Open AccessEGFR point mutation in non‐small cell lung cancer is occasionally accompanied by a second mutation or amplification
Author(s) -
Yokoyama Toshihiko,
Kondo Masashi,
Goto Yasuhiro,
Fukui Takayuki,
Yoshioka Hiromu,
Yokoi Kohei,
Osada Hirotaka,
Imaizumi Kazuyoshi,
Hasegawa Yoshinori,
Shimokata Kaoru,
Sekido Yoshitaka
Publication year - 2006
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2006.00233.x
Subject(s) - kras , gefitinib , point mutation , erlotinib , cancer research , missense mutation , biology , lung cancer , mutation , allele , adenocarcinoma , exon , gene , epidermal growth factor receptor , cancer , genetics , medicine , oncology
Activating mutations of EGFR are found frequently in a subgroup of patients with non‐small cell lung cancer (NSCLC) and are highly correlated with the response to gefitinib and erlotinib. In the present study, we searched for mutations of EGFR , HER2 and KRAS in 264 resected primary NSCLC from Japanese patients and determined whether there is a correlation between genetic alterations of these genes and clinicopathological factors, together with 85 tumors that we reported previously. EGFR mutations were found in 102 of the total 349 tumors, and seven tumors had two missense mutations. Reverse transcription–polymerase chain reaction of EGFR and subsequent subcloning analyses identified that the double mutations occurred in the same allele. Furthermore, in 202 NSCLC analyzed by Southern blotting, we identified 11 tumors with gene amplification of EGFR, with eight tumors containing a mutation in EGFR . Sequence analysis detected only weak or no signals of the wild‐type allele in the eight tumors, strongly suggesting that the mutated allele was amplified selectively. These findings indicate that a dual genetic change of EGFR can occur in the same allele either with a possible second‐hit mutation or with amplification, which may imply a more selective growth advantage in a cancer cell. Meanwhile, HER2 mutations and amplifications were found in six of 349 tumors and three of 202 tumors, respectively, and KRAS mutations in 21 of 349 tumors. Mutations of the EGFR and HER2 genes were more frequently found in female never or light‐smoking patients with adenocarcinoma, and there were no tumors that had two or more mutations simultaneously among EGFR , HER2 and KRAS . The current study further demonstrates that a double genetic event in EGFR can occasionally occur in lung cancer, thus providing new clues for understanding the involvement of epidermal growth factor receptor signaling cascades in the pathogenesis of NSCLC. ( Cancer Sci 2006; 97: 753–759)