Novel Germline Mutation in the Transmembrane Domain of HER2 in Familial Lung Adenocarcinomas

• Published in: JNCI : Journal of the National Cancer Institute Vol. 106; no. 1; p. djt338
• Main Authors: YAMAMOTO, Hiromasa, HIGASA, Koichiro, MATSUO, Keitaro, KIURA, Katsuyuki, MIYOSHI, Shinichiro, MATSUDA, Fumihiko, TOYOOKA, Shinichi, SAKAGUCHI, Masakiyo, SHIEN, Kazuhiko, SOH, Junichi, ICHIMURA, Koichi, FURUKAWA, Masashi, HASHIDA, Shinsuke, TSUKUDA, Kazunori, TAKIGAWA, Nagio
• Format: Journal Article
• Language: English
• Published: Cary, NC Oxford University Press 01-01-2014; Oxford Publishing Limited (England)
• Subjects: Adenocarcinoma - genetics; Adenocarcinoma of Lung; Adult; Asian Continental Ancestry Group - genetics; Aspartic Acid; Biological and medical sciences; Brief Communication; Epidermal growth factor; Female; Genetic Predisposition to Disease; Genetics; Genomics; Germ-Line Mutation; Glutamic Acid; Glycine; Humans; Japan; Lung cancer; Lung Neoplasms - genetics; Male; Medical sciences; Membranes; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Mutation; Pedigree; Pneumology; Proteins; Receptor, ErbB-2 - genetics; Tumors; Tumors of the respiratory system and mediastinum; Valine; Japan; Lung disease; Respiratory disease; Lung cancer; erbB2 Gene; Malignant tumor; Bronchopulmonary adenocarcinoma; Human Epidermal growth factor Receptor 2; Cancerology; C-Onc gene; Germ line; Bronchus disease; Genetics; Mutation; Protooncogene; Cancer
• ISSN: 0027-8874; 1460-2105
• DOI: 10.1093/jnci/djt338

We encountered a family of Japanese descent in which multiple members developed lung cancer. Using whole-exome sequencing, we identified a novel germline mutation in the transmembrane domain of the human epidermal growth factor receptor 2 (HER2) gene (G660D). A novel somatic mutation (V659E) was also detected in the transmembrane domain of HER2 in one of 253 sporadic lung adenocarcinomas. Because the transmembrane domain of HER2 is considered to be responsible for the dimerization and subsequent activation of the HER family and downstream signaling pathways, we performed functional analyses of these HER2 mutants. Mutant HER2 G660D and V659E proteins were more stable than wild-type protein. Both the G660D and V659E mutants activated Akt. In addition, they activated p38, which is thought to promote cell proliferation in lung adenocarcinoma. Our findings strongly suggest that mutations in the transmembrane domain of HER2 may be oncogenic, causing hereditary and sporadic lung adenocarcinomas.