Interactions Between Smoking and Single Nucleotide Polymorphisms Influence Urothelial Cancer Risk - Expert Commentary

Smoking is a major modifiable risk factor for bladder cancer. N-acetyltransferase-2 (NAT2) is a gene that encodes an enzyme that detoxifies carcinogens, such as those found in tobacco smoke. To provide insights for personalized prevention of smoking among individuals with vulnerable genotypes, the authors of this study investigated interactions between smoking, 18 single-nucleotide polymorphisms (SNPs), and urothelial cancer risk. They used data on 25,453 individuals from the Malmö Diet and Cancer Study (MDCS) cohort. The cohort included 520 individuals diagnosed with urothelial cancer during the follow-up period (average of 21 years). 28% were current smokers, and 34% were ex-smokers at baseline.

The hazard ratio for urothelial cancer was 3.73 for current smokers versus those who had never smoked and 2.78 for those who had ever smoked versus never smoked. Researchers then used a genetic risk score (GRS) to evaluate the combined effect of 18 SNPs and smoking on urothelial cancer risk. GRS and smoking showed an additive interaction, meaning that the risk of bladder cancer from both of these factors exceeded the risk of either of them individually. Current smokers with a high GRS had a hazard ratio of 7.52 compared to those with a low GRS who had never smoked.

The researchers also evaluated the effect of individual SNPs and found significant interactions for those found in the genes NAT2, APOBEC3A, SLC14A1, and MYNN. The strongest gene-smoking interaction was with NAT2 and aggressive urothelial cancer, with a higher hazard ratio (5.00) for those with the slow acetylation genotype who had ever smoked compared to those with the intermediate or fast genotypes (1.50). In terms of absolute risk, in 60-year-old men with low GRS, the 20-year risk of developing urothelial cancer was 1.5% in those who had never smoked compared to 4.2% in those who had smoked. The corresponding figures for those with high GRS were 1.9% and 5.8%, respectively.

This study provides further insights into the interactions between genotype and smoking on the risk of developing urothelial cancer. One of the limitations, however, is the limited number of urothelial cancer cases among the study population, particularly those with aggressive disease. Some interactions that appeared to be non-significant may become significant with sufficiently powered studies.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York City, New York


  1. Teleka, S., Jochems, S., Jirström, K., & Stocks, T. (2022). The interaction between smoking and bladder cancer genetic variants on urothelial cancer risk by disease aggressiveness. Cancer medicine, 10.1002/cam4.4654. Advance online publication.

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