Longevity-associated FOXO3 genotype mitigates the risk of lung cancer after smoking cessation: a prospective cohort study

Background: Smoking cessation lowers lung cancer (LC) risk, but the magnitude of risk reduction varies across individuals. FOXO3, a key regulator of cellular stress-response and longevity pathways, may influence susceptibility to LC after smoking cessation. The aim of the present study was to investigate whether FOXO3 genotype modifies the association between smoking cessation and incident LC.

Methods: We examined 4,339 ever-smoking American men of Japanese ancestry who were free of LC at baseline in the Kuakini Japan-Hawaii Cancer Study (1971–1975; mean age, 60 years). Participants were genotyped for FOXO3 rs2802292 and classified as FOXO3-G (TG/GG; longevity-associated G-allele carriers) or FOXO3-TT (TT, common allele homozygotes). Smoking status (former or current), cumulative exposure (pack-years), and duration of smoking cessation (years; current smokers assigned 0) were assessed. Incident LC cases through 1999 were identified. Cox proportional hazards models adjusted for potential confounders were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), and test interactions.

Results: During 28 years of follow-up, 180 LC cases occurred, including 117 non–small cell lung cancer (NSCLC) cases. Significant interactions were observed between smoking status and FOXO3 genotype for LC (P=0.02) and NSCLC (P=0.003). Among former smokers, FOXO3-G carriers had a lower risk than FOXO3-TT carriers (LC: HR, 0.42; 95% CI, 0.23–0.79; NSCLC: HR, 0.23; 95% CI, 0.09–0.60). In contrast, no genotype-related differences were observed among current smokers. Among FOXO3-G carriers, each additional year of smoking cessation was associated with a reduced risk of LC (HR, 0.87; 95% CI, 0.81–0.94) and NSCLC (HR, 0.72; 95% CI, 0.58–0.89), whereas only weaker associations were observed among FOXO3-TT carriers (LC: HR, 0.97; 95% CI, 0.94–1.00; NSCLC: HR, 0.98; 95% CI, 0.94–1.01).

Conclusions: FOXO3 genotype may modify LC risk associated with smoking cessation. Compared with carriers of the longevity-associated FOXO3 G allele, individuals with the FOXO3-TT genotype had a substantially elevated risk of LC after smoking cessation; this association was not observed among current smokers. These findings support the potential for genotype-informed precision prevention, pending replication in larger and more diverse cohorts.