EGFR exon 20 insertion mutation in Japanese lung cancer
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.
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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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