Differences in EGFR and KRAS mutation spectra in lung adenocarcinoma of never and heavy smokers

Takamochi,Kazuya; Oh,Shiaki; Suzuki,Kenji

doi:10.3892/ol.2013.1551

Differences in EGFR and KRAS mutation spectra in lung adenocarcinoma of never and heavy smokers

Authors:
- Kazuya Takamochi
- Shiaki Oh
- Kenji Suzuki
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Affiliations: Department of General Thoracic Surgery, Juntendo University School of Medicine, Bunkyo‑ku, Tokyo 113‑8431, Japan
Published online on: August 29, 2013 https://doi.org/10.3892/ol.2013.1551
Pages: 1207-1212

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Abstract

Epidermal growth factor receptor (EGFR) mutations are common in lung adenocarcinomas of never smokers, while KRAS mutations are more frequent among heavy smokers. Different clinicopathological and biological characteristics may, therefore, exist in lung adenocarcinoma according to smoking status. In the present study, a retrospective review was performed using 521 patients with surgically resected lung adenocarcinomas. The clinicopathological factors of age, gender, pathological tumor size, nodal status, lymphatic permeation and blood vessel invasion and the EGFR and KRAS mutation spectra were compared between never and heavy smokers. EGFR mutations were detected in 233 (45%) patients, while KRAS mutations were detected in 56 (11%) patients. EGFR‑mutated adenocarcinomas had a higher prevalence of females in the never smokers compared with the heavy smokers (P<0.001). KRAS‑mutated adenocarcinomas had a higher prevalence of females (P<0.001) and showed less frequent vascular invasion (P=0.018) in the never smokers compared with the heavy smokers. Minor EGFR mutations, excluding exon 21 L858R and exon 19 deletions, were more common in heavy smokers than never smokers (P=0.055). KRAS G to A transition was more common in never smokers, while KRAS G to T and G to C transversions were more common in heavy smokers (P=0.036). The clinicopathological characteristics and the spectra of the EGFR and KRAS mutations in lung adenocarcinoma were different between the never and heavy smokers. Further large‑scale studies are required to evaluate the efficacy of molecular targeting agents with consideration to specific EGFR and KRAS mutations.

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1	Shigematsu H, Lin L, Takahashi T, et al: Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst. 97:339–346. 2005. View Article : Google Scholar : PubMed/NCBI
2	Rodenhuis S, van de Wetering ML, Mooi WJ, Evers SG, van Zandwijk N and Bos JL: Mutational activation of the K-ras oncogene. A possible pathogenetic factor in adenocarcinoma of the lung. N Engl J Med. 317:929–935. 1987. View Article : Google Scholar : PubMed/NCBI
3	Chan SK, Gullick WJ and Hill ME: Mutations of the epidermal growth factor receptor in non-small cell lung cancer - search and destroy. Eur J Cancer. 42:17–23. 2006. View Article : Google Scholar : PubMed/NCBI
4	Ahrendt SA, Decker PA, Alawi EA, et al: Cigarette smoking is strongly associated with mutation of the K-ras gene in patients with primary adenocarcinoma of the lung. Cancer. 92:1525–1530. 2001. View Article : Google Scholar : PubMed/NCBI
5	Lynch TJ, Bell DW, Sordella R, et al: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 350:2129–2139. 2004. View Article : Google Scholar : PubMed/NCBI
6	Paez JG, Jänne PA, Lee JC, et al: EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 304:1497–1500. 2004. View Article : Google Scholar : PubMed/NCBI
7	Pham D, Kris MG, Riely GJ, et al: Use of cigarette-smoking history to estimate the likelihood of mutations in epidermal growth factor receptor gene exons 19 and 21 in lung adenocarcinomas. J Clin Oncol. 24:1700–1704. 2006. View Article : Google Scholar : PubMed/NCBI
8	Sugio K, Uramoto H, Ono K, et al: Mutations within the tyrosine kinase domain of EGFR gene specifically occur in lung adenocarcinoma patients with a low exposure of tobacco smoking. Br J Cancer. 94:896–903. 2006. View Article : Google Scholar : PubMed/NCBI
9	Pao W, Wang TY, Riely GJ, et al: KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med. 2:e172005. View Article : Google Scholar : PubMed/NCBI
10	Bos JL: ras oncogenes in human cancer: a review. Cancer Res. 49:4682–4689. 1989.PubMed/NCBI
11	Miller VA, Riely GJ, Zakowski MF, et al: Molecular characteristics of bronchioloalveolar carcinoma and adenocarcinoma, bronchioloalveolar carcinoma subtype, predict response to erlotinib. J Clin Oncol. 26:1472–1478. 2008. View Article : Google Scholar
12	Nagai Y, Miyazawa H, Huqun, et al: Genetic heterogeneity of the epidermal growth factor receptor in non-small cell lung cancer cell lines revealed by a rapid and sensitive detection system, the peptide nucleic acid-locked nucleic acid PCR clamp. Cancer Res. 65:7276–7282. 2005. View Article : Google Scholar
13	Thiede C, Bayerdörffer E, Blasczyk R, Wittig B and Neubauer A: Simple and sensitive detection of mutations in the ras proto-oncogenes using PNA-mediated PCR clamping. Nucleic Acids Res. 24:983–984. 1996. View Article : Google Scholar : PubMed/NCBI
14	Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Parkin DM: Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 127:2893–2917. 2010. View Article : Google Scholar : PubMed/NCBI
15	Toh CK, Gao F, Lim WT, et al: Never-smokers with lung cancer: epidemiologic evidence of a distinct disease entity. J Clin Oncol. 24:2245–2251. 2006. View Article : Google Scholar : PubMed/NCBI
16	Chen YR, Fu YN, Lin CH, et al: Distinctive activation patterns in constitutively active and gefitinib-sensitive EGFR mutants. Oncogene. 25:1205–1215. 2006. View Article : Google Scholar : PubMed/NCBI
17	Wu JY, Yu CJ, Chang YC, Yang CH, Shih JY and Yang PC: Effectiveness of tyrosine kinase inhibitors on ‘uncommon’ epidermal growth factor receptor mutations of unknown clinical significance in non-small cell lung cancer. Clin Cancer Res. 17:3812–3821. 2011.
18	De Pas T, Toffalorio F, Manzotti M, et al: Activity of epidermal growth factor receptor-tyrosine kinase inhibitors in patients with non-small cell lung cancer harboring rare epidermal growth factor receptor mutations. J Thorac Oncol. 6:1895–1901. 2011.
19	Bennett WP, Hussain SP, Vahakangas KH, Khan MA, Shields PG and Harris CC: Molecular epidemiology of human cancer risk: gene-environment interactions and p53 mutation spectrum in human lung cancer. J Pathol. 187:8–18. 1999. View Article : Google Scholar : PubMed/NCBI
20	Le Calvez F, Mukeria A, Hunt JD, et al: TP53 and KRAS mutation load and types in lung cancers in relation to tobacco smoke: distinct patterns in never, former, and current smokers. Cancer Res. 65:5076–5083. 2005.PubMed/NCBI
21	Riely GJ, Kris MG, Rosenbaum D, et al: Frequency and distinctive spectrum of KRAS mutations in never smokers with lung adenocarcinoma. Clin Cancer Res. 14:5731–5734. 2008. View Article : Google Scholar : PubMed/NCBI
22	Allegra CJ, Jessup JM, Somerfield MR, et al: American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol. 27:2091–2096. 2009. View Article : Google Scholar
23	O’Byrne KJ, Gatzemeier U, Bondarenko I, et al: Molecular biomarkers in non-small-cell lung cancer: a retrospective analysis of data from the phase 3 FLEX study. Lancet Oncol. 12:795–805. 2011.PubMed/NCBI
24	Pirker R, Pereira JR, Szczesna A, et al: Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet. 373:1525–1531. 2009. View Article : Google Scholar : PubMed/NCBI
25	Mollerup S, Jorgensen K, Berge G and Haugen A: Expression of estrogen receptors alpha and beta in human lung tissue and cell lines. Lung Cancer. 37:153–159. 2002. View Article : Google Scholar : PubMed/NCBI
26	Stabile LP, Davis AL, Gubish CT, et al: Human non-small cell lung tumors and cells derived from normal lung express both estrogen receptor alpha and beta and show biological responses to estrogen. Cancer Res. 62:2141–2150. 2002.
27	Yu IT, Chiu YL, Au JS, Wong TW and Tang JL: Dose-response relationship between cooking fumes exposures and lung cancer among Chinese nonsmoking women. Cancer Res. 66:4961–4967. 2006. View Article : Google Scholar
28	Kleinerman RA, Wang Z, Wang L, et al: Lung cancer and indoor exposure to coal and biomass in rural China. J Occup Environ Med. 44:338–344. 2002. View Article : Google Scholar : PubMed/NCBI