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Genome-wide Association Study of Bladder Cancer Reveals New Biological and Translational Insights.

About this Publication
Title
Genome-wide Association Study of Bladder Cancer Reveals New Biological and Translational Insights.
Pubmed ID
37210288 (View this publication on the PubMed website)
Digital Object Identifier
Publication
Eur Urol. 2023 May 18
Authors
Koutros S, Kiemeney LA, Pal Choudhury P, Milne RL, Lopez de Maturana E, Ye Y, Joseph V, Florez-Vargas O, Dyrskjøt L, Figueroa J, Dutta D, Giles GG, Hildebrandt MAT, Offit K, Kogevinas M, Weiderpass E, McCullough ML, Freedman ND, Albanes D, Kooperberg C, ...show more Cortessis VK, Karagas MR, Johnson A, Schwenn MR, Baris D, Furberg H, Bajorin DF, Cussenot O, Cancel-Tassin G, Benhamou S, Kraft P, Porru S, Carta A, Bishop T, Southey MC, Matullo G, Fletcher T, Kumar R, Taylor JA, Lamy P, Prip F, Kalisz M, Weinstein SJ, Hengstler JG, Selinski S, Harland M, Teo M, Kiltie AE, Tardón A, Serra C, Carrato A, García-Closas R, Lloreta J, Schned A, Lenz P, Riboli E, Brennan P, Tjønneland A, Otto T, Ovsiannikov D, Volkert F, Vermeulen SH, Aben KK, Galesloot TE, Turman C, De Vivo I, Giovannucci E, Hunter DJ, Hohensee C, Hunt R, Patel AV, Huang WY, Thorleifsson G, Gago-Dominguez M, Amiano P, Golka K, Stern MC, UROMOL Consortium, Yan W, Liu J, Li SA, Katta S, Hutchinson A, Hicks B, Wheeler WA, Purdue MP, McGlynn KA, Kitahara CM, Haiman CA, Greene MH, Rafnar T, Chatterjee N, Chanock SJ, Wu X, Real FX, Silverman DT, Garcia-Closas M, Stefansson K, Prokunina-Olsson L, Malats N, Rothman N
Affiliations
  • Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA. Electronic address: koutross@mail.nih.gov.
  • Department for Health Evidence, Radboud University Medical Center, Nijmegen, The Netherlands.
  • Trans-Divisional Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA; American Cancer Society, Atlanta, GA, USA.
  • Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia; Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Australia.
  • Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Centre (CNIO) and CIBERONC, Madrid, Spain.
  • Zhejiang University, Hangzhou, China.
  • Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
  • Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
  • Usher Institute, University of Edinburgh, Edinburgh, UK; Integrative Tumor Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
...show more
  • Integrative Tumor Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
  • University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Instituto de Salud Global, Barcelona, Spain.
  • International Agency for Research on Cancer, Lyon, France.
  • Population Science, American Cancer Society, Atlanta, GA, USA.
  • Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
  • Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.
  • Department of Population and Public Health Sciences, Epidemiology and Genetics, University of Southern California, Los Angeles, CA, USA.
  • Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
  • Vermont Department of Health, Burlington, VT, USA.
  • Retired, Maine Cancer Registry, Augusta, ME, USA.
  • Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
  • Centre de Recherche sur les Pathologies Prostatiques et Urologiques, Paris, France.
  • Centre de Recherche sur les Pathologies Prostatiques et Urologiques, Paris, France; GRC 5 Predictive Onco-Urology, Sorbonne University, Paris, France.
  • INSERM U1018, Research Centre on Epidemiology and Population Health, Villejuif, France.
  • Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
  • Department of Diagnostics and Public Health, Section of Occupational Medicine, University of Verona, Verona, Italy.
  • Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
  • Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Australia; Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Australia; Department of Clinical Pathology, The University of Melbourne, Parkville, Australia.
  • Department of Medical Sciences, University of Turin, Turin, Italy.
  • London School of Hygiene and Tropical Medicine, London, UK.
  • Division of Functional Genome Analysis, German Cancer Research Center, Heidelberg, Germany.
  • Epidemiology Branch and Epigenetic and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
  • Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
  • Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre (CNIO) and CIBERONC, Madrid, Spain.
  • Leibniz Research Centre for Working Environment and Human Factors at TU Dortmund (IfADo), Dortmund, Germany.
  • Rowett Institute, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK.
  • Department of Preventive Medicine, Universidad de Oviedo, ISPA and CIBERESP, Spain.
  • Center for Research in Occupational Health, Universitat Pompeu Fabra, Hospital del Mar Medical Research Institut, CIBERESP, Barcelona, Spain.
  • Department of Medicine, Alcalá University, IRYCIS, CIBERONC, Madrid, Spain.
  • Hospital Universitario de Canarias, Tenerife, Spain.
  • Hospital del Mar, Universitat Pompeu Fabra, Barcelona, Spain.
  • Department of Pathology, Dartmouth Medical School, Hanover, NH, USA.
  • Cancer Genomics Research Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
  • School of Public Health, Imperial College London, London, UK.
  • Danish Cancer Society Research Center, Copenhagen, Denmark.
  • Department of Urology, Rheinland Klinikum, Lukaskrankenhaus, Neuss, Germany.
  • Department of Urology, St.-Josefs-Hospital, Dortmund, Germany.
  • Department of Urology, Evangelic Hospital, Paul Gerhardt Foundation, Lutherstadt Wittenberg, Germany.
  • Department for Health Evidence, Radboud University Medical Center, Nijmegen, The Netherlands; Netherlands Comprehensive Cancer Organisation, Utrecht, The Netherlands.
  • Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Medicine, Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Nuffield Department of Population Health, University of Oxford, Oxford, UK.
  • deCODE genetics/Amgen, Reykjavik, Iceland.
  • Fundación Pública Galega de Medicina Xenómica, Servicio Galego de Saude, Health Research Institute of Santiago de Compostela, Santiago de Compostela, Spain.
  • Ministry of Health of the Basque Government, Sub Directorate for Public Health and Addictions of Gipuzkoa, San Sebastian, Spain; Biodonostia Health Research Institute, Epidemiology of Chronic and Communicable Diseases Group, San Sebastian, Spain; Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain.
  • Department of Population and Public Health Sciences, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Information Management Services, Inc, Rockville, MD, USA.
  • Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
  • Center for Genetic Epidemiology, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
  • Johns Hopkins University, Baltimore, MD, USA.
  • Office of the Director, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
  • Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre (CNIO) and CIBERONC, Madrid, Spain; Departament de Medicina i Ciències de la Vida, Universitat Pompeu Fabra, Barcelona, Spain.
  • Trans-Divisional Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
Abstract

BACKGROUND: Genomic regions identified by genome-wide association studies (GWAS) for bladder cancer risk provide new insights into etiology.

OBJECTIVE: To identify new susceptibility variants for bladder cancer in a meta-analysis of new and existing genome-wide genotype data.

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.

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.

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.

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.

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.

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