Altered Nuclear Expression of the Deubiquitylase BAP1 Cannot be Used as a Prognostic Marker for Canine Melanoma

Our plain-English summary of Altered Nuclear Expression of the Deubiquitylase BAP1 Cannot be Used as a Prognostic Marker for Canine Melanoma, by N. Jama, N. Farquhar, Z. Butt, et al (Journal of Comparative Pathology, 2018).

The study

• Authors: N. Jama, N. Farquhar, Z. Butt, S.E. Coupland, J.J. Sacco, T. Scase, A.B. Fielding, J.M. Coulson, H. Kalirai, D.R. Killick
• Journal: Journal of Comparative Pathology
• Published: 2018;162:50-58
• Cited by: 4 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

BRCA1-associated protein-1 (BAP1) is a nuclear localized deubiquitylating enzyme that belongs to the ubiquitin c-terminal hydrolase subfamily. The encoded protein is highly homologous between man and dogs, suggesting a functional significance preserved by evolution. BAP1 has multiple properties, including tumour suppressor activity. Loss of BAP1 function is implicated in the oncogenesis of several types of cancers including uveal, mucosal and some cutaneous melanomas in humans, as well as in mesothelioma. In this study we investigate the significance of BAP1 in canine melanoma. Nuclear BAP1 protein was detected in five canine oral melanoma cell lines using an antibody commonly used for analysis of human tissues. BAP1 loss of function mutations often lead to loss of nuclear BAP1 (nBAP1) expression in humans; this is associated with a poorer prognosis in uveal and mucosal melanoma. Therefore, as a prelude to a study evaluating the prognostic significance of nBAP1 expression in dogs, immunohistochemistry (IHC) was used to assess cases of canine melanoma for nBAP1 expression. In 89 cases where tumour cells were identified by melan-A labelling, 100% of tumour cells were positive for nBAP1 expression, including eight uveal tract and 29 oral mucosal melanomas. This finding indicates that BAP1 IHC cannot be used as a prognostic marker in canine uveal and mucosal melanoma. Moreover, this observation suggests that either BAP1 has a different functional significance in canine melanoma or that loss of BAP1 function is achieved by a different route. This is a novel finding that warrants further investigation to determine the comparative biological relevance.

Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

In plain English

This laboratory study looked at a protein called BAP1 in melanoma, a cancer of pigment cells, in dogs. It did not study asbestos or any fiber exposure. Two human mesothelioma cell lines served only as antibody test controls. The authors compared dog and human BAP1 and found 98% amino acid homology. A human BAP1 antibody detected the protein in all five dog oral melanoma cell lines; in the three examined for location, it was mainly in the nucleus. The authors then stained 90 dog melanoma samples from clinical cases submitted to the pathology company Bridge Pathology. The samples came from the digits (toes), skin, mouth, eye (uveal tract) and tissue around the eye. All 89 cases with tumour cells confirmed by the melanoma marker melan-A showed nuclear BAP1 in 100% of tumour cells, including all 28 oral and 8 uveal cases. One digit case was only faintly positive. The authors said this likely reflected a technical issue. The work was planned as a first step before an outcome study. The authors concluded that BAP1 staining cannot be used for prognosis in canine melanoma.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study: comparison of dog and human BAP1 sequences, antibody tests on dog melanoma cell lines, and immunohistochemistry staining of a tissue microarray of dog melanoma samples, planned as a first step before a study of whether BAP1 predicts outcome
• Who was studied: Five canine oral melanoma cell lines (from the University of California Davis), and 90 dog melanoma tissue samples from clinical cases submitted to Bridge Pathology. Of 105 samples retrieved, 15 were excluded. The 90 included 37 females and 53 males from 25 breeds, median age 9 years. Sites: digit 19, skin 22, oral 28, uveal 8, periocular 13. No study dates are given.
• Exposure: No asbestos or fiber exposure was studied. The study measured BAP1 protein expression in dog melanoma. Human mesothelioma cell lines (MSTO-211H, BAP1 positive; NCI-H28, BAP1 negative) served only as laboratory controls.
• Main results:
  • The predicted dog BAP1 protein had 98% amino acid homology with human BAP1.
  • In immunoblotting, a BAP1 band of around 85 kDa was detected in each of the five dog oral melanoma cell lines.
  • In the three dog melanoma cell lines examined by immunofluorescence (UCDK9M1, UCDK9M3 and UCDK9M5), BAP1 was mainly in the nucleus.
  • All 89 melan-A-positive dog melanoma cases showed nuclear BAP1 in 100% of tumour cells. By site: skin 22/22, oral 28/28, uveal 8/8, periocular 13/13, digit 18/19.
  • The one remaining case, a digital melanoma, was melan-A negative and showed only faint, focal nuclear BAP1. The authors considered this likely a technical issue, because the sample had been decalcified.
  • Strong to weak BAP1 staining in the cytoplasm was also seen in every case.
• The authors' conclusion: The authors concluded that, because all samples expressed nuclear BAP1, BAP1 immunohistochemistry cannot be used for prognosis in canine melanoma. They suggested that BAP1 may not matter in canine melanoma, or that its function may be lost by another route their method could not detect.
• Limitations the authors state:
  • The method could not detect loss of BAP1 function that occurs without loss of the protein from the nucleus.
  • The effect of the amino acid differences between dog and human BAP1 on how the dog protein works is unknown.

Topics

Medical terms in this study, explained in our Lexicon: BAP1, Oncogenesis, Mesothelioma, Prognosis, Immunohistochemistry.

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• Analysis of BAP1 Germline Gene Mutation in Young Uveal Melanoma Patients — C.M. Cebulla, E.M. Binkley, et al. (2015)
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• Germline BAP1-positive patients: the dilemmas of cancer surveillance and a proposed interdisciplinary consensus monitoring strategy — P. Star, A. Goodwin, et al. (2018)
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