title: Integrative molecular analysis of intrahepatic cholangiocarcinoma reveals 2 classes that have different outcomes.
abstract: OBJECTIVE
  Cholangiocarcinoma, the second most common liver cancer, can be classified as intrahepatic cholangiocarcinoma (ICC) or extrahepatic cholangiocarcinoma. We performed an integrative genomic analysis of ICC samples from a large series of patients.
  
  
  METHODS
  We performed a gene expression profile, high-density single-nucleotide polymorphism array, and mutation analyses using formalin-fixed ICC samples from 149 patients. Associations with clinicopathologic traits and patient outcomes were examined for 119 cases. Class discovery was based on a non-negative matrix factorization algorithm and significant copy number variations were identified by Genomic Identification of Significant Targets in Cancer (GISTIC) analysis. Gene set enrichment analysis was used to identify signaling pathways activated in specific molecular classes of tumors, and to analyze their genomic overlap with hepatocellular carcinoma (HCC).
  
  
  RESULTS
  We identified 2 main biological classes of ICC. The inflammation class (38% of ICCs) is characterized by activation of inflammatory signaling pathways, overexpression of cytokines, and STAT3 activation. The proliferation class (62%) is characterized by activation of oncogenic signaling pathways (including RAS, mitogen-activated protein kinase, and MET), DNA amplifications at 11q13.2, deletions at 14q22.1, mutations in KRAS and BRAF, and gene expression signatures previously associated with poor outcomes for patients with HCC. Copy number variation-based clustering was able to refine these molecular groups further. We identified high-level amplifications in 5 regions, including 1p13 (9%) and 11q13.2 (4%), and several focal deletions, such as 9p21.3 (18%) and 14q22.1 (12% in coding regions for the SAV1 tumor suppressor). In a complementary approach, we identified a gene expression signature that was associated with reduced survival times of patients with ICC; this signature was enriched in the proliferation class (P < .001).
  
  
  CONCLUSIONS
  We used an integrative genomic analysis to identify 2 classes of ICC. The proliferation class has specific copy number alterations, activation of oncogenic pathways, and is associated with worse outcome. Different classes of ICC, based on molecular features, therefore might require different treatment approaches.
authors.affiliation: Barcelona-Clínic Liver Cancer Group (HCC Translational Research Laboratory, Liver Unit, Pathology Department), Institut d'Investigacions Biomèdiques August Pi I Sunyer, Liver Unit, Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain.
authors.forename: Daniela
authors.initials: D
authors.lastname: Sia
authors.forename: Yujin
authors.initials: Y
authors.lastname: Hoshida
authors.forename: Augusto
authors.initials: A
authors.lastname: Villanueva
authors.forename: Sasan
authors.initials: S
authors.lastname: Roayaie
authors.forename: Joana
authors.initials: J
authors.lastname: Ferrer
authors.forename: Barbara
authors.initials: B
authors.lastname: Tabak
authors.forename: Judit
authors.initials: J
authors.lastname: Peix
authors.forename: Manel
authors.initials: M
authors.lastname: Sole
authors.forename: Victoria
authors.initials: V
authors.lastname: Tovar
authors.forename: Clara
authors.initials: C
authors.lastname: Alsinet
authors.forename: Helena
authors.initials: H
authors.lastname: Cornella
authors.forename: Brandy
authors.initials: B
authors.lastname: Klotzle
authors.forename: Jian-Bing
authors.initials: JB
authors.lastname: Fan
authors.forename: Christian
authors.initials: C
authors.lastname: Cotsoglou
authors.forename: Swan N
authors.initials: SN
authors.lastname: Thung
authors.forename: Josep
authors.initials: J
authors.lastname: Fuster
authors.forename: Samuel
authors.initials: S
authors.lastname: Waxman
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Garcia-Valdecasas
authors.forename: Jordi
authors.initials: J
authors.lastname: Bruix
authors.forename: Myron E
authors.initials: ME
authors.lastname: Schwartz
authors.forename: Rameen
authors.initials: R
authors.lastname: Beroukhim
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Mazzaferro
authors.forename: Josep M
authors.initials: JM
authors.lastname: Llovet
mesh_terms: D000368:Aged; D001650:Bile Duct Neoplasms; D001653:Bile Ducts, Intrahepatic; D001707:Biopsy, Needle; D018281:Cholangiocarcinoma / Q000145:classification / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D016208:Databases, Factual; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000145:classification / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012189:Retrospective Studies; D016019:Survival Analysis