title: Cholangiocarcinoma Heterogeneity Revealed by Multigene Mutational Profiling: Clinical and Prognostic Relevance in Surgically Resected Patients.
abstract: BACKGROUND
  Cholangiocarcinoma can be classified in intrahepatic cholangiocarcinoma (ICC) and perihilar cholangiocarcinoma (PCC). Moreover, PCC includes two different forms: extrahepatic (EH) PCC, which arises from the perihilar EH large ducts, and intrahepatic (IH) PCC, in which a significant liver mass invades the perihilar bile ducts. In this study, we investigated the molecular profile and molecular prognostic factors in EH-PCC, IH-PCC, and ICC submitted to curative surgery.
  
  
  METHODS
  Ninety-one patients with cholangiocarcinoma (38 EH-PCC, 18 IH-PCC, and 35 ICC), who underwent curative surgery in a single tertiary hepatobiliary surgery referral center were assessed for mutational status in 56 cancer-related genes.
  
  
  RESULTS
  The most frequently mutated genes in EH-PCC were KRAS (47.4 %), TP53 (23.7 %) and ARID1A (15.8 %); in IH-PCC were KRAS (22.2 %), PBRM1 (16.7 %), and PIK3CA (16.7 %); and in ICC were IDH1 (17.1 %), NRAS (17.1 %), and BAP1 (14.3 %). The presence of mutations in ALK, IDH1, and TP53 genes was significantly associated with poor prognosis in patients with EH-PCC (p < 0.001, p = 0.043, and p = 0.019, respectively). Mutation of the TP53 gene was significantly associated with poor prognosis in patients with IH-PCC (p = 0.049). The presence of mutations in ARID1A, PIK3C2G, STK11, TGFBR2, and TP53 genes was significantly associated with poor prognosis in patients with ICC (p = 0.012, p = 0.030, p = 0.030, p = 0.011, and p = 0.011, respectively).
  
  
  CONCLUSIONS
  Mutational gene profiling identified different gene mutations in EH-PCC, IH-PCC, and ICC. Moreover, our study reported specific prognostic genes that can identify patients with poor prognosis after curative surgery who may benefit from traditional or target adjuvant treatments.
authors.affiliation: Department of Surgery, General and Hepatobiliary Surgery, University Hospital G.B. Rossi, University of Verona, Verona, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ruzzenente
authors.affiliation: ARC-Net Research Center, University Hospital G.B. Rossi, University of Verona, Verona, Italy.|Department of Pathology and Diagnostics, University Hospital G.B. Rossi, University of Verona, Verona, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Fassan
authors.affiliation: Department of Surgery, General and Hepatobiliary Surgery, University Hospital G.B. Rossi, University of Verona, Verona, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Conci
authors.affiliation: ARC-Net Research Center, University Hospital G.B. Rossi, University of Verona, Verona, Italy.|Department of Pathology and Diagnostics, University Hospital G.B. Rossi, University of Verona, Verona, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Simbolo
authors.affiliation: ARC-Net Research Center, University Hospital G.B. Rossi, University of Verona, Verona, Italy.|Department of Pathology and Diagnostics, University Hospital G.B. Rossi, University of Verona, Verona, Italy.
authors.forename: Rita T
authors.initials: RT
authors.lastname: Lawlor
authors.affiliation: Department of Surgery, General and Hepatobiliary Surgery, University Hospital G.B. Rossi, University of Verona, Verona, Italy.
authors.forename: Corrado
authors.initials: C
authors.lastname: Pedrazzani
authors.affiliation: Department of Pathology and Diagnostics, University Hospital G.B. Rossi, University of Verona, Verona, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Capelli
authors.affiliation: Department of Radiology, University Hospital G.B. Rossi, University of Verona, Verona, Italy.
authors.forename: Mirko
authors.initials: M
authors.lastname: D'Onofrio
authors.affiliation: Department of Surgery, General and Hepatobiliary Surgery, University Hospital G.B. Rossi, University of Verona, Verona, Italy.
authors.forename: Calogero
authors.initials: C
authors.lastname: Iacono
authors.affiliation: ARC-Net Research Center, University Hospital G.B. Rossi, University of Verona, Verona, Italy.|Department of Pathology and Diagnostics, University Hospital G.B. Rossi, University of Verona, Verona, Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Scarpa
authors.affiliation: Department of Surgery, General and Hepatobiliary Surgery, University Hospital G.B. Rossi, University of Verona, Verona, Italy. alfredo.guglielmi@univr.it.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Guglielmi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001650:Bile Duct Neoplasms / Q000235:genetics / Q000473:pathology* / Q000601:surgery; D017734:Bile Ducts, Extrahepatic / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D001653:Bile Ducts, Intrahepatic / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D014408:Biomarkers, Tumor / Q000235:genetics*; D018281:Cholangiocarcinoma / Q000235:genetics / Q000473:pathology* / Q000601:surgery; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011446:Prospective Studies; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor