A smoking-related plasma protein score and smoking-related cancer risk and mortality in the Atherosclerosis Risk in Communities study

BACKGROUND: Self-reported smoking may not fully capture individualized risk of smoking-related cancer, but circulating proteins may reflect biological consequences of smoking. Thus, we developed a score based on smoking-related proteins and evaluated its association with smoking-related cancer. METHODS: This prospective cohort study included 10 563 participants aged 47-70 years in the Atherosclerosis Risk in Communities study. Plasma proteins were measured using the SomaScan Platform (SomaLogic Operating Co, Inc). The score was constructed from proteins associated with current smoking, pack-years, or recent quitting identified by linear regression and elastic net regression. Cox regression was used to estimate adjusted hazard ratios and 95% confidence intervals (CIs). We confirmed the association in a case-cohort study in the European Prospective Investigation into Cancer and Nutrition. RESULTS: Adjusted hazard ratios comparing score quartiles 4 to 1 for total incidence and mortality of 13 smoking-related cancers were 3.89 (95% CI = 3.06 to 4.96) and 5.73 (95% CI = 4.08 to 8.06) before and 2.28 (95% CI = 1.65 to 3.15) and 2.07 (95% CI = 1.74 to 4.10) after adjusting for self-reported smoking. Adjusted hazard ratios for lung cancer were 12.1 (95% CI = 7.11 to 20.6) and 14.2 (95% CI = 7.58 to 26.8) before and 3.04 (95% CI = 1.59 to 5.81) and 4.12 (95% CI = 1.99 to 8.53) after adjusting. In European Prospective Investigation into Cancer and Nutrition, adjusted hazard ratios for lung cancer were 9.47 (95% CI = 6.82 to 13.15) before and 2.23 (95% CI = 1.48 to 3.35) after adjusting. CONCLUSION: The smoking-related protein score provided relative risk information for smoking-associated cancers beyond self-reported smoking, which was confirmed in an independent cohort. Such a score may be considered for use in risk stratification for prevention and cancer screening in settings in which detailed smoking history cannot be obtained.