Genome-wide Association Study of Bladder Cancer Reveals New Biological and Translational Insights.
Male
Humans
Female
Genome-Wide Association Study
Prospective Studies
Risk Factors
Genotype
Urinary Bladder Neoplasms
/ genetics
Genetic Predisposition to Disease
Polymorphism, Single Nucleotide
Arylamine N-Acetyltransferase
Microtubule-Associated Proteins
Membrane Proteins
Adaptor Proteins, Signal Transducing
Bladder cancer
Gene-environment interaction
Genome-Wide Association Study (GWAS)
Germline genetics
Journal
European urology
ISSN: 1873-7560
Titre abrégé: Eur Urol
Pays: Switzerland
ID NLM: 7512719
Informations de publication
Date de publication:
07 2023
07 2023
Historique:
received:
05
12
2022
revised:
16
03
2023
accepted:
19
04
2023
pmc-release:
01
07
2024
medline:
20
6
2023
pubmed:
21
5
2023
entrez:
20
5
2023
Statut:
ppublish
Résumé
Genomic regions identified by genome-wide association studies (GWAS) for bladder cancer risk provide new insights into etiology. To identify new susceptibility variants for bladder cancer in a meta-analysis of new and existing genome-wide genotype data. Data from 32 studies that includes 13,790 bladder cancer cases and 343,502 controls of European ancestry were used for meta-analysis. 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. 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 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. 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.
Sections du résumé
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
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.
Identifiants
pubmed: 37210288
pii: S0302-2838(23)02780-X
doi: 10.1016/j.eururo.2023.04.020
pmc: PMC10330197
mid: NIHMS1896587
pii:
doi:
Substances chimiques
NAT2 protein, human
EC 2.3.1.5
Arylamine N-Acetyltransferase
EC 2.3.1.5
TACC3 protein, human
0
Microtubule-Associated Proteins
0
PAG1 protein, human
0
Membrane Proteins
0
Adaptor Proteins, Signal Transducing
0
Types de publication
Meta-Analysis
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
127-137Subventions
Organisme : NHLBI NIH HHS
ID : 75N92021D00002
Pays : United States
Organisme : WHI NIH HHS
ID : 75N92021D00005
Pays : United States
Organisme : NCI NIH HHS
ID : R21 CA266660
Pays : United States
Organisme : NHLBI NIH HHS
ID : 75N92021D00001
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA221745
Pays : United States
Organisme : Intramural NIH HHS
ID : Z99 CA999999
Pays : United States
Organisme : WHI NIH HHS
ID : 75N92021D00003
Pays : United States
Organisme : WHI NIH HHS
ID : 75N92021D00004
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA CP010187
Pays : United States
Informations de copyright
Published by Elsevier B.V.
Références
Hum Mol Genet. 2012 Apr 15;21(8):1918-30
pubmed: 22228101
Nat Commun. 2018 Feb 8;9(1):556
pubmed: 29422604
Nat Genet. 2010 Nov;42(11):978-84
pubmed: 20972438
J Natl Cancer Inst. 2015 Sep 14;107(11):
pubmed: 26374428
Cell Death Discov. 2019 Mar 6;5:74
pubmed: 30854233
Nat Genet. 2010 May;42(5):415-9
pubmed: 20348956
BJU Int. 2003 Oct;92(6):563-6
pubmed: 14511034
Proc Natl Acad Sci U S A. 2012 Mar 27;109(13):4974-9
pubmed: 22416122
Nat Genet. 2020 Jun;52(6):572-581
pubmed: 32424353
Hum Mol Genet. 2014 Oct 15;23(20):5545-57
pubmed: 24861552
Open Forum Infect Dis. 2020 Sep 24;7(11):ofaa450
pubmed: 33204752
Oncotarget. 2017 Oct 19;8(57):97246-97259
pubmed: 29228607
Hum Mol Genet. 2016 Mar 15;25(6):1203-14
pubmed: 26732427
Nat Genet. 2016 Nov;48(11):1330-1338
pubmed: 27643540
Nat Rev Genet. 2016 Jul;17(7):392-406
pubmed: 27140283
Cancer Res. 2014 Oct 15;74(20):5808-18
pubmed: 25320178
Commun Biol. 2020 Dec 17;3(1):784
pubmed: 33335285
Nat Genet. 2017 May;49(5):680-691
pubmed: 28346442
JAMA. 2016 Jan 5;315(1):68-76
pubmed: 26746459
Mol Carcinog. 2013 Nov;52(11):916-21
pubmed: 22711262
Eur Urol. 2023 Jan;83(1):70-81
pubmed: 36273937
Nat Genet. 2013 Apr;45(4):353-61, 361e1-2
pubmed: 23535729
Hum Mol Genet. 2014 Mar 1;23(5):1387-98
pubmed: 24163127
Nat Genet. 2009 Sep;41(9):991-5
pubmed: 19648920
Front Oncol. 2020 Feb 11;10:134
pubmed: 32117775
Cancer Res. 2016 Jun 1;76(11):3277-84
pubmed: 27206850
Oncotarget. 2017 Jul 21;8(53):91734-91764
pubmed: 29207682
Eur Urol. 2020 Apr;77(4):420-433
pubmed: 31563503
Nature. 2021 Mar;591(7849):211-219
pubmed: 33692554
Hum Mol Genet. 2019 Sep 15;28(18):3148-3160
pubmed: 31174203
Hum Mol Genet. 2015 Feb 15;24(4):1177-84
pubmed: 25281661
Oncogene. 2008 Apr 24;27(19):2716-27
pubmed: 18037967
Hum Mol Genet. 2011 Nov 1;20(21):4282-9
pubmed: 21824976
J Natl Cancer Inst. 2013 Jan 2;105(1):69-73
pubmed: 23266392
Nat Genet. 2008 Nov;40(11):1307-12
pubmed: 18794855
Hum Mol Genet. 2011 Nov 1;20(21):4268-81
pubmed: 21750109
Pharmacogenet Genomics. 2011 Apr;21(4):231-6
pubmed: 20739907
Pharmacogenetics. 2000 Mar;10(2):115-22
pubmed: 10761999
Int J Cancer. 2013 Dec 15;133(12):3008-13
pubmed: 23754249
Cancer Res. 2013 Apr 1;73(7):2211-20
pubmed: 23536561
J Natl Cancer Inst. 2015 Oct 12;107(12):djv279
pubmed: 26464424
Nat Rev Cancer. 2015 Jan;15(1):25-41
pubmed: 25533674
Lancet. 2005 Aug 20-26;366(9486):649-59
pubmed: 16112301