title: Mutational landscape of intrahepatic cholangiocarcinoma.
abstract: Intrahepatic cholangiocarcinoma (ICC) is a fatal primary liver cancer (PLC) that affects 5-10% of all PLCs. Here we sequence tumour and matching control sample pairs of a large cohort of 103 ICC patients in China, resulting in the identification of an ICC-specific somatic mutational signature that is associated with liver inflammation, fibrosis and cirrhosis. We further uncover 25 significantly mutated genes including eight potential driver genes (TP53, KRAS, IDH1, PTEN, ARID1A, EPPK1, ECE2 and FYN). We find that TP53-defective ICC patients are more likely to be HBsAg-seropositive, whereas mutations in the oncogene KRAS are nearly exclusively found in HBsAg-seronegative ICC patients. Three pathways (Ras/phosphatidylinositol-4,5-bisphosphate 3-kinase signalling, p53/cell cycle signalling and transforming growth factor-β/Smad signalling), genes important for epigenetic regulation and oxidative phosphorylation are substantially affected in ICC. We reveal mutations in this study that may be valuable for designing further studies, better diagnosis and effective therapies.
authors.affiliation: Department of Hepatobiliary Medicine I, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Zou
authors.affiliation: 1] Department of Molecular Biology and Biochemistry, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia V5A 1S6, Canada [2] Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China.
authors.forename: Jiarui
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Hepatobiliary Medicine I, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.
authors.forename: Huabang
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia V5A 1S6, Canada.
authors.forename: Christian
authors.initials: C
authors.lastname: Frech
authors.affiliation: Department of Hepatobiliary Medicine I, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Wuhan Frasergen Bioinformatics Co. Ltd, 666 Gaoxin Road, East Lake High-tech Zone, Wuhan 430075, China.
authors.forename: Jeffrey S C
authors.initials: JS
authors.lastname: Chu
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia V5A 1S6, Canada.
authors.forename: Xinyin
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Hepatobiliary Medicine I, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.
authors.forename: Yuqiong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Hepatobiliary Medicine I, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.
authors.forename: Qiaomei
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Hepatobiliary Medicine I, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: School of Medicine, Jiao Tong University, Shanghai 200025, China.
authors.forename: Jingyi
authors.initials: J
authors.lastname: Hu
authors.affiliation: Wuhan Frasergen Bioinformatics Co. Ltd, 666 Gaoxin Road, East Lake High-tech Zone, Wuhan 430075, China.
authors.forename: Guanyi
authors.initials: G
authors.lastname: Kong
authors.affiliation: Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.
authors.forename: Mengchao
authors.initials: M
authors.lastname: Wu
authors.affiliation: Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China.
authors.forename: Chuanfan
authors.initials: C
authors.lastname: Ding
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia V5A 1S6, Canada.
authors.forename: Nansheng
authors.initials: N
authors.lastname: Chen
authors.affiliation: Department of Hepatobiliary Medicine I, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.
authors.forename: Heping
authors.initials: H
authors.lastname: Hu
mesh_terms: D000328:Adult; D000368:Aged; D001650:Bile Duct Neoplasms / Q000235:genetics*; D001653:Bile Ducts, Intrahepatic; D002681:China; D018281:Cholangiocarcinoma / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins