Introduction : To profile the somatic mutation spectrum in gallbladder cancers(GBCs), to determine the oncogenic effects of the ERBB3 and ERBB2 mutations, and to find whether targeted therapy focus on ERBB signaling pathway is available for these kind of GBC patients.

Methods : We performed a combination of exome sequencing and ultra-deep sequencing of cancer-related genes on 57 tumor-normal pairs. The mutation pattern is defined by a dominant prevalence of C>T mutations at TCN sites.Three patients with staged IV GBCs and ERBB signaling pathway mutated who were not benefit from traditional chemo-radio therapy, were treated with ERBB signaling pathway targeted therapy.

Results : Genes with a significant frequency of non-silent mutations include TP53 (47.1%), KRAS (7.8%) and ERBB3 (11.8%). Moreover, ErbB signaling (including EGFR, ERBB2, ERBB3, ERBB4 and their downstream genes) , which have not been described previously in GBC, is the most extensively mutated pathway, affecting 36.8% (21/57) of the GBC samples. Multivariate analyses further show that the mutations have a worse outcome. Over-expression of each ERBB mutant resulted in a significant increase in proliferation in at least one cell line.The tumor maker expression including CA-199 and CA-125 had a different level of decline.The primary or metastasis tumor size also revealed a trend of decrease. And the average survival time have exceeded more than 12months.

Conclusions : Our findings provide insight into the somatic mutational landscape in GBC and highlight the key role of the ErbB signaling pathway in GBC pathogenesis.And our results suggest that patients harboring mutations in the ErbB pathway might benefit from targeted therapies.