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.

doi:10.1158/0008-5472.can-04-4235

Cited by 678Lung Cancer Treatments and MutationsHER2/EGFR in Cancer ResearchCancer Genomics and Diagnostics

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. +5 more·2005·Cancer Research

DOI 10.1158/0008-5472.can-04-4235

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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% (11 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.

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The A775_G776insYVMA mutation accounts for most HER2 exon 20 mutations observed in NSCLC.
“with the A775_G776insYVMA mutation accounting for most of the mutations seen in NSCLC (17–21).”
From Response Heterogeneity of EGFR and HER2 Exon 20 Insertions to Covalent EGFR and HER2 Inhibitors (2017) · cites this paper as [18]

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Authors: Shigematsu, H., Takahashi, T., Nomura, M., Majmudar, K., Suzuki, M., Lee, H., Wistuba, I. I., Fong, K. M., Toyooka, S., Shimizu, N., Fujisawa, T., Minna, J. D., & Gazdar, A. F.
Affiliations: Okayama University (JP)
1Hamon Center for Therapeutic Oncology Research, Departments of
Chiba University (JP)
Chung Shan Medical University (TW)
The University of Texas MD Anderson Cancer Center (US)
Prince Charles Hospital (AU)
The University of Texas Southwestern Medical Center (US)
ORCID: Majmudar, Kuntal
Suzuki, Makoto
Wistuba, Ignacio I.
Fong, Kwun M.
Toyooka, Shinichi
Minna, John D.
Gazdar, Adi F.
Venue: Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2005-03-01
Volume: 65
Issue: 5
Pages: 1642-1646
ISSN: 0008-5472 (ISSN-L)
1538-7445
DOI: 10.1158/0008-5472.can-04-4235
OpenAlex: W2133867160
Cited by: 678
References: 28
Citations by year: 2026: 8 · 2025: 17 · 2024: 13 · 2023: 18 · 2022: 16 · 2021: 36 · 2020: 29 · 2019: 27 · 2018: 36 · 2017: 23 · 2016: 27 · 2015: 46 · 2014: 46 · 2013: 54 · 2012: 34
FWCI: 42.08
Type: journal article
Language: en
Open access: closed
Locations: Cancer Research (publishedVersion)
PubMed (publishedVersion)
Funders: National Cancer Institute ((P50-CA70907, P50CA070907, 5U01 CA 8497102)
Topics: Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Keywords: HER2 mutation, lung adenocarcinoma, non-small cell lung cancer, EGFR mutation, KRAS mutation, tyrosine kinase domain, never smokers, ethnic differences in mutation frequency, lung cancer etiology, EGFR kinase inhibitors
MeSH terms: Adenocarcinoma, Aged, Aged, 80 and over, Amino Acid Sequence, Female, Humans, Lung Neoplasms, Male, Middle Aged, Molecular Sequence Data, Mutation, Neoplasms, Glandular and Epithelial, Genes, ras, Sequence Homology, Amino Acid, Genes, erbB-2, Genes, erbB-1

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Somatic Mutations of the HER2 Kinase Domain in Lung Adenocarcinomas

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