Whole-exome mutational landscape of neuroendocrine carcinomas of the gallbladder  

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

机构地区：[1]Department of General Surgery,Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,Yangpu District,Shanghai 200092,China [2]Shanghai Key Laboratory of Biliary Tract Disease,Yangpu District,Shanghai 200092,China [3]State Key Laboratory of Oncogenes and Related Genes,Shanghai,China [4]Shanghai Research Center of Biliary Tract Disease,Yangpu District,Shanghai 200092,China [5]Department of Biliary-Pancreatic Surgery,Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,Shanghai,China [6]Department of Minimal Invasive Surgery,Ningbo Medical Center Lihuili Hospital,Ningbo,Zhejiang 315040,China [7]Department of hepatopancreatobiliary surgery,Ganzhou hospital affiliated to Nanchang university,Jiangxi 341000,China [8]Department of Pediatric Surgery,Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,Yangpu District,Shanghai 200092,China [9]Information and Big Data Center,Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,Yangpu District,Shanghai 200092,China [10]Department of Surgery,Second Affiliated Hospital,School of Medicine,Zhejiang University,Hangzhou,Zhejiang 310009,China [11]Department of Gastric Surgery,Cancer Hospital of the University of Chinese Academy of Sciences,Hangzhou,Zhejiang 310022,China

出　　处：《Signal Transduction and Targeted Therapy》2021年第3期897-908,共12页信号转导与靶向治疗（英文）

基　　金：supported by the National Natural Science Foundation of China(Nos.81902361,31620103910,81874181,91940305,and 81702381);the Shanghai Sailing Program(19YF1433000);the Shanghai Artificial Intelligence Innovation and Development Project(2019-RGZN-01096);the Medical Science and Technology Project of Zhejiang Provincial Health Commission(No.2019334001);the Medical Science and Technology Program of Ningbo(No.2019Y06);the Natural Science Foundation of Ningbo(No.2019A610208);the Shanghai Key Laboratory of Biliary Tract Disease Research Foundation(17DZ2260200);appreciate the support from the Youth Science and Technology Innovation Studio of Shanghai Jiao Tong University School of Medicine(JYKCGZS04).

摘　　要：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.Inthe present study,we applied whole-exome sequencing(WES)technology to detect gene mutations and predicted somatic singlenucleotide variants(SNVs)in 15 cases of GB-NEC and 22 cases of general GBC.in 15 GB-NECs,the C>T mutation was predominantamong the 6 types of SNVs.TP53 showed the highest mutation frequency(73%,11/15).Compared with neuroendocrine carcinomasof other organs,signifcantly mutated genes(SMGs)in GB-NECs were more similar to those in pulmonary large-cell euroendocrinecarcinomas(LCNECs),with drver roles for TP53 and RB1.Iin 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 ERB82 and ERBB3,were identified exclusively in GBC.Mutations in RB1 and NAB2 were significanty related to downregulation of the RB1 and NAB2 proteins,respectively,according to immunohistochemical(IHC)data(p values=0.0453 and0.0303).Clinically actionable genes indicated 23 mutated genes,including ALK,BRCA1,and BRCA2.Iin addition,potential somaticSNVs predicted by ISowN and SomVarlUS 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-RASpathways.In summary,we have systematically identified the mutation landscape of GB-NEC,and these findings may providemechanistic insights into the specifc pathogenesis of this deadly disease.

关 键 词：GALLBLADDER CARCINOMAS ORGANS 

分 类 号：R735.8[医药卫生—肿瘤]