Increased methylation of lung cancer-associated genes in sputum DNA of former smokers with chronic mucous hypersecretion

Shannon Bruse,Randall Willink,Steven A Belinsky,Joel Weissfeld,Kieu Do,Jill Siegfried,Hans Petersen,Yohannes Tesfaigzi,Maria Picchi

doi:10.1186/1465-9921-15-2

Abstract

BackgroundChronic mucous hypersecretion (CMH) contributes to COPD exacerbations and increased risk for lung cancer. Because methylation of gene promoters in sputum has been shown to be associated with lung cancer risk, we tested whether such methylation was more common in persons with CMH.MethodsEleven genes commonly silenced by promoter methylation in lung cancer and associated with cancer risk were selected. Methylation specific PCR (MSP) was used to profile the sputum of 900 individuals in the Lovelace Smokers Cohort (LSC). Replication was performed in 490 individuals from the Pittsburgh Lung Screening Study (PLuSS).ResultsCMH was significantly associated with an overall increased number of methylated genes, with SULF2 methylation demonstrating the most consistent association. The association between SULF2 methylation and CMH was significantly increased in males but not in females both in the LSC and PLuSS (OR = 2.72, 95% CI = 1.51-4.91, p = 0.001 and OR = 2.97, 95% CI = 1.48-5.95, p = 0.002, respectively). Further, the association between methylation and CMH was more pronounced among 139 male former smokers with persistent CMH compared to current smokers (SULF2; OR = 3.65, 95% CI = 1.59-8.37, p = 0.002).ConclusionsThese findings demonstrate that especially male former smokers with persistent CMH have markedly increased promoter methylation of lung cancer risk genes and potentially could be at increased risk for lung cancer.

Highlights

Chronic mucous hypersecretion (CMH) contributes to Chronic obstructive pulmonary disorder (COPD) exacerbations and increased risk for lung cancer
CMH is associated with higher prevalence of gene promoter methylation in smokers The initial study was conducted in 900 non-Hispanic white (NHW) current and former smokers from the Lovelace Smokers Cohort (LSC) with available sputum methylation data
A replication study was performed in the Pittsburgh Lung Screening Study (PLuSS), comprised of 140 smokers with and 350 smokers without CMH, Table 1 Select variables by CMH status in the LSC

Summary

Introduction

Chronic mucous hypersecretion (CMH) contributes to COPD exacerbations and increased risk for lung cancer. Chronic obstructive pulmonary disorder (COPD) is predicted to become the third leading cause of death worldwide by 2020 [1]. Prevalence is increasing both in developing and developed countries as a result of tobacco consumption [2,3], environmental exposures such as pollution and biomass fuel smoke [4,5] and the growing elderly population [6]. While smoking clearly contributes to both diseases, analyses controlling for smoking have demonstrated that the association between lung cancer and prior CMH is at least partially independent of smoking [15,16]. Previous case–control studies of incident lung cancer assessing the same genes as in the current study demonstrated that promoter methylation of these genes is associated with lung cancer risk [17,18]

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