P Zeegers, Lambertus A L M Kiemeney, Sita H Vermeulen
Radboud university medical center, IQ Health science department, Nijmegen, the Netherlands; Aarhus University, Center for Quantitative Genetics and Genomics, Aarhus, Denmark. Electronic address: ., Radboud university medical center, IQ Health science department, Nijmegen, the Netherlands., Radboud university medical center, IQ Health science department, Nijmegen, the Netherlands; Netherlands Comprehensive Cancer Organization, Department of Research and Development, Nijmegen, the Netherlands., Department of Cancer & Genomic Sciences, College of Medicine and Health, University of Birmingham, Birmingham, UK; Bladder Cancer Research Centre, College of Medicine and Health, University of Birmingham, Birmingham, UK., Academic Urology Unit, University of Sheffield, Sheffield, UK., Institute of Applied Health Research, University of Birmingham, Birmingham, UK., Department of Urology, Princess Margaret Cancer Centre, Toronto, Canada., Radboud university medical center, Department of Urology, Nijmegen, the Netherlands., Department of Cancer & Genomic Sciences, College of Medicine and Health, University of Birmingham, Birmingham, UK., Department and Laboratory of Urology, Hospital Clínic, IDIBAPS, Universitat de Barcelona, Barcelona, Spain., Department of Epidemiology, School of Nutrition and Translational Research in Metabolism, Maastricht University, the Netherlands., Radboud university medical center, IQ Health science department, Nijmegen, the Netherlands; Radboud university medical center, Department of Urology, Nijmegen, the Netherlands.