Novel germline mutation in the transmembrane domain of HER2 in familial lung adenocarcinomas

Hiromasa Yamamoto, Koichiro Higasa, Masakiyo Sakaguchi, Kazuhiko Shien, Junichi Soh, Koichi Ichimura, Masashi Furukawa, Shinsuke Hashida, Kazunori Tsukuda, Nagio Takigawa, Keitaro Matsuo, Katsuyuki Kiura, Shinichiro Miyoshi, Fumihiko Matsuda, Shinichi Toyooka

Research output: Contribution to journalArticle

64 Citations (Scopus)

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.

Original languageEnglish
Article numberdjt338
JournalJournal of the National Cancer Institute
Volume106
Issue number1
DOIs
Publication statusPublished - Jan 24 2014

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Novel germline mutation in the transmembrane domain of HER2 in familial lung adenocarcinomas'. Together they form a unique fingerprint.

  • Cite this

    Yamamoto, H., Higasa, K., Sakaguchi, M., Shien, K., Soh, J., Ichimura, K., Furukawa, M., Hashida, S., Tsukuda, K., Takigawa, N., Matsuo, K., Kiura, K., Miyoshi, S., Matsuda, F., & Toyooka, S. (2014). Novel germline mutation in the transmembrane domain of HER2 in familial lung adenocarcinomas. Journal of the National Cancer Institute, 106(1), [djt338]. https://doi.org/10.1093/jnci/djt338