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Somatic Mutations of the HER2 Kinase Domain in Lung Adenocarcinomas

¹ Hamon Center for Therapeutic Oncology Research, Departments of ² Internal Medicine, ³ Pharmacology, and ⁴ Pathology, University of Texas Southwestern Medical Center, Dallas, Texas; ⁵ Department of Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan; ⁶ Institute of Medical and Molecular Toxicology, Chung Shan Medical University, Taichung, Taiwan; ⁷ Department of Pathology and Thoracic/Head and Neck Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas; ⁸ Prince Charles Hospital, Brisbane, Australia; and ⁹ Department of Cancer and Thoracic Surgery, Graduate School of Medicine and Dentistry, Okayama University, Okayama, Japan

Requests for reprints: Adi F. Gazdar, Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas TX, 75390-8593. Phone: 214-648-4921; Fax: 214-648-4940; E-mail: adi.gazdar{at}utsouthwestern.edu.

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.

Key Words: HER2 • EGFR • KRAS • mutation • lung cancer

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