Smoking contributes to a higher risk of colorectal cancer (CRC) regardless of genetic risk, and abstinence from smoking can compensate for a substantial proportion of the genetically determined CRC risk, according to a study in Clinical and Translational Gastroenterology.
Researchers sought to assess the individual and joint impact of smoking and polygenic risk score (PRS) on CRC risk with use of a genetic risk equivalent (GRE). They used a PRS based on 140 CRC-related single nucleotide polymorphisms to quantify genetic risk, and GREs were calculated from logistic regression models as ratios of the regression coefficients of smoking and PRS percentiles.
Data were obtained from the Darmkrebs: Chancen der Verhütung durch Screening study of patients with CRC in Germany. A total of 5086 patients with CRC (median age, 69 years; 60.2% male) and 4120 controls (median age, 70 years; 61.3% male) who were recruited from 2003 to 2017 were included in the analysis.
In the overall cohort, smoking was significantly associated with an increased risk of CRC. The adjusted odds ratios were 1.48 (95% CI, 1.27-1.72) for current smokers and 1.26 (95% CI, 1.14-1.40) for former smokers, compared with never smokers.
A PRS in the top decile was associated with a 3.6-, 4.8-, and 5.6-fold increased risk of CRC compared with a PRS in the lowest decile in never, former, and current smokers, respectively. The magnitude of the association of the PRS with CRC risk appeared to be stronger in current smokers compared with never or former smokers; however, a test for interaction did not reach statistical significance (P = 0.53). In addition, no interaction (P = 0.58) was observed between pack-years of smoking and the PRS.
A PRS higher than the 90th percentile was significantly associated with a 3.6-, 4.3-, and 6.4-fold increased risk of CRC among never, former, and current smokers, respectively, compared with a PRS below the 10th percentile among never smokers. No significant difference was found for CRC risk for current, former, and never smokers among participants with a PRS below the 10th percentile.
Current smokers had a GRE of 29.9 (95% CI, 17.7-42.1) versus that of never smokers. This may suggest that the effect of smoking on CRC risk was equivalent to that of having a 30 percentile higher level of PRS, according to the study authors. The GRE for participants with 20 or more pack-years of smoking was 31 PRS percentiles (95% CI, 20-42).
The researchers noted several study limitations. Bias cannot be ruled out because information about potential risks and protective factors was gathered retrospectively through personal interviews with standardized questionnaires. Additionally, the population was exclusively white.
“The novel metric of GRE may be useful for comparing risk based on lifestyle and genetic factors, providing a possible avenue for improving risk communication to the public and targeting prevention at individuals with high genetic predisposition,” stated the researchers.
Chen X, Jansen L, Guo F, et al. Smoking, genetic predisposition, and colorectal cancer risk. Clin Transl Gastroenterol. 2021;12(3):e00317. doi: 10.14309/ctg.0000000000000317