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

UROMOL Consortium

doi:10.1016/j.eururo.2023.04.020

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

UROMOL Consortium

The Rowett Institute of Nutrition and Health

Research output: Contribution to journal › Article › peer-review

13 Citations (Scopus)

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 [p M-I] = 0.004), 8q21.13 (PAG1; p M-I = 0.01), and 9p21.3 (LOC107987026/MTAP/CDKN2A; p M-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.

Original language	English
Pages (from-to)	127-137
Number of pages	11
Journal	European Urology
Volume	84
Issue number	1
Early online date	16 Jun 2023
DOIs	https://doi.org/10.1016/j.eururo.2023.04.020
Publication status	Published - 1 Jul 2023

Bibliographical note

Funding Information:
Acknowledgments: The authors would like to thank the participants from all the contributing studies. Specifically, we acknowledge the Netherlands Comprehensive Cancer Organization and all urologists from southeastern Netherlands for patient recruitment. The authors express sincere appreciation to all Cancer Prevention Study-II Nutrition Cohort participants, and to each member of the study and biospecimen management group. The authors would like to acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention National Program of Cancer Registries and the cancer registries supported by the National Cancer Institute Surveillance, Epidemiology and End Results Program. This research was conducted using the UK Biobank Resource under application number 47618. Support for title page creation and format was provided by AuthorArranger, a tool developed at the US National Cancer Institute.

Funding Information:
Funding/Support and role of the sponsor: This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics (ZIA CP010187-18). The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial is supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, and contracts from the Division of Cancer Prevention, National Cancer Institute. Funding for the Nijmegen Bladder Cancer Study was supported by intramural research investment funds from Radboud University Medical Center. Work in the laboratory of Francisco X. Real is funded by Fundación Científica de la Asociación Española Contra el Cáncer. The CNIO/UROMOL study and analyses are supported by EU-7FP (HEALTH-F2-2008-201663) and Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III (#PI18/01347). The American Cancer Society funds the creation, maintenance, and updating of the Cancer Prevention Study-II Nutrition Cohort. The Womens Health Initiative program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health through contracts 75N92021D00001, 75N92021D00002, 75N92021D00003, 75N92021D00004, and 75N92021D00005. Melbourne Collaborative Cohort Study (MCCS) cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further augmented by Australian National Health and Medical Research Council grants 209057, 396414, and 1074383, and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry and the Australian Institute of Health and Welfare, including the Australian Cancer Database. The funding bodies played no direct role in the study. This work was partially supported by The V Foundation for Cancer Research and The Cycle for Survival grants to Vijai Joseph and Helena Furberg. In addition, this research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748 to Memorial Sloan Kettering Cancer Center.

Publisher Copyright:
© 2023

Data Availability Statement

Summary statistics for all the analyses presented here will be available on dbGaP. Requests can additionally be
made directly to the corresponding author for access to summary
statistics

Keywords

Bladder cancer
Gene-environment interaction
Genome-Wide Association Study (GWAS)
Germline genetics
Genome-Wide Association Study
Genetic Predisposition to Disease
Prospective Studies
Humans
Risk Factors
Microtubule-Associated Proteins
Male
Genotype
Membrane Proteins
Arylamine N-Acetyltransferase
Adaptor Proteins, Signal Transducing
Urinary Bladder Neoplasms/genetics
Female
Polymorphism, Single Nucleotide

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.eururo.2023.04.020

Cite this

@article{13dc786a8e6d4944ad306669b9a9ee4c,

title = "Genome-wide Association Study of Bladder Cancer Reveals New Biological and Translational Insights",

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 [p M-I] = 0.004), 8q21.13 (PAG1; p M-I = 0.01), and 9p21.3 (LOC107987026/MTAP/CDKN2A; p M-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.",

keywords = "Bladder cancer, Gene-environment interaction, Genome-Wide Association Study (GWAS), Germline genetics, Genome-Wide Association Study, Genetic Predisposition to Disease, Prospective Studies, Humans, Risk Factors, Microtubule-Associated Proteins, Male, Genotype, Membrane Proteins, Arylamine N-Acetyltransferase, Adaptor Proteins, Signal Transducing, Urinary Bladder Neoplasms/genetics, Female, Polymorphism, Single Nucleotide",

author = "Stella Koutros and Kiemeney, {Lambertus A.} and {Pal Choudhury}, Parichoy and Milne, {Roger L.} and {Lopez de Maturana}, Evangelina and Yuanqing Ye and Vijai Joseph and Oscar Florez-Vargas and Lars Dyrskj{\o}t and Jonine Figueroa and Diptavo Dutta and Giles, {Graham G.} and Hildebrandt, {Michelle A.T.} and Kenneth Offit and Manolis Kogevinas and Elisabete Weiderpass and McCullough, {Marjorie L.} and Freedman, {Neal D.} and Demetrius Albanes and Charles Kooperberg and Cortessis, {Victoria K.} and Karagas, {Margaret R.} and Alison Johnson and Schwenn, {Molly R.} and Dalsu Baris and Helena Furberg and Bajorin, {Dean F.} and Olivier Cussenot and Geraldine Cancel-Tassin and Simone Benhamou and Peter Kraft and Stefano Porru and Angela Carta and Timothy Bishop and Southey, {Melissa C.} and Giuseppe Matullo and Tony Fletcher and Rajiv Kumar and Taylor, {Jack A.} and Philippe Lamy and Frederik Prip and Mark Kalisz and Weinstein, {Stephanie J.} and Hengstler, {Jan G.} and Silvia Selinski and Mark Harland and Mark Teo and Kiltie, {Anne E.} and Adonina Tard{\'o}n and Consol Serra and {UROMOL Consortium}",

note = "Funding Information: Acknowledgments: The authors would like to thank the participants from all the contributing studies. Specifically, we acknowledge the Netherlands Comprehensive Cancer Organization and all urologists from southeastern Netherlands for patient recruitment. The authors express sincere appreciation to all Cancer Prevention Study-II Nutrition Cohort participants, and to each member of the study and biospecimen management group. The authors would like to acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention National Program of Cancer Registries and the cancer registries supported by the National Cancer Institute Surveillance, Epidemiology and End Results Program. This research was conducted using the UK Biobank Resource under application number 47618. Support for title page creation and format was provided by AuthorArranger, a tool developed at the US National Cancer Institute. Funding Information: Funding/Support and role of the sponsor: This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics (ZIA CP010187-18). The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial is supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, and contracts from the Division of Cancer Prevention, National Cancer Institute. Funding for the Nijmegen Bladder Cancer Study was supported by intramural research investment funds from Radboud University Medical Center. Work in the laboratory of Francisco X. Real is funded by Fundaci{\'o}n Cient{\'i}fica de la Asociaci{\'o}n Espa{\~n}ola Contra el C{\'a}ncer. The CNIO/UROMOL study and analyses are supported by EU-7FP (HEALTH-F2-2008-201663) and Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III (#PI18/01347). The American Cancer Society funds the creation, maintenance, and updating of the Cancer Prevention Study-II Nutrition Cohort. The Womens Health Initiative program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health through contracts 75N92021D00001, 75N92021D00002, 75N92021D00003, 75N92021D00004, and 75N92021D00005. Melbourne Collaborative Cohort Study (MCCS) cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further augmented by Australian National Health and Medical Research Council grants 209057, 396414, and 1074383, and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry and the Australian Institute of Health and Welfare, including the Australian Cancer Database. The funding bodies played no direct role in the study. This work was partially supported by The V Foundation for Cancer Research and The Cycle for Survival grants to Vijai Joseph and Helena Furberg. In addition, this research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748 to Memorial Sloan Kettering Cancer Center. Publisher Copyright: {\textcopyright} 2023",

year = "2023",

month = jul,

day = "1",

doi = "10.1016/j.eururo.2023.04.020",

language = "English",

volume = "84",

pages = "127--137",

journal = "European Urology",

issn = "0302-2838",

publisher = "Elsevier",

number = "1",

}

TY - JOUR

T1 - Genome-wide Association Study of Bladder Cancer Reveals New Biological and Translational Insights

AU - Koutros, Stella

AU - Kiemeney, Lambertus A.

AU - Pal Choudhury, Parichoy

AU - Milne, Roger L.

AU - Lopez de Maturana, Evangelina

AU - Ye, Yuanqing

AU - Joseph, Vijai

AU - Florez-Vargas, Oscar

AU - Dyrskjøt, Lars

AU - Figueroa, Jonine

AU - Dutta, Diptavo

AU - Giles, Graham G.

AU - Hildebrandt, Michelle A.T.

AU - Offit, Kenneth

AU - Kogevinas, Manolis

AU - Weiderpass, Elisabete

AU - McCullough, Marjorie L.

AU - Freedman, Neal D.

AU - Albanes, Demetrius

AU - Kooperberg, Charles

AU - Cortessis, Victoria K.

AU - Karagas, Margaret R.

AU - Johnson, Alison

AU - Schwenn, Molly R.

AU - Baris, Dalsu

AU - Furberg, Helena

AU - Bajorin, Dean F.

AU - Cussenot, Olivier

AU - Cancel-Tassin, Geraldine

AU - Benhamou, Simone

AU - Kraft, Peter

AU - Porru, Stefano

AU - Carta, Angela

AU - Bishop, Timothy

AU - Southey, Melissa C.

AU - Matullo, Giuseppe

AU - Fletcher, Tony

AU - Kumar, Rajiv

AU - Taylor, Jack A.

AU - Lamy, Philippe

AU - Prip, Frederik

AU - Kalisz, Mark

AU - Weinstein, Stephanie J.

AU - Hengstler, Jan G.

AU - Selinski, Silvia

AU - Harland, Mark

AU - Teo, Mark

AU - Kiltie, Anne E.

AU - Tardón, Adonina

AU - Serra, Consol

AU - UROMOL Consortium

N1 - Funding Information: Acknowledgments: The authors would like to thank the participants from all the contributing studies. Specifically, we acknowledge the Netherlands Comprehensive Cancer Organization and all urologists from southeastern Netherlands for patient recruitment. The authors express sincere appreciation to all Cancer Prevention Study-II Nutrition Cohort participants, and to each member of the study and biospecimen management group. The authors would like to acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention National Program of Cancer Registries and the cancer registries supported by the National Cancer Institute Surveillance, Epidemiology and End Results Program. This research was conducted using the UK Biobank Resource under application number 47618. Support for title page creation and format was provided by AuthorArranger, a tool developed at the US National Cancer Institute. Funding Information: Funding/Support and role of the sponsor: This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics (ZIA CP010187-18). The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial is supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, and contracts from the Division of Cancer Prevention, National Cancer Institute. Funding for the Nijmegen Bladder Cancer Study was supported by intramural research investment funds from Radboud University Medical Center. Work in the laboratory of Francisco X. Real is funded by Fundación Científica de la Asociación Española Contra el Cáncer. The CNIO/UROMOL study and analyses are supported by EU-7FP (HEALTH-F2-2008-201663) and Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III (#PI18/01347). The American Cancer Society funds the creation, maintenance, and updating of the Cancer Prevention Study-II Nutrition Cohort. The Womens Health Initiative program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health through contracts 75N92021D00001, 75N92021D00002, 75N92021D00003, 75N92021D00004, and 75N92021D00005. Melbourne Collaborative Cohort Study (MCCS) cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further augmented by Australian National Health and Medical Research Council grants 209057, 396414, and 1074383, and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry and the Australian Institute of Health and Welfare, including the Australian Cancer Database. The funding bodies played no direct role in the study. This work was partially supported by The V Foundation for Cancer Research and The Cycle for Survival grants to Vijai Joseph and Helena Furberg. In addition, this research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748 to Memorial Sloan Kettering Cancer Center. Publisher Copyright: © 2023

PY - 2023/7/1

Y1 - 2023/7/1

N2 - 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 [p M-I] = 0.004), 8q21.13 (PAG1; p M-I = 0.01), and 9p21.3 (LOC107987026/MTAP/CDKN2A; p M-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.

AB - 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 [p M-I] = 0.004), 8q21.13 (PAG1; p M-I = 0.01), and 9p21.3 (LOC107987026/MTAP/CDKN2A; p M-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.

KW - Bladder cancer

KW - Gene-environment interaction

KW - Genome-Wide Association Study (GWAS)

KW - Germline genetics

KW - Genome-Wide Association Study

KW - Genetic Predisposition to Disease

KW - Prospective Studies

KW - Humans

KW - Risk Factors

KW - Microtubule-Associated Proteins

KW - Male

KW - Genotype

KW - Membrane Proteins

KW - Arylamine N-Acetyltransferase

KW - Adaptor Proteins, Signal Transducing

KW - Urinary Bladder Neoplasms/genetics

KW - Female

KW - Polymorphism, Single Nucleotide

UR - http://www.scopus.com/inward/record.url?scp=85160031554&partnerID=8YFLogxK

U2 - 10.1016/j.eururo.2023.04.020

DO - 10.1016/j.eururo.2023.04.020

M3 - Article

C2 - 37210288

AN - SCOPUS:85160031554

SN - 0302-2838

VL - 84

SP - 127

EP - 137

JO - European Urology

JF - European Urology

IS - 1

ER -

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

Abstract

Bibliographical note

Data Availability Statement

Keywords

UN SDGs

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Cite this