| Title: | Genome-wide Association Study of Bladder Cancer Reveals New Biological and Translational Insights |
| Journal: | European Urology |
| Published: | 19 May 2023 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/37210288/ |
| DOI: | https://doi.org/10.1016/j.eururo.2023.04.020 |
Publication 11468
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Abstract
BACKGROUND: Genomic regions identified by genome-wide association studies (GWAS) for bladder cancer risk provide new insights into etiology.</p>
OBJECTIVE: To identify new susceptibility variants for bladder cancer in a meta-analysis of new and existing genome-wide genotype data.</p>
DESIGN, SETTING, AND PARTICIPANTS: Data from 32 studies that includes 13,790 bladder cancer cases and 343,502 controls of European ancestry were used for meta-analysis.</p>
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: Log-additive associations of genetic variants were assessed using logistic regression models. A fixed-effects model was used for meta-analysis of the results. Stratified analyses were conducted to evaluate effect modification by sex and smoking status. A polygenic risk score (PRS) was generated on the basis of known and novel susceptibility variants and tested for interaction with smoking.</p>
RESULTS AND LIMITATIONS: Multiple novel bladder cancer susceptibility loci (6p.22.3, 7q36.3, 8q21.13, 9p21.3, 10q22.1, 19q13.33) as well as improved signals in three known regions (4p16.3, 5p15.33, 11p15.5) were identified, bringing the number of independent markers at genome-wide significance (p < 5 × 10-8) to 24. The 4p16.3 (FGFR3/TACC3) locus was associated with a stronger risk for women than for men (p-interaction = 0.002). Bladder cancer risk was increased by interactions between smoking status and genetic variants at 8p22 (NAT2; multiplicative p value for interaction [pM-I] = 0.004), 8q21.13 (PAG1; pM-I = 0.01), and 9p21.3 (LOC107987026/MTAP/CDKN2A; pM-I = 0.02). The PRS based on the 24 independent GWAS markers (odds ratio per standard deviation increase 1.49, 95% confidence interval 1.44-1.53), which also showed comparable results in two prospective cohorts (UK Biobank, PLCO trial), revealed an approximately fourfold difference in the lifetime risk of bladder cancer according to the PRS (e.g., 1st vs 10th decile) for both smokers and nonsmokers.</p>
CONCLUSIONS: We report novel loci associated with risk of bladder cancer that provide clues to its biological underpinnings. Using 24 independent markers, we constructed a PRS to stratify lifetime risk. The PRS combined with smoking history, and other established risk factors, has the potential to inform future screening efforts for bladder cancer.</p>
PATIENT SUMMARY: We identified new genetic markers that provide biological insights into the genetic causes of bladder cancer. These genetic risk factors combined with lifestyle risk factors, such as smoking, may inform future preventive and screening strategies for bladder cancer.</p>
101 Authors
- Stella Koutros
- Lambertus A. Kiemeney
- Parichoy Pal Choudhury
- Roger L. Milne
- Evangelina Lopez de Maturana
- Yuanqing Ye
- Vijai Joseph
- Oscar Florez-Vargas
- Lars Dyrskjøt
- Jonine Figueroa
- Diptavo Dutta
- Graham G. Giles
- Michelle A.T. Hildebrandt
- Kenneth Offit
- Manolis Kogevinas
- Elisabete Weiderpass
- Marjorie L. McCullough
- Neal D. Freedman
- Demetrius Albanes
- Charles Kooperberg
- Victoria K. Cortessis
- Margaret R. Karagas
- Alison Johnson
- Molly R. Schwenn
- Dalsu Baris
- Helena Furberg
- Dean F. Bajorin
- Olivier Cussenot
- Geraldine Cancel-Tassin
- Simone Benhamou
- Peter Kraft
- Stefano Porru
- Angela Carta
- Timothy Bishop
- Melissa C. Southey
- Giuseppe Matullo
- Tony Fletcher
- Rajiv Kumar
- Jack A. Taylor
- Philippe Lamy
- Frederik Prip
- Mark Kalisz
- Stephanie J. Weinstein
- Jan G. Hengstler
- Silvia Selinski
- Mark Harland
- Mark Teo
- Anne E. Kiltie
- Adonina Tardón
- Consol Serra
- Alfredo Carrato
- Reina García-Closas
- Josep Lloreta
- Alan Schned
- Petra Lenz
- Elio Riboli
- Paul Brennan
- Anne Tjønneland
- Thomas Otto
- Daniel Ovsiannikov
- Frank Volkert
- Sita H. Vermeulen
- Katja K. Aben
- Tessel E. Galesloot
- Constance Turman
- Immaculata De Vivo
- Edward Giovannucci
- David J. Hunter
- Hohensee
- Rebecca Hunt
- Alpa V. Patel
- Wen-Yi Huang
- Gudmar Thorleifsson
- Manuela Gago-Dominguez
- Pilar Amiano
- Klaus Golka
- Mariana C. Stern
- UROMOL Consortium
- Wusheng Yan
- Jia Liu
- Shengchao Alfred Li
- Shilpa Katta
- Amy Hutchinson
- Belynda Hicks
- William A. Wheeler
- Mark P. Purdue
- Katherine A. McGlynn
- Cari M. Kitahara
- Christopher A. Haiman
- Mark H. Greene
- Thorunn Rafnar
- Nilanjan Chatterjee
- Stephen J. Chanock
- Xifeng Wu
- Francisco X. Real
- Debra T. Silverman
- Montserrat Garcia-Closas
- Kari Stefansson
- Ludmila Prokunina-Olsson
- Núria Malats
- Nathaniel Rothman
1 Application
| Application ID | Title |
|---|---|
| 47618 | Lifestyle and genetic factors and bladder cancer risk |
Enabling scientific discoveries that improve human health