Tessel E Galesloot1, Anne J Grotenhuis2, Dimitar Kolev2, Katja K Aben3, Richard T Bryan4, James W F Catto5, Kar K Cheng6, Samantha Conroy5, Lars Dyrskjøt7, Neil E Fleshner8, Nicholas D James9, Philippe Lamy10, Sia Viborg Lindskrog7, Núria Malats11, Lourdes Mengual12, Gerald Verhaegh13, Maurice P Zeegers14, Lambertus A L M Kiemeney15, Sita H Vermeulen2. 1. Department for Health Evidence, Radboud university medical center, Nijmegen, The Netherlands. Electronic address: Tessel.Galesloot@radboudumc.nl. 2. Department for Health Evidence, Radboud university medical center, Nijmegen, The Netherlands. 3. Department for Health Evidence, Radboud university medical center, Nijmegen, The Netherlands; Netherlands Comprehensive Cancer Organisation, Utrecht, The Netherlands. 4. Institute of Cancer & Genomic Sciences, University of Birmingham, Birmingham, UK; Bladder Cancer Research Centre, University of Birmingham, Birmingham, UK. 5. Academic Urology Unit, University of Sheffield, Sheffield, UK. 6. Institute of Applied Health Research, University of Birmingham, Birmingham, UK. 7. Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark. 8. Department of Urology, Princess Margaret Cancer Centre, Toronto, Canada. 9. Institute of Cancer & Genomic Sciences, University of Birmingham, Birmingham, UK. 10. Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark. 11. Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain; CIBERONC, Madrid, Spain. 12. Department and Laboratory of Urology, Hospital Clínic, IDIBAPS, Universitat de Barcelona, Barcelona, Spain. 13. Department of Urology, Radboud university medical center, Nijmegen, The Netherlands. 14. Institute of Cancer & Genomic Sciences, University of Birmingham, Birmingham, UK; Department of Complex Genetics and Epidemiology, School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands; CAPHRI School for Public Health and Primary Care, University of Maastricht, Maastricht, The Netherlands. 15. Department for Health Evidence, Radboud university medical center, Nijmegen, The Netherlands; Department of Urology, Radboud university medical center, Nijmegen, The Netherlands.
Abstract
BACKGROUND: Non-muscle-invasive bladder cancer (NMIBC) is characterized by frequent recurrences and a risk of progression in stage and grade. Increased knowledge of underlying biological mechanisms is needed. OBJECTIVE: To identify single nucleotide polymorphisms (SNPs) associated with recurrence-free (RFS) and progression-free (PFS) survival in NMIBC. DESIGN, SETTING, AND PARTICIPANTS: We analyzed outcome data from 3400 newly diagnosed NMIBC patients from the Netherlands, the UK, Canada, and Spain. We generated genome-wide germline SNP data using Illumina OmniExpress and Infinium Global Screening Array in combination with genotype imputation. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Cohort-specific genome-wide association studies (GWASs) for RFS and PFS were performed using a Cox proportional hazard model. Results were combined in a fixed-effect inverse-variance weighted meta-analysis. Candidate genes for the identified SNP associations were prioritized using functional annotation, gene-based analysis, expression quantitative trait locus analysis, and transcription factor binding site databases. Tumor expression levels of prioritized genes were tested for association with RFS and PFS in an independent NMIBC cohort. RESULTS AND LIMITATIONS: This meta-analysis revealed a genome-wide significant locus for RFS on chromosome 14 (lead SNP rs12885353, hazard ratio [HR] C vs T allele 1.55, 95% confidence interval [CI] 1.33-1.82, p = 4.0 × 10-8), containing genes G2E3 and SCFD1. Higher expression of SCFD1 was associated with increased RFS (HR 0.70, 95% CI 0.59-0.84, pFDR = 0.003). Twelve other loci were suggestively associated with RFS (p < 10-5), pointing toward 18 additional candidate genes. For PFS, ten loci showed suggestive evidence of association, indicating 36 candidate genes. Expression levels of ten of these genes were statistically significantly associated with PFS, of which four (IFT140, UBE2I, FAHD1, and NME3) showed directional consistency with our meta-analysis results and published literature. CONCLUSIONS: In this first prognostic GWAS in NMIBC, we identified several novel candidate loci and five genes that showed convincing associations with recurrence or progression. PATIENT SUMMARY: In this study, we searched for inherited DNA changes that affect the outcome of non-muscle-invasive bladder cancer (NMIBC). We identified several genes that are associated with disease recurrence and progression. The roles and mechanisms of these genes in NMIBC prognosis should be investigated in future studies.
BACKGROUND: Non-muscle-invasive bladder cancer (NMIBC) is characterized by frequent recurrences and a risk of progression in stage and grade. Increased knowledge of underlying biological mechanisms is needed. OBJECTIVE: To identify single nucleotide polymorphisms (SNPs) associated with recurrence-free (RFS) and progression-free (PFS) survival in NMIBC. DESIGN, SETTING, AND PARTICIPANTS: We analyzed outcome data from 3400 newly diagnosed NMIBC patients from the Netherlands, the UK, Canada, and Spain. We generated genome-wide germline SNP data using Illumina OmniExpress and Infinium Global Screening Array in combination with genotype imputation. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Cohort-specific genome-wide association studies (GWASs) for RFS and PFS were performed using a Cox proportional hazard model. Results were combined in a fixed-effect inverse-variance weighted meta-analysis. Candidate genes for the identified SNP associations were prioritized using functional annotation, gene-based analysis, expression quantitative trait locus analysis, and transcription factor binding site databases. Tumor expression levels of prioritized genes were tested for association with RFS and PFS in an independent NMIBC cohort. RESULTS AND LIMITATIONS: This meta-analysis revealed a genome-wide significant locus for RFS on chromosome 14 (lead SNP rs12885353, hazard ratio [HR] C vs T allele 1.55, 95% confidence interval [CI] 1.33-1.82, p = 4.0 × 10-8), containing genes G2E3 and SCFD1. Higher expression of SCFD1 was associated with increased RFS (HR 0.70, 95% CI 0.59-0.84, pFDR = 0.003). Twelve other loci were suggestively associated with RFS (p < 10-5), pointing toward 18 additional candidate genes. For PFS, ten loci showed suggestive evidence of association, indicating 36 candidate genes. Expression levels of ten of these genes were statistically significantly associated with PFS, of which four (IFT140, UBE2I, FAHD1, and NME3) showed directional consistency with our meta-analysis results and published literature. CONCLUSIONS: In this first prognostic GWAS in NMIBC, we identified several novel candidate loci and five genes that showed convincing associations with recurrence or progression. PATIENT SUMMARY: In this study, we searched for inherited DNA changes that affect the outcome of non-muscle-invasive bladder cancer (NMIBC). We identified several genes that are associated with disease recurrence and progression. The roles and mechanisms of these genes in NMIBC prognosis should be investigated in future studies.
Authors: Alexander Pemov; Talia Wegman-Ostrosky; Jung Kim; Stella Koutros; Brenna Douthitt; Kristine Jones; Bin Zhu; Dalsu Baris; Molly Schwenn; Alison Johnson; Margaret R Karagas; Brian D Carter; Marjorie L McCullough; Maria Teresa Landi; Neal D Freedman; Demetrius Albanes; Debra T Silverman; Nathaniel Rothman; Neil E Caporaso; Mark H Greene; Joseph F Fraumeni; Douglas R Stewart Journal: JCO Precis Oncol Date: 2021-12-22