EGFR point mutation in non-small cell lung cancer is occasionally accompanied by a second mutation or amplification

Toshihiko Yokoyama, Masashi Kondo, Yasuhiro Goto, Takayuki Fukui, Hiromu Yoshioka, Kohei Yokoi, Hirotaka Osada, Kazuyoshi Imaizumi, Yoshinori Hasegawa, Kaoru Shimokata, Yoshitaka Sekido

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Abstract

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.

Original languageEnglish
Pages (from-to)753-759
Number of pages7
JournalCancer Science
Volume97
Issue number8
DOIs
Publication statusPublished - 01-08-2006

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Point Mutation
Non-Small Cell Lung Carcinoma
Mutation
Neoplasms
Alleles
erbB-2 Genes
erbB-1 Genes
Gene Amplification
Missense Mutation
Southern Blotting
Epidermal Growth Factor Receptor
Reverse Transcription
Sequence Analysis
Lung Neoplasms
Adenocarcinoma
Smoking
Light
Polymerase Chain Reaction

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Yokoyama, Toshihiko ; Kondo, Masashi ; Goto, Yasuhiro ; Fukui, Takayuki ; Yoshioka, Hiromu ; Yokoi, Kohei ; Osada, Hirotaka ; Imaizumi, Kazuyoshi ; Hasegawa, Yoshinori ; Shimokata, Kaoru ; Sekido, Yoshitaka. / EGFR point mutation in non-small cell lung cancer is occasionally accompanied by a second mutation or amplification. In: Cancer Science. 2006 ; Vol. 97, No. 8. pp. 753-759.
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abstract = "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.",
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Yokoyama, T, Kondo, M, Goto, Y, Fukui, T, Yoshioka, H, Yokoi, K, Osada, H, Imaizumi, K, Hasegawa, Y, Shimokata, K & Sekido, Y 2006, 'EGFR point mutation in non-small cell lung cancer is occasionally accompanied by a second mutation or amplification', Cancer Science, vol. 97, no. 8, pp. 753-759. https://doi.org/10.1111/j.1349-7006.2006.00233.x

EGFR point mutation in non-small cell lung cancer is occasionally accompanied by a second mutation or amplification. / Yokoyama, Toshihiko; Kondo, Masashi; Goto, Yasuhiro; Fukui, Takayuki; Yoshioka, Hiromu; Yokoi, Kohei; Osada, Hirotaka; Imaizumi, Kazuyoshi; Hasegawa, Yoshinori; Shimokata, Kaoru; Sekido, Yoshitaka.

In: Cancer Science, Vol. 97, No. 8, 01.08.2006, p. 753-759.

Research output: Contribution to journalArticle

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T1 - EGFR point mutation in non-small cell lung cancer is occasionally accompanied by a second mutation or amplification

AU - Yokoyama, Toshihiko

AU - Kondo, Masashi

AU - Goto, Yasuhiro

AU - Fukui, Takayuki

AU - Yoshioka, Hiromu

AU - Yokoi, Kohei

AU - Osada, Hirotaka

AU - Imaizumi, Kazuyoshi

AU - Hasegawa, Yoshinori

AU - Shimokata, Kaoru

AU - Sekido, Yoshitaka

PY - 2006/8/1

Y1 - 2006/8/1

N2 - 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.

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