Original article
EGFR, ERBB2, and KRAS mutations in Korean non-small cell lung cancer patients

https://doi.org/10.1016/j.cancergencyto.2006.10.007Get rights and content

Abstract

The epidermal growth factor receptor (EGFR), and its family members play an important role in the development and progression of lung cancers. It has been reported that somatic mutations in the tyrosine kinase domain of the EGFR or ERBB2 genes occur in a subset of patients with lung cancer. We searched for mutations of the EGFR, ERBB2, and KRAS genes in surgically resected non-small cell lung cancers (NSCLCs) to determine the prevalence of these mutations in Korean lung cancer patients. In addition, we examined the relationship between the mutations and clinicopathologic features of lung cancers. Mutations of the EGFR, ERBB2, and KRAS genes were determined by polymerase chain reaction–based direct sequencing in 115 surgically resected non-small cell lung cancers. EGFR mutations were present in 20 patients (17.4%). The EGFR mutations were found only in adenocarcinomas (20 of 55 adenocarcinomas, 36.4%). The ERBB2 mutation was found in 1 adenocarcinoma of the 115 NSCLCs (0.9% overall; 1.8% of the 55 adenocarcinomas). KRAS mutations were found in 6 (5.2%) of the 115 NSCLCs (2 of 60 squamous cell carcinomas, or 3.3%, and 4 of 55 adenocarcinomas, or 7.3%). EGFR mutations in adenocarcinomas were more frequent in women (P = 0.02) and in never-smokers (P = 0.004). EGFR mutations in adenocarcinomas were not associated with pathologic stage in never-smokers, but were more frequent in pathologic stage II–IV than in stage I in ever-smokers (P = 0.01). Of the 55 adenocarcinomas, 25 (45.5%) had mutations of one or another of the three genes; EGFR mutations were never found in adenocarcinomas together with ERBB2 or KRAS mutations. These findings suggest that the EGFR mutation is frequent in Korean lung cancer patients, and that the ERBB2 mutation is rare. Further studies are needed to investigate the role of EGFR mutations in the carcinogenesis of adenocarcinoma among smokers.

Introduction

The epidermal growth factor receptor (EGFR) signal transduction cascade plays an important role in many tumorigenic processes, including cell proliferation, angiogenesis, and metastasis, as well as protection of the cell from apoptosis [1]. These effects are mediated by the activation of downstream signal transduction cascades, including Ras-Raf-mitogen activated protein kinase, phosphatidylinositol-3 kinase–Akt, and Janus tyrosine kinase–STAT (signal transducer and activator of transcription) pathways [2], [3], [4], [5].

Several studies have shown that mutations in the tyrosine kinase (TK) domain of the EGFR gene (previously ERBB) are present in a subset of non-small cell lung cancers (NSCLCs), and those tumors with the EGFR mutations have been reported to be highly sensitive to gefitinib, an EGFR TK inhibitor [6], [7], [8].

With ERBB (alias ERBB1) reclassified as EFGR, the ERBB gene family consists of ERBB2 (previously NGL; alias EGFR2, HER2, NEU), ERBB2IP, ERBB3 (alias EGFR3, HER3), and ERBB4 (alias EGFR4, HER4) (see http://www.gene.ucl.ac.uk/nomenclature/).

Several studies have shown that ERBB2 is overexpressed in ∼20% of NSCLCs, and ERBB2 overexpression has been associated with an unfavorable prognosis [9], [10]. Stephens et al. [11] reported that 5 of 120 NSCLCs (4.2%) and 5 of 51 adenocarcinomas (9.8%) harbored mutations in the ERBB2 TK domain. Shigematsu et al. [12] have recently reported that, similar to the EGFR mutations in lung cancers, mutations in the ERBB2 TK domain preferentially targeted adenocarcinoma histology, women, never-smokers, and Asian ethnicity.

Several studies have observed that simultaneous alterations of genes in the same signaling pathways are rarely found in a single tumor. For example, CDKN2A (alias p16INK4a) methylation and retinoblastoma (RB1) gene mutation, which negatively regulate the phosphorylation of Rb, are rarely found together in individual tumors [13], [14]. As in the case of the p16INK4a–Rb pathway, it has been reported that EGFR mutations were never found in lung cancers with KRAS mutation [8], [15], suggesting that EGFR and KRAS mutations are mutually exclusive.

Because the prevalence of genetic alterations often varies depending on the patient's ethnicity, we searched for mutations of the EGFR, ERBB2, and KRAS genes in surgically resected NSCLC samples to determine the prevalence of these mutations in Korean lung cancer patients. In addition, we examined the relationship between these mutations and clinicopathologic features in lung cancers. We also searched for these mutations in the normal lung tissues of patients with NSCLC.

Section snippets

Patients and tissue samples

Tumor and corresponding normal lung tissue specimens were obtained from 115 NSCLC patients who underwent curative resection at Kyungpook National University Hospital (Daegu, Korea) from January 2003 to December 2005. None of the patients had received chemotherapy or radiotherapy before surgery. Written informed consent was obtained from each patient before the surgery. This study was approved by the institutional review board of the Kyungpook National University Hospital.

Histologic type was

Results

Because EGFR mutations in lung cancers were limited to the first four exons (exons 18–21) of the TK domain in previous studies [6], [7], [8], [15], [19], [20], we searched for mutations in these four exons. Of 115 NSCLC patients who underwent surgical resection of their tumors, EGFR TK domain mutations were found in 20 cases (17.4%). All EGFR mutations were found in adenocarcinomas only (20 of 55 adenocarcinomas, 36.4%). Of these 20 mutations, 9 (45%) were in-frame deletions in exon 19, 10

Discussion

Although EGFR mutations in lung cancers have been extensively studied, most previous studies have investigated mutations in patients with advanced stage of lung cancer. In the present study, we searched for EGFR mutations in Korean NSCLC patients who underwent curative surgical resection and explored the relationship between EGFR mutational status and clinicopathologic features, including the presence of ERBB2 or KRAS mutations. Mutations in the TK domain of either the EGFR or ERBB2 genes were

Acknowledgments

This study was supported by Grant no. RTI04-01-01, The Regional Technology Innovation Program of The Ministry of Commerce, Industry and Energy (MOCIE), Republic of Korea, and in part by the Brain Korea 21 Project in 2006.

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