Frequency and significance of epidermal growth factor receptor mutations detected by PCR methods in patients with non‑small cell lung cancer

Nakajima,Eiji; Sugita,Michio; Furukawa,Kinya; Takahashi,Hidenobu; Uchida,Osamu; Kawaguchi,Youhei; Ohira,Tatsuo; Matsubayashi,Jun; Ikeda,Norihiko; Hirsch,Fred  R.; Franklin,Wilbur  A.

doi:10.3892/ol.2019.10157

June-2019 Volume 17 Issue 6

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June-2019 Volume 17 Issue 6

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Article

Frequency and significance of epidermal growth factor receptor mutations detected by PCR methods in patients with non‑small cell lung cancer

Authors:
- Eiji Nakajima
- Michio Sugita
- Kinya Furukawa
- Hidenobu Takahashi
- Osamu Uchida
- Youhei Kawaguchi
- Tatsuo Ohira
- Jun Matsubayashi
- Norihiko Ikeda
- Fred R. Hirsch
- Wilbur A. Franklin
View Affiliations / Copyright

Affiliations: Department of Thoracic Surgery, Tokyo Medical University Ibaraki Medical Center, Ibaraki 300‑0395, Japan, Department of Pathology, University of Colorado Health Sciences Center, Aurora, CO 80045, USA, Department of Thoracic Surgery, Tokyo Medical University Hachioji Medical Center, Tokyo 193‑0998, Japan, Department of Thoracic Surgery, Tokyo Medical University Hospital, Tokyo 160‑0023, Japan, Department of Pathology, Tokyo Medical University Hospital, Tokyo 160‑0023, Japan, Division of Medical Oncology, University of Colorado Health Sciences Center, Aurora, CO 80045, USA
Pages: 5125-5131
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Published online on: March 18, 2019

https://doi.org/10.3892/ol.2019.10157
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Abstract

Epidermal growth factor receptor (EGFR) is the most important driver gene of non‑small cell lung cancer (NSCLC) as EGFR mutations determine the efficacy of EGFR tyrosine kinase inhibitor (EGFR‑TKI) therapy. In the present study, the comprehensive ability of widely used polymerase chain reaction (PCR) methods to detect EGFR mutations was determined. Among the 35 EGFR mutations detected via the direct sequencing of 73 patients with NSCLC, 11 types were identified in exons 18, 19 and 21. Among the 11 mutation types, all exon 18 and 21 mutations were identified by 2 widely used PCR methods, namely, Scorpion‑Amplification Refractory Mutation System and cobas v2. However, among the 9 different exon 19 deletions, 3 types were not identified by the 2 methods. In addition, 25 samples with EGFR mutations were analyzed by the 2 methods, including a sample from a patient with an unidentified exon 19 deletion, the T751_I759 deletion and insertion S; this patient had long‑term disease control as a result of EGFR‑TKI therapy. The 2 methods could not detect this unidentified deletion, whereas sizing capillary electrophoresis for the comprehensive detection of exon 19 deletions detected this deletion. It is generally thought that patients with exon 19 mutations have higher response rates to EGFR‑TKI therapy than patients with exon 21 mutations. The present study confirmed the EGFR mutation status by comparing the mutations with the Catalog Of Somatic Mutations In Cancer, which is the world's largest and most comprehensive resource for analyzing the effects of somatic mutations in human cancers. The predicted frequency of EGFR mutations identified by the 2 methods was 85%. The frequency of mutations detectable by the 2 methods was less for exon 19 than exon 21. Therefore, the results of the present study suggest that decreasing false‑negative detection of exon 19 deletions is crucial for the clinical testing of EGFR mutations.

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1	Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, et al: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 361:947–957. 2009. View Article : Google Scholar : PubMed/NCBI
2	Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, Seto T, Satouchi M, Tada H, Hirashima T, et al: Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): An open label, randomised phase 3 trial. Lancet Oncol. 11:121–128. 2010. View Article : Google Scholar : PubMed/NCBI
3	Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I, et al: Gefitinib or chemotherapy for non-small cell lung cancer with mutated EGFR. N Engl J Med. 362:2380–2388. 2010. View Article : Google Scholar : PubMed/NCBI
4	Yang JC, Wu YL, Schuler M, Sebastian M, Popat S, Yamamoto N, Zhou C, Hu CP, O'Byrne K, Feng J, et al: Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): Analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol. 16:141–151. 2015. View Article : Google Scholar : PubMed/NCBI
5	Wu YL, Cheng Y, Zhou X, Lee KH, Nakagawa K, Niho S, Tsuji F, Linke R, Rosell R, Corral J, et al: Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): A randomised, open-label, phase 3 trial. Lancet Oncol. 18:1454–1466. 2017. View Article : Google Scholar : PubMed/NCBI
6	Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, Dechaphunkul A, Imamura F, Nogami N, Kurata T, et al: Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 378:113–125. 2018. View Article : Google Scholar : PubMed/NCBI
7	Kimura H, Kasahara K, Kawaishi M, Kunitoh H, Tamura T, Holloway B and Nishio K: Detection of epidermal growth factor receptor mutations in serum as a predictor of the response to gefitinib in patients with non-small-cell lung cancer. Clin Cancer Res. 12:3915–3921. 2006. View Article : Google Scholar : PubMed/NCBI
8	Kimura H, Ohira T, Uchida O, Matsubayashi J, Shimizu S, Nagao T, Ikeda N and Nishio K: Analytical performance of the cobas EGFR mutation assay for Japanese non-small lung cancer. Lung Cancer. 83:329–333. 2014. View Article : Google Scholar : PubMed/NCBI
9	Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC and Gwyther SG: New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 92:205–216. 2000. View Article : Google Scholar : PubMed/NCBI
10	Kosaka T, Yatabe Y, Endoh H, Kuwano H, Takahashi T and Mitsudomi T: Mutations of the epidermal growth factor receptor gene in lung cancer: Biological and clinical implications. Cancer Res. 64:8919–8923. 2004. View Article : Google Scholar : PubMed/NCBI
11	Tokumo M, Toyooka S, Kiura K, Shigematsu H, Tomii K, Aoe M, Ichimura K, Tsuda T, Yano M, Tsukuda K, et al: The relationship between epidermal growth factor receptor mutations and clinicopathologic features in non-small cell lung cancers. Clin Cancer Res. 11:1167–1173. 2005.PubMed/NCBI
12	Sonobe M, Manabe T, Wada H and Tanaka F: Mutations in the epidermal growth factor receptor gene are linked to smoking-independent, lung adenocarcinoma. Br J Cancer. 93:355–363. 2005. View Article : Google Scholar : PubMed/NCBI
13	Shigematsu H, Lin L, Takahashi T, Nomura M, Suzuki M, Wistuba II, Fong KM, Lee H, Toyooka S, Shimizu N, 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
14	Mitsudomi T, Kosaka T and Yatabe Y: Biological and clinical implications of EGFR mutations in lung cancer. Int J Clin Oncol. 11:190–198. 2006. View Article : Google Scholar : PubMed/NCBI
15	Kobayashi Y and Mitsudomi T: Not all epidermal growth factor receptor mutations in lung cancer are created equal: Perspectives for individualized treatment strategy. Cancer Sci. 107:1179–1186. 2016. View Article : Google Scholar : PubMed/NCBI
16	Riely GJ, Pao W, Pham D, Li AR, Rizvi N, Venkatraman ES, Zakowski MF, Kris MG, Ladanyi M and Miller VA: Clinical course of patients with non-small cell lung cancer and epidermal growth factor receptor exon 19 and exon 21 mutations treated with gefitinib or erlotinib. Clin Cancer Res. 12:839–844. 2006. View Article : Google Scholar : PubMed/NCBI
17	Jackman DM, Yeap BY, Sequist LV, Lindeman N, Holmes AJ, Joshi VA, Bell DW, Huberman MS, Halmos B, Rabin MS, et al: Exon 19 deletion mutations of epidermal growth factor receptor are associated with prolonged survival in non-small cell lung cancer patients treated with gefitinib or erlotinib. Clin Cancer Res. 12:3908–3914. 2006. View Article : Google Scholar : PubMed/NCBI
18	Hirsch FR, Varella-Garcia M, Cappuzzo F, McCoy J, Bemis L, Xavier AC, Dziadziuszko R, Gumerlock P, Chansky K, West H, et al: Combination of EGFR gene copy number and protein expression predicts outcome for advanced non-small-cell lung cancer patients treated with gefitinib. Ann Oncol. 18:752–760. 2007. View Article : Google Scholar : PubMed/NCBI
19	Lin MT, Mosier SL, Thiess M, Beierl KF, Debeljak M, Tseng LH, Chen G, Yegnasubramanian S, Ho H, Cope L, et al: Clinical validation of KRAS BRAF, and EGFR mutation detection using next-generation sequencing. Am J Clin Pathol. 141:856–866. 2014. View Article : Google Scholar : PubMed/NCBI
20	Xu X, Yang Y, Li H, Chen Z, Jiang G and Fei K: Assessment of the clinical application of detecting EGFR, KRAS, PIK3CA and BRAF mutations in patients with non-small cell lung cancer using next-generation sequencing. Scand J Clin Lab Invest. 76:386–392. 2016. View Article : Google Scholar : PubMed/NCBI

Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

Frequency and significance of epidermal growth factor receptor mutations detected by PCR methods in patients with non‑small cell lung cancer

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