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Annals of Surgical Oncology

, Volume 23, Issue 5, pp 1699–1707 | Cite as

Cholangiocarcinoma Heterogeneity Revealed by Multigene Mutational Profiling: Clinical and Prognostic Relevance in Surgically Resected Patients

  • Andrea Ruzzenente
  • Matteo Fassan
  • Simone Conci
  • Michele Simbolo
  • Rita T. Lawlor
  • Corrado Pedrazzani
  • Paola Capelli
  • Mirko D’Onofrio
  • Calogero Iacono
  • Aldo Scarpa
  • Alfredo Guglielmi
Hepatobiliary Tumors

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.

Keywords

Cholangiocarcinoma Molecular Profile IDH1 Mutation Biliary Tract Cancer TP53 Gene 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgment

Supported in part by Associazione Italiana per la Ricerca sul Cancro (AIRC) Grants 12182 and 6421, FP7 EU project CAM-PaC 602783, the Italian Cancer Genome Project Grant from the Italian Ministry of Research (FIRB-RBAP10AHJB), and FIMP–Ministry of Health (CUP_J33G13000210001).

Disclosure

The authors declare no conflict of interest.

Supplementary material

10434_2015_5046_MOESM1_ESM.doc (128 kb)
Supplementary material 1 (DOC 128 kb)

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Copyright information

© Society of Surgical Oncology 2015

Authors and Affiliations

  • Andrea Ruzzenente
    • 1
  • Matteo Fassan
    • 2
    • 3
  • Simone Conci
    • 1
  • Michele Simbolo
    • 2
    • 3
  • Rita T. Lawlor
    • 2
    • 3
  • Corrado Pedrazzani
    • 1
  • Paola Capelli
    • 3
  • Mirko D’Onofrio
    • 4
  • Calogero Iacono
    • 1
  • Aldo Scarpa
    • 2
    • 3
  • Alfredo Guglielmi
    • 1
  1. 1.Department of Surgery, General and Hepatobiliary Surgery, University Hospital G.B. RossiUniversity of VeronaVeronaItaly
  2. 2.ARC-Net Research Center, University Hospital G.B. RossiUniversity of VeronaVeronaItaly
  3. 3.Department of Pathology and Diagnostics, University Hospital G.B. RossiUniversity of VeronaVeronaItaly
  4. 4.Department of Radiology, University Hospital G.B. RossiUniversity of VeronaVeronaItaly

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