Molecular characterization of chronic obstructive pulmonary disease-related non-small cell lung cancer through aberrant methylation and alterations of EGFR signaling.
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).


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-12Rbeta2 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.
Suzuki
Makoto
M
Department of Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan. smakoto@faculty.chiba-u.jp
Wada
Hironobu
H
Yoshino
Mitsuru
M
Tian
Lei
L
Shigematsu
Hisayuki
H
Suzuki
Hidemi
H
Alaa
Mahmoud
M
Tamura
Hajime
H
Fujiwara
Taiki
T
Nagato
Kaoru
K
Motohashi
Shinichiro
S
Moriya
Yasumitsu
Y
Hoshino
Hidehisa
H
Yoshida
Shigetoshi
S
Shibuya
Kiyoshi
K
Hiroshima
Kenzo
K
Nakatani
Yukio
Y
Yoshino
Ichiro
I
D000230:Adenocarcinoma / Q000150:complications / Q000235:genetics / Q000473:pathology; D000368:Aged; D018287:Carcinoma, Large Cell / Q000150:complications / Q000235:genetics / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000150:complications / Q000235:genetics* / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000150:complications / Q000235:genetics / Q000473:pathology; D019175:DNA Methylation; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000150:complications / Q000235:genetics* / Q000473:pathology; D008297:Male; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D011379:Prognosis; D011401:Promoter Regions, Genetic; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics*; D015996:Survival Rate
C512478:EGFR protein, human; D066246:ErbB Receptors