title: Novel germline mutation in the transmembrane domain of HER2 in familial lung adenocarcinomas.
abstract: 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.
authors: Affiliations of authors: Department of Thoracic, Breast and Endocrinological Surgery (HY, KS, JS, MF, SH, KT, SM, ST), Department of Clinical Genomic Medicine (KS, ST), Department of Cell Biology (MS), Department of Pathology (KI), and Department of Hematology, Oncology and Respiratory Medicine (KK), Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; Center for Genomic Medicine, Kyoto University School of Medicine, Kyoto, Japan (KH, FM); Department of General Internal Medicine 4, Kawasaki Medical School, Okayama, Japan (NT); Department of Preventive Medicine, Kyushu University Faculty of Medical Sciences, Fukuoka, Japan (KM).
authors: Hiromasa
authors: H
authors: Yamamoto
authors: Koichiro
authors: K
authors: Higasa
authors: Masakiyo
authors: M
authors: Sakaguchi
authors: Kazuhiko
authors: K
authors: Shien
authors: Junichi
authors: J
authors: Soh
authors: Koichi
authors: K
authors: Ichimura
authors: Masashi
authors: M
authors: Furukawa
authors: Shinsuke
authors: S
authors: Hashida
authors: Kazunori
authors: K
authors: Tsukuda
authors: Nagio
authors: N
authors: Takigawa
authors: Keitaro
authors: K
authors: Matsuo
authors: Katsuyuki
authors: K
authors: Kiura
authors: Shinichiro
authors: S
authors: Miyoshi
authors: Fumihiko
authors: F
authors: Matsuda
authors: Shinichi
authors: S
authors: Toyooka
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000077192:Adenocarcinoma of Lung; D000328:Adult; D044466:Asian People / Q000235:genetics; D001224:Aspartic Acid; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D018698:Glutamic Acid; D005998:Glycine; D006801:Humans; D007564:Japan; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D014633:Valine
chemical_list: D001224:Aspartic Acid; D018698:Glutamic Acid; D005998:Glycine; D018719:Erb-b2 Receptor Tyrosine Kinases; D014633:Valine; C508053:ERBB2 protein, human