title: Genomic and transcriptional alterations of cholangiocarcinoma.
abstract: Cholangiocarcinoma (CCA) is one of the representative cancers refractory to any therapeutic approach. The incidence of CCA is highest in the northeastern part of Thailand, where chronic inflammation caused by liver fluke (Opisthorchis viverrini: Ov) infection is a major etiologic factor. The incidence of CCA is also increasing in other countries, including Japan. Here, we overview the genetic and transcriptional alterations of CCA with and without association with Ov infection. CCA with Ov shows enhanced expression of the genes involved in xenobiotic metabolism and chronic inflammatory responses, including cytokine signaling, whereas CCA without Ov shows enhanced expression of growth factor signaling, such as HER2. Exome and the following prevalence sequencing identified mutations of the BAP1, ARID1A, IDH1 and IDH2 genes in CCA, in addition to the high incidence of known mutations in the TP53, KRAS2 SMAD4, and CDKN2A genes, suggesting the role of chromatin modulators in CCA pathogenesis. CCA with Ov shows significantly higher incidence of the TP53 gene mutation, whereas CCA without Ov showed significantly more frequent mutations of the BAP1, IDH1 and IDH2 genes. However, CCAs with Ov and without Ov share a similar mutation spectrum dominated by C : G > T : A transitions mainly at CpG dinucleotides, suggesting that CCA shares etiologic factors with pancreatic ductal carcinoma but not with hepatocellular carcinoma. Comprehensive analyses of the genetic and transcriptional alterations of CCA with and without Ov infection would provide useful information for the prevention, early diagnosis, and treatment of CCA.
authors.affiliation: Division of Molecular Pathology, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan. ymurakam@ims.u-tokyo.ac.jp.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ito
authors.forename: Mika
authors.initials: M
authors.lastname: Sakurai-Yageta
authors.forename: Akiteru
authors.initials: A
authors.lastname: Goto
authors.forename: Chawalit
authors.initials: C
authors.lastname: Pairojkul
authors.forename: Puangrat
authors.initials: P
authors.lastname: Yongvanit
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Murakami
mesh_terms: D000818:Animals; D001650:Bile Duct Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic; D018281:Cholangiocarcinoma / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D014644:Genetic Variation / Q000235:genetics; D023281:Genomics; D006801:Humans; D007564:Japan / Q000453:epidemiology; D008297:Male; D009891:Opisthorchis / Q000302:isolation & purification; D013785:Thailand / Q000453:epidemiology; D015533:Transcriptional Activation / Q000235:genetics
keywords: Cholangiocarcinoma; KRAS; Liver fluke; Opisthorchis viverrini; TP53