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

Shuguang Leng, Brenda Diergaarde, Maria A. Picchi, David O. Wilson, Frank D. Gilliland, Jian Min Yuan, Jill M. Siegfried, Steven A. Belinsky

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)187-196
Number of pages10
JournalAmerican journal of respiratory and critical care medicine
Issue number2
StatePublished - Jul 15 2018

Bibliographical note

Funding Information:
Supported by National Cancer Institute grants R01 CA097356, R01 CA164782, P50 CA090440, P30 CA047904, and P30 CA118100 and by the State of New Mexico as a direct appropriation from the Tobacco Settlement Fund. The NIH and the State of New Mexico had no influence in study design; collection, analysis, and interpretation of data; in writing the report; or in the decision to submit the report for publication.

Funding Information:
The authors thank Dr. Joel L. Weissfeld, previously at the Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, for his contribution in data management and analysis at the initial stage of this study. They also thank Ms. Elise Calvillo at Lovelace Respiratory Research Institute for scientific editing of the figures.

Publisher Copyright:
Copyright © 2018 by the American Thoracic Society.


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