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Somatic mutations of the HER2 kinase domain in lung adenocarcinomas

Hisayuki Shigematsu1, Takao Takahashi, Masaharu Nomura

  • 1Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8593, USA.

Cancer Research
|March 9, 2005
PubMed

Insights

HER2 mutations, similar to EGFR mutations, occur in lung adenocarcinoma, particularly in never-smokers. These mutations are mutually exclusive with EGFR and KRAS, suggesting distinct lung cancer development pathways.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Epidermal growth factor receptor (EGFR) mutations in lung cancer predict sensitivity to kinase inhibitors.
  • HER2, a member of the EGFR family, plays a role in various cancers and has recently been reported in lung cancers.

Purpose of the Study:

  • To investigate the frequency and characteristics of HER2 mutations in non-small cell lung cancer (NSCLC) and other cancers.
  • To compare HER2 mutational status with clinicopathologic features and the presence of EGFR or KRAS mutations.

Main Methods:

  • Sequencing of the HER2 tyrosine kinase domain in 671 primary NSCLCs, 80 NSCLC cell lines, 55 SCLCs, and 85 other epithelial cancers.
  • Comparison of mutational status with clinicopathologic features and EGFR/KRAS mutations.

Main Results:

  • HER2 mutations were found in 1.6% of NSCLCs, exclusively in adenocarcinomas, and absent in other cancer types.
  • All HER2 mutations were in-frame insertions in exon 20, similar to EGFR insertions.
  • HER2 mutations were significantly more frequent in never-smokers, adenocarcinoma histology, Oriental ethnicity, and females.

Conclusions:

  • HER2 mutations in NSCLC share striking similarities with EGFR mutations in terms of tumor type, mutation type, and targeted subpopulations, suggesting similar etiologic factors.
  • EGFR, HER2, and KRAS mutations are mutually exclusive, indicating different pathways in lung cancer development, particularly between smokers and never-smokers.

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