Investigating the Associations Between Smoking and Genetic Variants of Bladder Cancer

By Patrick Daly - Last Updated: March 21, 2022

According to Stanley Teleka, PhD, MMS, and colleagues from the Department of Clinical Sciences of Lund University in Lund, Sweden, previously published literature has observed that smoking interacts with bladder cancer (BC) genetic variations and may inform BC risk—particularly N-acetyltransferase-2 (NAT2), a tobacco smoke metabolism gene.

They conducted a study, published in Cancer Medicine, to evaluate interactions between smoking and single nucleotide polymorphisms (SNPs) of BC and any associations with urothelial cancer (UC) risk, including BC. They ultimately concluded that smoking increased risk of UC “more than expected” in patients with certain genetic risk factors.

The study examined 18 SNPs of BC and smoking in a data sample of 25,453 individuals with 520 incident UCs during follow-up. Of these, 339 were non-aggressive (non-fatal and non-muscle invasive) and 163 were aggressive. The primary endpoints of the study were hazard ratios (HRs), absolute risks, and additive/multiplicative interactions within two-by-two combinations of never or ever smoking and low or high genetic risk.

Dr. Teleka and colleagues observed that smoking and NAT2 rs1495741 were strongly and positively associated with aggressive UC in both multiplicate (p = 0.004) and additive (p = 0.002) capacities—an interaction which was not seen in non-aggressive UC (p ≥ 0.6). According to the researchers, “this manifested in a higher HR of aggressive UC by ever-smoking for the slow acetylation NAT2 genotype than for intermediate/fast acetylation NAT2” (HR = 5.00; 95% confidence interval [CI], 2.67–9.38; and HR = 1.50; 95% CI, 0.83–2.71). The investigators also found a difference in absolute risk based on smoking and NAT2 genotype. Smoking also interacted additively and positively with the genetic risk score (GRS) of any UC (p = 0.01) and non-aggressive UC (p = 0.02), but not with aggressive UC (p = 0.01). Lastly, less powerful gene-smoking interactions of NAT2 were seen in the APOBEC3A, SLC14A1, and MYNN SNPs.

In closing, the study’s authors suggested that their findings highlighted “the potential for smoking interventions targeting individuals with high genetic risk, such as individuals with the slow acetylation NAT2 variant to prevent lethal UC.” However, they acknowledged that their findings required validation in larger studies and that, “because UC is a relatively rare disease, the findings should be evaluated alongside gene-smoking interactions for other major smoking-related diseases.”