Molecular Characterization of Chronic Obstructive Pulmonary Disease-Related Non-Small Cell Lung Cancer Through Aberrant Methylation and Alterations of EGFR Signaling

Makoto Suzuki MD, Hironobu Wada MD, Mitsuru Yoshino MD, Lei Tian MD, Hisayuki Shigematsu MD, Hidemi Suzuki MD, Mahmoud Alaa MD, Hajime Tamura MD, Taiki Fujiwara MD, Kaoru Nagato MD, Shinichiro Motohashi MD, Yasumitsu Moriya MD, Hidehisa Hoshino MD, Shigetoshi Yoshida MD, Kiyoshi Shibuya MD, Kenzo Hiroshima MD, Yukio Nakatani MD, Ichiro Yoshino MD
Translational Research and Biomarkers
Volume 17, Issue 3 / March , 2009

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Abstract

Background

The aim of this study was to evaluate the molecular influence of chronic obstructive pulmonary diseases (COPD) on the pathogenesis of non-small cell lung cancer (NSCLC).

Materials and Methods

The methylation profiles of 12 genes, and the epidermal growth factor receptor (EGFR) and KRAS mutations were determined for samples from 229 NSCLC patients. In addition, protein expression of EGFR and HER2 in 116 NSCLCs was analyzed based on the presence or absence of COPD.

Results

IL-12Rβ2 and Wif-1 methylation and HER2 overexpression were more frequent events in the COPD group. Eighty nonmalignant lung tissues had no correlation with any molecular changes between the COPD and the non-COPD group. EGFR mutation was significantly higher in the non-COPD group, while EGFR expression was inversely correlated with %FEV1.0. In the COPD group, unmethylated SPARC and sFRP-2 genes or a negative CpG island methylator phenotype (CIMP) was a negative prognostic factor, while methylation of p16^INK4A and WNT antagonist genes was a negative prognostic factor in the non-COPD group.

Conclusions

Novel characteristics of COPD-related NSCLC were identified by examination of methylation profiles and alterations of EGFR signaling. In consideration of the high sensitivity to smoking in patients with COPD, NSCLC with COPD might be a distinct population of smoke-related NSCLC, the genetic profile of which is quite different from non-COPD NSCLC.

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