title: Whole-exome and targeted gene sequencing of gallbladder carcinoma identifies recurrent mutations in the ErbB pathway.
abstract: Individuals with gallbladder carcinoma (GBC), the most aggressive malignancy of the biliary tract, have a poor prognosis. Here we report the identification of somatic mutations for GBC in 57 tumor-normal pairs through a combination of exome sequencing and ultra-deep sequencing of cancer-related genes. The mutation pattern is defined by a dominant prevalence of C>T mutations at TCN sites. Genes with a significant frequency (false discovery rate (FDR)<0.05) 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) is the most extensively mutated pathway, affecting 36.8% (21/57) of the GBC samples. Multivariate analyses further show that cases with ErbB pathway mutations have a worse outcome (P=0.001). These findings provide insight into the somatic mutational landscape in GBC and highlight the key role of the ErbB signaling pathway in GBC pathogenesis.
authors.affiliation: 1] Department of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. [2] Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [3].
authors.forename: Maolan
authors.initials: M
authors.lastname: Li
authors.affiliation: 1] Department of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. [2] Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [3] Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Center, Shanghai Jiao Tong University, Shanghai, China. [4].
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: 1] Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China. [2].
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Li
authors.affiliation: Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
authors.forename: Junyi
authors.initials: J
authors.lastname: Ye
authors.affiliation: 1] Department of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. [2] Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Xiangsong
authors.initials: X
authors.lastname: Wu
authors.affiliation: 1] Department of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. [2] Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Zhujun
authors.initials: Z
authors.lastname: Tan
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, China.
authors.forename: Chang
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Baiyong
authors.initials: B
authors.lastname: Shen
authors.affiliation: 1] Department of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. [2] Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Xu-An
authors.initials: XA
authors.lastname: Wang
authors.affiliation: 1] Department of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. [2] Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Wenguang
authors.initials: W
authors.lastname: Wu
authors.affiliation: Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Center, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Daizhan
authors.initials: D
authors.lastname: Zhou
authors.affiliation: Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Center, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Di
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Center, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Bingya
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Qu
authors.affiliation: 1] Department of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. [2] Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Qichen
authors.initials: Q
authors.lastname: Ding
authors.affiliation: 1] Department of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. [2] Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Weng
authors.affiliation: 1] Department of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. [2] Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Ding
authors.affiliation: 1] Department of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. [2] Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jiasheng
authors.initials: J
authors.lastname: Mu
authors.affiliation: 1] Department of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. [2] Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yijun
authors.initials: Y
authors.lastname: Shu
authors.affiliation: 1] Department of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. [2] Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Runfa
authors.initials: R
authors.lastname: Bao
authors.affiliation: 1] Department of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. [2] Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
authors.forename: Peizhan
authors.initials: P
authors.lastname: Chen
authors.affiliation: 1] Department of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. [2] Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Tianyu
authors.initials: T
authors.lastname: Liu
authors.affiliation: 1] Department of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. [2] Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Jiang
authors.affiliation: 1] Department of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. [2] Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yunping
authors.initials: Y
authors.lastname: Hu
authors.affiliation: 1] Department of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. [2] Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Dong
authors.affiliation: 1] Department of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. [2] Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Gu
authors.affiliation: 1] Department of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. [2] Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
authors.affiliation: 1] Department of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. [2] Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Weibin
authors.initials: W
authors.lastname: Shi
authors.affiliation: 1] Department of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. [2] Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Lu
authors.affiliation: 1] Department of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. [2] Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Gong
authors.affiliation: 1] Department of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. [2] Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Tang
authors.affiliation: 1] Department of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. [2] Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: 1] Department of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. [2] Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Wang
authors.affiliation: Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Y Eugene
authors.initials: YE
authors.lastname: Chin
authors.affiliation: Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Weng
authors.affiliation: Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Tang
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Yonglan
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: 1] Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Center, Shanghai Jiao Tong University, Shanghai, China. [2] Institutes of Biomedical Sciences, Fudan University, Shanghai, China. [3] Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Lin
authors.initials: L
authors.lastname: He
authors.affiliation: 1] Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China. [2] Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing, China. [3].
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: 1] Institutes of Biomedical Sciences, Fudan University, Shanghai, China. [2].
authors.forename: Yun
authors.initials: Y
authors.lastname: Liu
authors.affiliation: 1] Department of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. [2] Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [3].
authors.forename: Yingbin
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002277:Carcinoma / Q000201:enzymology / Q000235:genetics*; D002460:Cell Line; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000235:genetics*; D059472:Exome; D005260:Female; D005706:Gallbladder Neoplasms / Q000201:enzymology / Q000235:genetics*; D057809:HEK293 Cells; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000201:enzymology / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics
chemical_list: C512478:EGFR protein, human; D066246:ErbB Receptors