Abstract LB-291: Novel germline G660D mutation in HER2 gene detected by whole-exome sequencing can predispose a patient to developing familial lung adenocarcinoma

Abstract

Abstract Familial cancers arising from several organs are often reported including breast and colon cancers, although familial lung cancers are few reported. We encountered a family of Japanese descent in which multiple members developed lung adenocarcinomas. 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 same 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, an effector kinase regarding to cell survival. In addition, they activated the other kinase, p38 at a remarkable level, which is thought to promote critically cell proliferation in lung adenocarcinoma. Coupling experiments revealed that mutant HER2 avidly dimerized with EGFR, HER3 and HER4 in the same manner to those with wild type HER2. The formation of mutant HER2 homodimers was also observed, whereas we less detected homodimers of wild type HER2. Our findings strongly suggest that mutations in the transmembrane domain of HER2 are oncogenic, causing hereditary and sporadic lung adenocarcinomas. Citation Format: Hiromasa Yamamoto, Koichiro Higasa, Masakiyo Sakaguchi, Kazuhiko Shien, Junichi Soh, Koichi Ichimura, Masashi Furukawa, Shinsuke Hashida, Kazunori Tsukuda, Nagio Takigawa, Keitaro Matsuo, Katsuyuki Kiura, Sinichiro Miyoshi, Fumihiko Matsuda, Shinichi Toyooka. Novel germline G660D mutation in HER2 gene detected by whole-exome sequencing can predispose a patient to developing familial lung adenocarcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-291. doi:10.1158/1538-7445.AM2014-LB-291