title: High throughput molecular profiling reveals differential mutation patterns in intrahepatic cholangiocarcinomas arising in chronic advanced liver diseases.
abstract: Intrahepatic cholangiocarcinomas occur mostly in the normal liver but they also arise in chronic advanced liver diseases. However, genetic differences between two groups have yet to be examined. High throughput mass spectrometry-based platform was used to interrogate mutations in intrahepatic cholangiocarcinomas and to compare the mutation profiles between 43 intrahepatic cholangiocarcinomas with normal liver and 38 with chronic advanced liver diseases. Forty seven mutations in 11 genes were identified in 38 of 81 cases (46.9%). The most commonly mutated gene was KRAS (11/81, 13.6%), followed by MLH1 (7/81, 8.6%), NRAS (7/81, 8.6%), GNAS (6/81, 7.4%), and EGFR (6/81, 7.4%). BRAF, APC, PIK3CA, CDKN2A, PTEN, and TP53 mutations were found with less than 5%. Overall mutation rate of intrahepatic cholangiocarcinomas with chronic advanced liver disease (15/38, 39.5%, 95% confidence interval: 23.9-55.0) was lower than that of intrahepatic cholangiocarcinomas with normal liver (23/43, 53.5%, 95% confidence interval: 38.5-68.3). Intrahepatic cholangiocarcinomas with chronic advanced liver disease showed higher EGFR mutation rate (5/38, 13.2% vs 1/43, 2.3%) and lower mutation rates of KRAS (3/38, 7.9% vs 8/43, 18.6%), MLH1 (2/38, 5.3% vs 5/43, 11.6%), and GNAS (1/38, 2.6% vs 5/43, 11.6%), compared with those in intrahepatic cholangiocarcinomas with normal liver. Mutations in PIK3CA, PTEN, CDKN2A, and TP53 were harbored only in intrahepatic cholangiocarcinomas with normal liver. KRAS (P=0.0075) or GNAS mutations (P=0.0256) were associated with poor overall survival in all patients with intrahepatic cholangiocarcinoma. Differential mutation patterns of intrahepatic cholangiocarcinomas with chronic advanced liver disease suggest different cholangiocarcinogenesis depending upon the predisposing factors, and support that different strategy for targeted therapy should be applied in intrahepatic cholangiocarcinoma subtypes.
authors.affiliation: 1] Department of Pathology, University of Ulsan College of Medicine, ASAN Medical Center, Seoul, Korea [2] ASAN Center for Cancer Genome Discovery, ASAN Institute for Life Sciences, University of Ulsan College of Medicine, ASAN Medical Center, Seoul, Korea.
authors.forename: Sejin
authors.initials: S
authors.lastname: Jang
authors.affiliation: 1] Department of Pathology, University of Ulsan College of Medicine, ASAN Medical Center, Seoul, Korea [2] ASAN Center for Cancer Genome Discovery, ASAN Institute for Life Sciences, University of Ulsan College of Medicine, ASAN Medical Center, Seoul, Korea.
authors.forename: Sung-Min
authors.initials: SM
authors.lastname: Chun
authors.affiliation: Department of Pathology, University of Ulsan College of Medicine, ASAN Medical Center, Seoul, Korea.
authors.forename: Seoung-Mo
authors.initials: SM
authors.lastname: Hong
authors.affiliation: Department of Pathology, University of Ulsan College of Medicine, ASAN Medical Center, Seoul, Korea.
authors.forename: Chang Ohk
authors.initials: CO
authors.lastname: Sung
authors.affiliation: Department of Pathology, University of Ulsan College of Medicine, ASAN Medical Center, Seoul, Korea.
authors.forename: Hosub
authors.initials: H
authors.lastname: Park
authors.affiliation: Department of Pathology, University of Ulsan College of Medicine, ASAN Medical Center, Seoul, Korea.
authors.forename: Hyo Jeong
authors.initials: HJ
authors.lastname: Kang
authors.affiliation: Department of Internal Medicine, University of Ulsan College of Medicine, ASAN Medical Center, Seoul, Korea.
authors.forename: Kyu-pyo
authors.initials: KP
authors.lastname: Kim
authors.affiliation: Department of Surgery, University of Ulsan College of Medicine, ASAN Medical Center, Seoul, Korea.
authors.forename: Young Joo
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: 1] Department of Pathology, University of Ulsan College of Medicine, ASAN Medical Center, Seoul, Korea [2] ASAN Center for Cancer Genome Discovery, ASAN Institute for Life Sciences, University of Ulsan College of Medicine, ASAN Medical Center, Seoul, Korea.
authors.forename: Eunsil
authors.initials: E
authors.lastname: Yu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000328:Adult; D000368:Aged; D001650:Bile Duct Neoplasms / Q000235:genetics* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000473:pathology; D018281:Cholangiocarcinoma / Q000235:genetics* / Q000473:pathology; D002864:Chromogranins; D004252:DNA Mutational Analysis; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics; D006801:Humans; D008107:Liver Diseases / Q000235:genetics* / Q000473:pathology; D008297:Male; D013058:Mass Spectrometry; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002864:Chromogranins; C117307:KRAS protein, human; C501486:MLH1 protein, human; D008565:Membrane Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors; C406732:GNAS protein, human; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D000070957:MutL Protein Homolog 1; D019205:GTP-Binding Protein alpha Subunits, Gs; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins