Elsevier

Lung Cancer

Volume 58, Issue 3, December 2007, Pages 324-328
Lung Cancer

EGFR exon 20 insertion mutation in Japanese lung cancer

https://doi.org/10.1016/j.lungcan.2007.06.024Get rights and content

Summary

Mutations of the epidermal growth factor receptor (EGFR) gene have been reported in non-small cell lung cancer (NSCLC), especially in female, never smoker patients with adenocarcinoma. Some common somatic mutations in EGFR, including deletion mutations in exon 19 and leucine to arginine substitution at amino acid position 858 (L858R) in exon 21, have been examined for their ability to predict sensitivity to gefitinib or erlotinib. On the other hand, previous report has shown that the insertion mutation at exon 20 is related to gefitinib resistance. We investigated the exon 20 EGFR mutation statuses in 322 surgically treated non-small cell lung cancer cases. Two hundred and five adenocarcinoma cases were included. The presence or absence of EGFR mutations of kinase domains was analyzed by direct sequences. EGFR insertion mutations at exon 20 were found from 7 of 322 (2.17%) lung cancer patients. We also detected the 18 deletion type mutations in exon 19, and 25 L858R type mutations in exon 21. There was a tendency towards higher exon 20 insertion ratio in never smoker (never smoker 4.4% versus smoker 1.3%, p = 0.0996) and female (female 4.5% versus male 1.3%, p = 0.0917). Two exon 20 insertion cases were treated with gefitinib and failed to response.

EGFR insertion mutation in exon 20 could not be ignored from Japanese lung cancers.

Introduction

Lung cancer is a major cause of death from malignant diseases, due to its high incidence, malignant behavior and lack of major advancements in treatment strategy [1]. There are much accumulated evidences that epidermal growth factor receptor (EGFR) and its family members are strongly implicated in the development and progression of numerous human tumors, including lung cancer [2], [3]. The EGFR tyrosine kinase inhibitor, gefitinib, was approved in Japan for the treatment of non-small cell lung cancer (NSCLC) since 2002. Original two reports showed that EGFR mutations statuses at ATP binding pockets in NSCLC patients were correlated with the clinico-pathological features related to good response to gefitinib [4], [5]. These EGFR mutations are predominantly found in Japanese lung cancer patients (about 25–40%) [4], [6], [7], [8], [9] when compared to USA patients (about 8–10%) [4], [5], [7], [10] or European patients [7], [11]. Actually, EGFR mutations in lung cancer have been correlated with clinical response to gefitinib therapy in vivo and in vitro[4], [5], [10]. Although many EGFR mutations have been reported, not all have been associated with responsiveness to gefitinib. The two most common EGFR mutations that have been identified, representing 85–90% of EGFR mutations, are the EGFR exon 19 deletion that eliminates a leucine–arginine–glutamate–alanine motif in the tyrosine kinase domain of EGFR and a thymine to guanine transversion that results in an arginine for leucine substitution at amino acid 858 (L858R). These two mutants responded significantly better for gefitinib therapy than other types of mutants [12], [13]. However, Greulich et al. showed transformation by an exon 20 insertion, made cells resistant to gefitinib or erlotinib [14]. To determine the EGFR mutation status and correlation with clinico-pathological features in Japanese lung carcinoma, we investigated exon 20 insertion mutation status by direct sequences. The findings were compared to the clinico-pathological features of lung cancer.

Section snippets

Patients

The study group included 295 lung cancer patients who had undergone surgery at the Department of Surgery II, Nagoya City University Medical School between 1994 and 2005. We have also investigated EGFR mutation status for 27 lung cancer patients who had undergone surgery followed by treated with gefitinib at the National Hospital Organization, Kinki-chuo Chest Medical Center. Gefitinib was used after lung cancer recurrence, and clinical outcome was shown in reference [9]. The lung tumors were

EGFR gene mutation status in Japanese lung cancer patients

The clinical and pathological characteristics of the 322 lung cancer patients are as follows: 234 (72.7%) were males and 88 were females. Two hundred and five (63.7%) were diagnosed as adenocarcinoma, and 117 were diagnosed as other types of carcinoma. Two hundred and thirty-one (71.7%) were smokers and 90 were non-smokers (one unknown). Of 295 lung cancer patients from Nagoya City University, 167 (56.6%) were stage I.

Most of the sequencing results about exon 18, 19 and 21 were already reported

Discussion

We obtained findings that exon 20 insertion type EGFR mutations tend to be higher in female gender and never smoker, as like as other EGFR mutation subtypes [8], [9], [10], [11], [12], [13], [14]. From the original three papers published by Lynch et al., Paez et al. and Pao et al., there was no EGFR exon 20 insertion subtypes. Shigematsu et al. reported that 12 of 617 (1.9%) had exon 20 insertion mutation, however, 356 of 617 patients were either from Japan or Taiwan [11]. Sonobe et al.

Conflict of interest

None declared.

Acknowledgements

The authors would like to thank Mr. Naoya Hosono and Mrs. Yuri Yamamoto for their excellent technical assistances.

Grant Sponsor: AstraZeneca Research Grant 2004 and Grants-in-Aid for Science Research (Nos. 18659407,18390381, 18790998) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan.

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