Mutation of the epidermal growth factor receptor gene in the development of adenocarcinoma of the lung

doi:10.1016/j.lungcan.2007.04.011

Lung Cancer

Volume 58, Issue 1, October 2007, Pages 30-35

https://doi.org/10.1016/j.lungcan.2007.04.011 Get rights and content

Summary

Recently, a mutation of the epidermal growth factor receptor (EGFR) gene has been reported to be implicated in the development of pulmonary adenocarcinoma. However, the involvement of the mutation in atypical adenomatous hyperplasia (AAH) and multiple adenocarcinomas still remains unclear. We herein examined the EGFR mutations in 9 AAH and 31 adenocarcinoma lesions obtained from 30 Japanese patients. Nine patients had synchronous or metachronous multiple adenocarcinomas and/or AAH. Mutations in exons 18–21 of EGFR gene were analysed using polymerase chain reaction and direct sequence methods. EGFR mutations were detected in 4 (44%) of 9 AAH and in 7 (23%) of 31 adenocarcinomas. A gefitinib-resistant point mutation (T790M) in exon 20 without gefitinib treatment was detected in 1 AAH and 1 adenocarcinoma. The patient with T790M mutated AAH, which also had an exon 19 mutation of D761Y, had synchronous adenocarcinoma, which had only an exon 19 mutation of D761Y. The other exon 19 mutations were all in-frame deletions. In the two patients with synchronous AAH and adenocarcinoma, AAH had mutations at exon 19 although adenocarcinoma did not have any mutations. In the patient with synchronous 2 adenocarcinomas, each had different mutations (exons 19 and 21). In two patients with double adenocarcinomas, 1 adenocarcinoma harbored exon 21 mutations, while the other demonstrated no mutations. Although EGFR mutations appeared to be partially associated with the early steps of adenocarcinoma development, such mutations may possibly occur randomly even in multiple lesions in a single patient.

Introduction

Lung cancer is one of the most common tumours worldwide, with 900,000 new cases being reported each year in men and 330,000 in women [1] and it is also the leading cause of death in cancer patients. Although platinum-based two-drug combination chemotherapy is considered to be the standard for treatment for advanced non-small cell lung cancer (NSCLC) [2], [3], the survival benefit is modest. Meanwhile, gefitinib, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), showed a remarkable benefit in a subset of relapsed or chemo-resistant NSCLC [4], [5]. Lynch et al. and Paez et al. reported a somatic activating mutation of EGFR to be significantly associated with the response to EGFR-TKI such as gefitinib or erlotinib [6], [7]. These somatic mutations were more frequently observed in females, non-smokers, adenocarcinoma patients, and the Asian population. Up to a 40–50% mutation rate in adenocarcinoma has been reported [8], [9], [10], [11]. The relationship between EGFR mutation and adenocarcinoma carcinogenesis has been demonstrated in transgenic mice [12], [13].

Pulmonary atypical adenomatous hyperplasia (AAH) is considered to be a benign disease and it is also recognized as a pre-malignant lesion of adenocarcinoma [14], [15]. This is supported by the abnormal gene profiles frequently seen in AAH, such as the activation of oncogene (K-ras or c-erb-B2) or the suppression of the p53 gene [16], [17], [18]. However, the molecular mechanism of progression from AAH to adenocarcinoma still remains unclear. In this study, we investigated the EGFR gene mutation in AAH and adenocarcinoma to elucidate whether these somatic mutations are associated with the development of adenocarcinoma.

Section snippets

Patients

Since June 1997 to September 1999, 9 AAH and 31 adenocarcinoma tissue specimens were obtained from 30 consecutive Japanese patients who underwent surgery for pulmonary adenocarcinoma of clinical stage I or AAH at the National Shikoku Cancer Center Hospital, Japan. Among 30 patients, 2 had synchronous double adenocarcinomas, 1 had synchronous triple adenocarcinomas, and 4 had concomitant AAH and adenocarcinoma. Two patients who had adenocarcinoma were revealed to have undergone a previous

Results

All nine patients with AAH were female non-smokers. Thirty-one adenocarcinoma samples were obtained from 25 patients. Twenty samples were obtained from 16 female patients, 11 samples were obtained from 9 male patients. Ten adenocarcinoma samples were obtained from 7 current or former smokers and 21 adenocarcinoma samples were obtained from 18 non-smokers.

The sense sequencing chromatograms of representative EGFR mutations are shown in Fig. 1. EGFR mutations in exons 19 and 21 were detected in 11

Discussion

We determined the frequency of EGFR mutations in exons 18–21 in AAH and adenocarcinoma to be similar. The frequency of EGFR mutation in AAH and adenocarcinoma has already been reported to be 3% (1/35) and 25% (17/68), 0% (0/5) and 39% (37/95), 29% (2/7) and 50% (97/195), respectively [23], [24], [25]. EGFR mutations have been considered to have a higher frequency in adenocarcinoma than in AAH. In the present study, four (44%) of nine AAH harbored mutations. The differences in these frequencies

Conflict of interest

None declared.

Acknowledgements

This work was supported in part by research funds from the Ministry of Education, Culture, Sports, Science and Technology of Japan Grant no. 18590851.

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¹: Present address: Division of Thoracic Surgery, Department of Surgery, Kawasaki Medical School, 577 Matsushima, Kurashiki 701-0192, Japan.

²: Present address: Department of Pathology and Laboratory Medicine, Higashi-hiroshima Medical Center, 513 Jike, Saijo, Higashi-hiroshima 739-0041, Japan.

³: Present address: Oncology Center, Division of Medical Oncology, Tokai University of Medicine, 143 Shimokasuya, Isehara 259-1193, Japan.

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Mutation of the epidermal growth factor receptor gene in the development of adenocarcinoma of the lung

Summary

Introduction

Section snippets

Patients

Results

Discussion

Conflict of interest

Acknowledgements

Cancer Cell

J Thorac Cardiovasc Surg

Lung Cancer

Lung Cancer

Lung Cancer

Human cancers by organ site: lung cancer

Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer

N Engl J Med

Phase III randomized trial comparing three platinum-based doublets in advanced non-small-cell lung cancer

J Clin Oncol

Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial)

J Clin Oncol

Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial

JAMA

Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib

N Engl J Med

EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy

Science

The relationship between epidermal growth factor receptor mutations and clinicopathologic features in non-small cell lung cancers

Clin Cancer Res

Mutations of the epidermal growth factor receptor gene in lung cancer: biological and clinical implications

Cancer Res

High frequency of epidermal growth factor receptor mutations with complex patterns in non-small cell lung cancers related to gefitinib responsiveness in Taiwan

Clin Cancer Res

Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers

J Natl Cancer Inst