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Prognostic role of BAP-1 and PBRM-1 expression in intrahepatic cholangiocarcinoma

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Abstract

Intrahepatic cholangiocarcinoma (ICC) has universally poor outcome, mainly due to its late clinical presentation. Identification of specific biomarkers and development of effective treatment are still urgently required. Mutations in PBRM-1 and BAP-1 genes, and the expression of S100P have been related to survival in ICC. miR-31 seems also to play important regulatory functions in ICC and it directly regulates BAP-1 expression in lung cancer. In this study, tissue expression of BAP-1, PBRM-1, S100P, and miR-31 was investigated in ICC and correlated with clinical-pathological features. Sixty-one consecutive patients who underwent curative hepatic resection for ICC were enrolled. None received any therapy prior to surgery. Immunostaining for BAP-1, PBRM-1, and S100P, and in situ hybridization for miR-31 were performed, using tissue microarray slides. A strong retained expression of BAP-1 and PBRM-1 was associated with a reduced overall (p = 0.04 and p = 0.002, respectively) and disease-free survival (p = 0.05 and p = 0.02, respectively). An overexpression of S100P was related to a reduced overall survival (p = 0.005). The multivariate analyses identified the presence of perineural invasion and the retained PBRM-1 expression as independent predictors of worse overall [p = 0.02, hazard ratio (HR) = 2.25 (1.16–4.39) and p = 0.001, HR = 3.13 (1.56–6.28), respectively] and disease-free survivals [p = 0.03, HR = 2.43 (1.09–5.4) and p = 0.03, HR = 2.51 (1.11–5.67), respectively]. An overexpression of S100P was predictive of a worse overall survival [p = 0.02, HR = 1.66 (1.08–2.55)]. High levels of miR-31 were significantly associated to a low expression of BAP-1 protein (p = 0.03). In ICC, a retained expression of BAP-1 and PBRM-1, and an overexpression of S100P are related to a poor prognosis.

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Author information

Author notes

  1. Samantha Sarcognato and Enrico Gringeri contributed equally to this work.

Authors and Affiliations

  1. Surgical Pathology & Cytopathology Unit, Department of Medicine – DIMED, University of Padova, Padova, Italy

    Samantha Sarcognato, Matteo Fassan, Valeria Maffeis, Vincenza Guzzardo & Maria Guido

  2. Department of Surgery, Oncology and Gastroenterology, Hepatobiliary Surgery and Liver Transplantation Unit, Padova University Hospital, Padova, Italy

    Enrico Gringeri, Michela Di Giunta & Umberto Cillo

  3. Istituto di Anatomia Patologica, via Gabelli 61, 35121, Padova, Italy

    Maria Guido

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  1. Samantha Sarcognato
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  2. Enrico Gringeri
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  3. Matteo Fassan
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  4. Michela Di Giunta
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Contributions

Samantha Sarcognato: conception and design, acquisition of data, analysis and interpretation of data, writing and revision of the manuscript;

Enrico Gringeri: conception and design, acquisition of data, analysis and interpretation of data, writing and revision of the manuscript;

Matteo Fassan: conception and design, development of methodology, acquisition of data, analysis and interpretation of data, writing and revision of the manuscript;

Michela Di Giunta: acquisition of data, analysis and interpretation of data;

Valeria Maffeis: analysis and interpretation of data;

Vincenza Guzzardo: development of methodology, technical and material support;

Umberto Cillo: conception and design, interpretation of data, revision of the manuscript;

Maria Guido: conception and design, analysis and interpretation of data, writing and revision of the manuscript, study supervision.

All authors gave final approval for publication.

Maria Guido takes full responsibility for the work as a whole, including the study design, access to data and the decision to submit and publish the manuscript.

Corresponding author

Correspondence to Maria Guido.

Ethics declarations

The study complies with the ethical guidelines of the 1975 Declaration of Helsinki and obtained the approval from the local Ethics Committee (Ethics Committee for Clinical Research—University Hospital of Padova, Italy; protocol #: 0038038/2017).

Informed consent

All the patients gave their appropriate informed consent to the surgical procedure.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical responsibilities of authors

All of the authors confirm that each of them qualifies for every one of the 4 criteria of authorship.

Electronic supplementary material

Supplementary Fig. 1

An example of a negative (A, original magnification 10x) and a positive (B, original magnification 10x) PBRM-1 reaction in intrahepatic cholangiocarcinoma (PNG 743 kb)

High Resolution Image (TIF 3973 kb)

(PNG 1228 kb)

High Resolution Image (TIF 4677 kb)

Supplementary Fig. 2

A significantly reduced overall survival was observed in cases with an overexpression of S100P, as shown by the Kaplan-Meier curve (PNG 106 kb)

High Resolution Image (TIFF 380 kb)

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Sarcognato, S., Gringeri, E., Fassan, M. et al. Prognostic role of BAP-1 and PBRM-1 expression in intrahepatic cholangiocarcinoma. Virchows Arch 474, 29–37 (2019). https://doi.org/10.1007/s00428-018-2478-y

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  • DOI: https://doi.org/10.1007/s00428-018-2478-y

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