Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Annals of Surgical Oncology
Published in: Annals of Surgical Oncology 3/2010

01-03-2010 | Translational Research and Biomarkers

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

Authors: 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

Published in: Annals of Surgical Oncology | Issue 3/2010

Login to get access

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 p16INK4A 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.
Appendix
Available only for authorised users
Literature
1.
Skillrud DM, Offord KP, Miller RD. Higher risk of lung cancer in chronic obstructive pulmonary disease. A prospective, matched, controlled study. Ann Intern Med. 1986;105:503–7.PubMed
2.
Kuller LH, Ockene J, Meilahn E, Svendsen KH. Relation of forced expiratory volume in one-second (FEV1) to lung cancer mortality in the Multiple Risk Factor Intervention Trial (MRFIT). Am J Epidemiol. 1990;132:265–74.PubMed
3.
Sekine Y, Iwata T, Chiyo M, Yasufuku K, Motohashi S, Yoshida S, et al. Minimal alteration of pulmonary function after lobectomy in lung cancer patients with chronic obstructive pulmonary disease. Ann Thorac Surg. 2003;76:356–61; discussion 62.CrossRefPubMed
4.
Sekine Y, Yamada Y, Chiyo M, Iwata T, Nakajima T, Yasufuku K, et al. Association of chronic obstructive pulmonary disease and tumor recurrence in patients with stage IA lung cancer after complete resection. Ann Thorac Surg. 2007;84:946–50.CrossRefPubMed
5.
Lourenco RV, Klimek MF, Borowski CJ. Deposition and clearance of 2 micron particles in the tracheobronchial tree of normal subjects–smokers and nonsmokers. J Clin Invest. 1971;50:1411–20.CrossRefPubMed
6.
Galaris D, Evangelou A. The role of oxidative stress in mechanisms of metal-induced carcinogenesis. Crit Rev Oncol Hematol. 2002;42:93–103.CrossRefPubMed
7.
Cerda S, Weitzman SA. Influence of oxygen radical injury on DNA methylation. Mutat Res. 1997;386:141–52.CrossRefPubMed
8.
Dialyna IA, Miyakis S, Georgatou N, Spandidos DA. Genetic polymorphisms of CYP1A1, GSTM1 and GSTT1 genes and lung cancer risk. Oncol Rep. 2003;10:1829–35.PubMed
9.
London SJ, Idle JR, Daly AK, Coetzee GA. Genetic variation of CYP2A6, smoking, and risk of cancer. Lancet. 1999;353:898–9.CrossRefPubMed
10.
Baylin SB, Herman JG, Graff JR, Vertino PM, Issa JP. Alterations in DNA methylation: a fundamental aspect of neoplasia. Adv Cancer Res. 1998;72:141–96.CrossRefPubMed
11.
Scagliotti GV, Selvaggi G, Novello S, Hirsch FR. The biology of epidermal growth factor receptor in lung cancer. Clin Cancer Res. 2004;10:4227s–32s.CrossRefPubMed
12.
Lenferink AE, Pinkas-Kramarski R, van de Poll ML, van Vugt MJ, Klapper LN, Tzahar E, et al. Differential endocytic routing of homo- and hetero-dimeric ErbB tyrosine kinases confers signaling superiority to receptor heterodimers. Embo J. 1998;17:3385–97.CrossRefPubMed
13.
Hirsch FR, Varella-Garcia M, Franklin WA, Veve R, Chen L, Helfrich B, et al. Evaluation of HER-2/neu gene amplification and protein expression in non-small cell lung carcinomas. Br J Cancer. 2002;86:1449–56.CrossRefPubMed
14.
Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350:2129–39.CrossRefPubMed
15.
Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304:1497–500.CrossRefPubMed
16.
17.
Sano A, Kage H, Sugimoto K, Kitagawa H, Aki N, Goto A, et al. A second-generation profiling system for quantitative methylation analysis of multiple gene promoters: application to lung cancer. Oncogene. 2007;26:6518–25.CrossRefPubMed
18.
Park J, Brena RM, Gruidl M, Zhou J, Huang T, Plass C, et al. CpG island hypermethylation profiling of lung cancer using restriction landmark genomic scanning (RLGS) analysis. Cancer Biomark. 2005;1:193–200.PubMed
19.
Suzuki M, Shigematsu H, Iizasa T, Hiroshima K, Nakatani Y, Minna JD, et al. Exclusive mutation in epidermal growth factor receptor gene, HER-2, and KRAS, and synchronous methylation of nonsmall cell lung cancer. Cancer. 2006;106:2200–7.CrossRefPubMed
20.
Suzuki M, Shigematsu H, Nakajima T, Kubo R, Motohashi S, Sekine Y, et al. Synchronous alterations of Wnt and epidermal growth factor receptor signaling pathways through aberrant methylation and mutation in non small cell lung cancer. Clin Cancer Res. 2007;13:6087–92.CrossRefPubMed
21.
Suzuki M, Shigematsu H, Takahashi T, Shivapurkar N, Sathyanarayana UG, Iizasa T, et al. Aberrant methylation of Reprimo in lung cancer. Lung Cancer. 2005;47:309–14.CrossRefPubMed
22.
Suzuki M, Hao C, Takahashi T, Shigematsu H, Shivapurkar N, Sathyanarayana UG, et al. Aberrant methylation of SPARC in human lung cancers. Br J Cancer. 2005;92:942–8.CrossRefPubMed
23.
Suzuki M, Shigematsu H, Shames DS, Sunaga N, Takahashi T, Shivapurkar N, et al. DNA methylation-associated inactivation of TGFbeta-related genes DRM/Gremlin, RUNX3, and HPP1 in human cancers. Br J Cancer. 2005;93:1029–37.CrossRefPubMed
24.
Suzuki M, Iizasa T, Nakajima T, Kubo R, Iyoda A, Hiroshima K, et al. Aberrant methylation of IL-12Rbeta2 gene in lung adenocarcinoma cells is associated with unfavorable prognosis. Ann Surg Oncol. 2007;14:2636–42.CrossRefPubMed
25.
Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med. 2001;163:1256–76.PubMed
26.
Suzuki M, Toyooka S, Shivapurkar N, Shigematsu H, Miyajima K, Takahashi T, et al. Aberrant methylation profile of human malignant mesotheliomas and its relationship to SV40 infection. Oncogene. 2005;24:1302–8.CrossRefPubMed
27.
Maruyama R, Toyooka S, Toyooka KO, Virmani AK, Zöchbauer-Müller S, Farinas AJ, et al. Aberrant promoter methylation profile of prostate cancers and its relationship to clinicopathological features. Clin Cancer Res. 2002;8:514–9.PubMed
28.
Virmani AK, Rathi A, Zochbauer-Muller S, Sacchi N, Fukuyama Y, Bryant D, et al. Promoter methylation and silencing of the retinoic acid receptor-beta gene in lung carcinomas. J Natl Cancer Inst. 2000;92:1303–7.CrossRefPubMed
29.
Toyooka KO, Toyooka S, Virmani AK, Sathyanarayana UG, Euhus DM, Gilcrease M, et al. Loss of expression and aberrant methylation of the CDH13 (H-cadherin) gene in breast and lung carcinomas. Cancer Res. 2001;61:4556–60.PubMed
30.
Suzuki M, Sunaga N, Shames DS, Toyooka S, Gazdar AF, Minna JD. RNA interference-mediated knockdown of DNA methyltransferase 1 leads to promoter demethylation and gene re-expression in human lung and breast cancer cells. Cancer Res. 2004;64:3137–43.CrossRefPubMed
31.
Suzuki M, Shigematsu H, Hiroshima K, Iizasa T, Nakatani Y, Minna JD, et al. Epidermal growth factor receptor expression status in lung cancer correlates with its mutation. Hum Pathol. 2005;36:1127–34.CrossRefPubMed
32.
Toyota M, Ahuja N, Suzuki H, Itoh F, Ohe-Toyota M, Imai K, et al. Aberrant methylation in gastric cancer associated with the CpG island methylator phenotype. Cancer Res. 1999;59:5438–42.PubMed
33.
Oue N, Mitani Y, Motoshita J, Matsumura S, Yoshida K, Kuniyasu H, et al. Accumulation of DNA methylation is associated with tumor stage in gastric cancer. Cancer. 2006;106:1250–9.CrossRefPubMed
34.
Ottini L, Falchetti M, Lupi R, Rizzolo P, Agnese V, Colucci G, et al. Patterns of genomic instability in gastric cancer: clinical implications and perspectives. Ann Oncol. 2006;17:vii97–102.CrossRefPubMed
35.
Zhang C, Li Z, Cheng Y, Jia F, Li R, Wu M, et al. CpG island methylator phenotype association with elevated serum alpha-fetoprotein level in hepatocellular carcinoma. Clin Cancer Res. 2007;13:944–52.CrossRefPubMed
36.
Sekine Y, Behnia M, Fujisawa T. Impact of COPD on pulmonary complications and on long-term survival of patients undergoing surgery for NSCLC. Lung Cancer. 2002;37:95–101.CrossRefPubMed
37.
Iwasaki A, Shirakusa T, Enatsu S, Maekawa S, Yoshida Y, Yoshinaga Y. Surgical treatment for lung cancer with COPD based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD). Thorac Cardiovasc Surg. 2005;53:162–7.CrossRefPubMed
38.
Lapperre TS, Sont JK, van Schadewijk A, Gosman MM, Postma DS, Bajema IM, et al. Smoking cessation and bronchial epithelial remodelling in COPD: a cross-sectional study. Respir Res. 2007;8:85.CrossRefPubMed
39.
de Boer WI, Hau CM, van Schadewijk A, Stolk J, van Krieken JH, Hiemstra PS. Expression of epidermal growth factors and their receptors in the bronchial epithelium of subjects with chronic obstructive pulmonary disease. Am J Clin Pathol. 2006;125:184–92.PubMed
Metadata
Title
Molecular Characterization of Chronic Obstructive Pulmonary Disease-Related Non-Small Cell Lung Cancer Through Aberrant Methylation and Alterations of EGFR Signaling
Authors
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
Publication date
01-03-2010
Publisher
Springer-Verlag
Published in
Annals of Surgical Oncology / Issue 3/2010
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-009-0739-3

Other articles of this Issue 3/2010

Annals of Surgical Oncology 3/2010 Go to the issue

Breast Oncology

Obesity and Angiolymphatic Invasion in Primary Breast Cancer

Melanomas

Who Is to Blame for False-Negative Sentinel Node Biopsies in Melanoma?

Colorectal Cancer

Clinically-Staged T3N0 Rectal Cancer: Is Preoperative Chemoradiotherapy the Optimal Treatment?

Thoracic Oncology

How Does the Number of Resected Lymph Nodes Influence TNM Staging and Prognosis for Esophageal Carcinoma?

Translational Research and Biomarkers

CKS1B Overexpression Implicates Clinical Aggressiveness of Hepatocellular Carcinomas but Not p27Kip1 Protein Turnover: an Independent Prognosticator with Potential p27Kip1-Independent Oncogenic Attributes?

Endocrine Tumors

The Adrenal Mass: Correlation of Histopathology with Imaging