Novel germline mutation in the transmembrane domain of HER2 in familial lung adenocarcinomas.
Novel germline mutation in the transmembrane domain of HER2 in familial lung adenocarcinomas.
复制标题
DOI：
10.1093/jnci/djt338
复制
发表时间：
2014-01
期刊：
影响因子：
--
通讯作者：
Toyooka S
中科院分区：
文献类型：
--
作者：
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
我们遇到了一个日本血统的家庭，其中多名成员患上了肺癌。通过全外显子测序，我们在人表皮生长因子受体2(HER2)基因(G660D)的跨膜区发现了一个新的胚系突变。在253例散发性肺腺癌中发现一例新的体细胞突变(V659E)，位于HER2的跨膜区。由于HER2的跨膜结构域被认为与HER家族及其下游信号通路的二聚化和随后的激活有关，因此我们对这些HER2突变体进行了功能分析。突变的HER2、G660D和V659E蛋白比野生型蛋白更稳定。G660D和V659E突变体均激活Akt。此外，他们还激活了被认为促进肺腺癌细胞增殖的p38。我们的发现强烈表明，HER2跨膜区的突变可能是致癌的，导致遗传性和散发性肺腺癌。
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.