Whole-exome mutational landscape of neuroendocrine carcinomas of the gallbladder

Fatao Liu,Yongsheng Li,Liguo Liu,Dongjian Ying,Jiasheng Mu,Wei Jin,Yun Liu,Yingbin Liu,Guoqiang Li,Maolan Li,Shimei Qiu,Weihua Pan,Yong He,Yijian Zhang,Qin Zhu,Yunping Hu,Yang Cao

doi:10.1038/s41392-020-00412-3

Abstract

Neuroendocrine carcinoma (NEC) of the gallbladder (GB-NEC) is a rare but extremely malignant subtype of gallbladder cancer (GBC). The genetic and molecular signatures of GB-NEC are poorly understood; thus, molecular targeting is currently unavailable. In the present study, we applied whole-exome sequencing (WES) technology to detect gene mutations and predicted somatic single-nucleotide variants (SNVs) in 15 cases of GB-NEC and 22 cases of general GBC. In 15 GB-NECs, the C > T mutation was predominant among the 6 types of SNVs. TP53 showed the highest mutation frequency (73%, 11/15). Compared with neuroendocrine carcinomas of other organs, significantly mutated genes (SMGs) in GB-NECs were more similar to those in pulmonary large-cell neuroendocrine carcinomas (LCNECs), with driver roles for TP53 and RB1. In the COSMIC database of cancer-related genes, 211 genes were mutated. Strikingly, RB1 (4/15, 27%) and NAB2 (3/15, 20%) mutations were found specifically in GB-NECs; in contrast, mutations in 29 genes, including ERBB2 and ERBB3, were identified exclusively in GBC. Mutations in RB1 and NAB2 were significantly related to downregulation of the RB1 and NAB2 proteins, respectively, according to immunohistochemical (IHC) data (p values = 0.0453 and 0.0303). Clinically actionable genes indicated 23 mutated genes, including ALK, BRCA1, and BRCA2. In addition, potential somatic SNVs predicted by ISOWN and SomVarIUS constituted 6 primary COSMIC mutation signatures (1, 3, 30, 6, 7, and 13) in GB-NEC. Genes carrying somatic SNVs were enriched mainly in oncogenic signaling pathways involving the Notch, WNT, Hippo, and RTK-RAS pathways. In summary, we have systematically identified the mutation landscape of GB-NEC, and these findings may provide mechanistic insights into the specific pathogenesis of this deadly disease.

Highlights

Gallbladder cancer (GBC), a type of biliary tract cancer (BTC), accounts for 1.7% of all global cancer-related deaths.[1]
of WES data analysis results The genome-wide distribution of the mutations was visualized as a CIRCOS figure using ClicO FS.[52]. Maftools[53] was applied for the analysis
Pfam domains with significant mutations

Summary

Introduction

Gallbladder cancer (GBC), a type of biliary tract cancer (BTC), accounts for 1.7% of all global cancer-related deaths.[1] Neuroendocrine carcinoma (NEC) of the gallbladder (GB-NEC) is rare but more malignant than GBC, accounting for less than 1% of GBCs and is identified mostly in women.[2,3,4] Given that the symptoms of GBNEC are similar to those of other types of GBC, specific methods to distinguish it from other subtypes are currently lacking.[5] As a result, pathologic studies using immunohistochemical (IHC) of biopsy tissue currently serve as the first-line tool to diagnose the disease in combination with routine imaging examinations, including ultrasound, CT and MRI, and general serum markers.[6]. Since we lack sufficient knowledge on the pathologic mechanisms that govern the malignant transformation of GB-NEC, the only acceptable therapeutic modality for GB-NEC is the removal of the entire GB

Methods

Results

Discussion

Conclusion