Somatic mutations of the HER2 kinase domain in lung adenocarcinomas

Hisayuki Shigematsu, Takao Takahashi, Masaharu Nomura, Kuntal Majmudar, Makoto Suzuki, Huei Lee, Ignacio I. Wistuba, Kwun M. Fong, Shinichi Toyooka, Nobuyoshi Shimizu, Takehiko Fujisawa, John D. Minna, Adi F. Gazdar

Research output: Contribution to journalArticle

512 Citations (Scopus)

Abstract

Mutations in the epidermal growth factor receptor gene (EGFR) in lung cancers predict for sensitivity to EGFR kinase inhibitors. HER2 (also known as NEU, EGFR2, or ERBB2) is a member of the EGFR family of receptor tyrosine kinases and plays important roles in the pathogenesis of certain human cancers, and mutations have recently been reported in lung cancers. We sequenced the tyrosine kinase domain of HER2 in 671 primary non-small cell lung cancers (NSCLC), 80 NSCLC cell lines, and 55 SCLCs and other neuroendocrine lung tumors as well as 85 other epithelial cancers (breast, bladder, prostate, and colorectal cancers) and compared the mutational status with clinicopathologic features and the presence of EGFR or KRAS mutations. HER2 mutations were present in 1.6% (II of 671) of NSCLC and were absent in other types of cancers. Only one adenocarcinoma cell line (NCI-H1781) had a mutation. All HER2 mutations were in-frame insertions in exon 20 and target the identical corresponding region as did EGFR insertions. HER2 mutations were significantly more frequent in never smokers (3.2%, 8 of 248; P = 0.02) and adenocarcinoma histology (2.8%, 11 of 394; P = 0.003). In 394 adenocarcinoma cases, HER2 mutations preferentially targeted Oriental ethnicity (3.9%) compared with other ethnicities (0.7%), female gender (3.6%) compared with male gender (1.9%) and never smokers (4.1%) compared with smokers (1.4%). Mutations in EGFR, HER2, and KRAS genes were never present together in individual tumors and cell lines. The remarkable similarities of mutations in EGFR and HER2 genes involving tumor type and subtype, mutation type, gene location, and specific patient subpopulations targeted are unprecedented and suggest similar etiologic factors. EGFR, HER2, and KRAS mutations are mutually exclusive, suggesting different pathways to lung cancer in smokers and never smokers.

Original languageEnglish
Pages (from-to)1642-1646
Number of pages5
JournalCancer Research
Volume65
Issue number5
DOIs
Publication statusPublished - Mar 1 2005
Externally publishedYes

Fingerprint

erbB-1 Genes
Phosphotransferases
Mutation
Non-Small Cell Lung Carcinoma
erbB-2 Genes
Lung Neoplasms
Adenocarcinoma
Urinary Bladder Neoplasms
Adenocarcinoma of lung
Breast Neoplasms
Cell Line
Neoplasms
Neuroendocrine Tumors
Insertional Mutagenesis
Receptor Protein-Tyrosine Kinases
Tumor Cell Line
Epidermal Growth Factor Receptor
Protein-Tyrosine Kinases
Colorectal Neoplasms
Exons

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Shigematsu, H., Takahashi, T., Nomura, M., Majmudar, K., Suzuki, M., Lee, H., ... Gazdar, A. F. (2005). Somatic mutations of the HER2 kinase domain in lung adenocarcinomas. Cancer Research, 65(5), 1642-1646. https://doi.org/10.1158/0008-5472.CAN-04-4235

Somatic mutations of the HER2 kinase domain in lung adenocarcinomas. / Shigematsu, Hisayuki; Takahashi, Takao; Nomura, Masaharu; Majmudar, Kuntal; Suzuki, Makoto; Lee, Huei; Wistuba, Ignacio I.; Fong, Kwun M.; Toyooka, Shinichi; Shimizu, Nobuyoshi; Fujisawa, Takehiko; Minna, John D.; Gazdar, Adi F.

In: Cancer Research, Vol. 65, No. 5, 01.03.2005, p. 1642-1646.

Research output: Contribution to journalArticle

Shigematsu, H, Takahashi, T, Nomura, M, Majmudar, K, Suzuki, M, Lee, H, Wistuba, II, Fong, KM, Toyooka, S, Shimizu, N, Fujisawa, T, Minna, JD & Gazdar, AF 2005, 'Somatic mutations of the HER2 kinase domain in lung adenocarcinomas', Cancer Research, vol. 65, no. 5, pp. 1642-1646. https://doi.org/10.1158/0008-5472.CAN-04-4235
Shigematsu H, Takahashi T, Nomura M, Majmudar K, Suzuki M, Lee H et al. Somatic mutations of the HER2 kinase domain in lung adenocarcinomas. Cancer Research. 2005 Mar 1;65(5):1642-1646. https://doi.org/10.1158/0008-5472.CAN-04-4235
Shigematsu, Hisayuki ; Takahashi, Takao ; Nomura, Masaharu ; Majmudar, Kuntal ; Suzuki, Makoto ; Lee, Huei ; Wistuba, Ignacio I. ; Fong, Kwun M. ; Toyooka, Shinichi ; Shimizu, Nobuyoshi ; Fujisawa, Takehiko ; Minna, John D. ; Gazdar, Adi F. / Somatic mutations of the HER2 kinase domain in lung adenocarcinomas. In: Cancer Research. 2005 ; Vol. 65, No. 5. pp. 1642-1646.
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