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

  • Hepatobiliary Tumors
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

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.

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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.

Author information

Authors and Affiliations

  1. Department of Surgery, General and Hepatobiliary Surgery, University Hospital G.B. Rossi, University of Verona, Verona, Italy

    Andrea Ruzzenente MD, PhD, Simone Conci MD, Corrado Pedrazzani MD, Calogero Iacono MD & Alfredo Guglielmi MD

  2. ARC-Net Research Center, University Hospital G.B. Rossi, University of Verona, Verona, Italy

    Matteo Fassan MD, PhD, Michele Simbolo MD, Rita T. Lawlor MD & Aldo Scarpa MD

  3. Department of Pathology and Diagnostics, University Hospital G.B. Rossi, University of Verona, Verona, Italy

    Matteo Fassan MD, PhD, Michele Simbolo MD, Rita T. Lawlor MD, Paola Capelli MD & Aldo Scarpa MD

  4. Department of Radiology, University Hospital G.B. Rossi, University of Verona, Verona, Italy

    Mirko D’Onofrio MD

Authors
  1. Andrea Ruzzenente MD, PhD
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  2. Matteo Fassan MD, PhD
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  3. Simone Conci MD
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  4. Michele Simbolo MD
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  5. Rita T. Lawlor MD
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  6. Corrado Pedrazzani MD
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  7. Paola Capelli MD
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  8. Mirko D’Onofrio MD
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  9. Calogero Iacono MD
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  10. Aldo Scarpa MD
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  11. Alfredo Guglielmi MD
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Corresponding author

Correspondence to Alfredo Guglielmi MD.

Additional information

Andrea Ruzzenente and Matteo Fassan shared first authorship. Calogero Iacono and Aldo Scarpa shared last authorship.

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Ruzzenente, A., Fassan, M., Conci, S. et al. Cholangiocarcinoma Heterogeneity Revealed by Multigene Mutational Profiling: Clinical and Prognostic Relevance in Surgically Resected Patients. Ann Surg Oncol 23, 1699–1707 (2016). https://doi.org/10.1245/s10434-015-5046-6

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  • DOI: https://doi.org/10.1245/s10434-015-5046-6

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