Gene promoter hypermethylation detected in sputum predicts FEV₁ decline and all-cause mortality in smokers

Rationale: Gene promoter hypermethylation detected in sputum assesses the extent of field cancerization and predicts lung cancer (LC) risk in ever-smokers. A rapid decline of FEV₁ is a major driver for development of airway obstruction. Objectives: To assess the effects of methylation of 12 genes on FEV₁ decline and of FEV₁ decline on subsequent LC incidence using two independent, longitudinal cohorts (i.e., LSC [Lovelace Smokers Cohort] and PLuSS [Pittsburgh Lung Screening Study]). Methods: Gene methylation was measured in sputum using two-stage nested methylation-specific PCR. The linear mixed effects model was used to assess the effects of studied variables on FEV₁ decline. Measurements and Main Results: A dose-dependent relationship between number of genes methylated and FEV₁ decline was identified, with smokers with three or more methylated genes having 27.8% and 10.3% faster FEV₁ decline than smokers with zero to two methylated genes in the LSC and PLuSS cohort, respectively (all P, 0.01). High methylation in sputum was associated with a shorter latency for LC incidence (log-rank P = 0.0048) and worse all-cause mortality (log-rank P, 0.0001). Smokers with subsequent LC incidence had a more rapid annual decline of FEV₁ (by 5.2 ml, P = 0.038) than smoker control subjects. Conclusions: Gene methylation detected in sputum predicted FEV₁ decline, LC incidence, and all-cause mortality in smokers. Rapid FEV₁ decline may be a risk factor for LC incidence in smokers, which may explain a greater prevalence of airway obstruction seen in patients with LC.