The interaction between smoking and bladder cancer genetic variants on urothelial cancer risk by disease aggressiveness. (13th March 2022)

• Record Type: Journal Article
• Authors: Teleka, Stanley; Jochems, Sylvia H. J.; Jirström, Karin; Stocks, Tanja
• Is Part Of: Cancer medicine. Volume 11:Number 15(2022)
• Page Start: 2896
• Page End: 2905
• Publication Date: 2022-03-13
• Subjects: cohort study -- genetic risk -- interaction -- smoking -- urothelial cancer; 616.994005
• DOI: 10.1002/cam4.4654
• Languages: English
• ISSNs: 2045-7634

Abstract

Abstract: Background: Smoking has shown interactions with bladder cancer (BC) genetic variants, especially N‐acetyltransferase‐2 ( NAT2 ), a tobacco smoke metabolism gene, on BC risk. The interactions by disease aggressiveness are unknown. Methods: We investigated the interaction between smoking and 18 single nucleotide polymorphisms (SNPs) for BC, individually and in a genetic risk score (GRS), on urothelial cancer (UC) risk including BC. We analysed data from 25, 453 individuals with 520 incident UCs during follow‐up, 339 non‐aggressive (non‐fatal, non‐muscle invasive) and 163 aggressive (all other) UCs. Hazard ratios (HRs), absolute risks and additive and multiplicative interactions for two‐by‐two combinations of never/ever smoking with low/high genetic risk were calculated. Results: Smoking and NAT2 rs1495741 interacted strongly, positively on aggressive UC on both the multiplicative ( p = 0.004) and additive ( p = 0.0002) scale, which was not observed for non‐aggressive UC ( p interactions ≥ 0.6). This manifested in a higher HR of aggressive UC by ever smoking for the slow acetylation NAT2 genotype (HR, 5.00 [95% confidence interval, 2.67–9.38]) than for intermediate/fast acetylation NAT2 (HR, 1.50 [0.83–2.71]), and in differences in absolute risks by smoking and NAT2 genotype. Smoking also interacted additively and positively with the GRS on any UC ( p = 0.01) and non‐aggressive UC ( p = 0.02), but not on aggressive UC ( p = 0.1). Gene‐smoking interactions of lesser magnitude than for NAT2 were found for SNPs in APOBEC3A, SLC14A1 and MYNN . Conclusions: This study suggests that smoking increases UC risk more than expected when combined with certain genetic risks. Individuals with the slow acetylation NAT2 variant might particularly benefit from smoking intervention to prevent lethal UC; however, replication in larger studies is needed. Abstract : In this study, we found an interplay between smoking and genetic risk for BC in relation to UC risk, indicating that these factors jointly confer a greater UC risk than expected from the sum of their individual parts. We also found that smoking increased the risk of lethal UCs particularly in individuals with the slow acetylation genotype of NAT2 (rs1495741), suggesting that smoking prevention may be particularly important in this subgroup.