Stains & molecular markers
BAP1


Topic Completed: 30 October 2020

Minor changes: 30 October 2020

Copyright: 2003-2020, PathologyOutlines.com, Inc.

PubMed Search: BAP1[TI] free full text[sb] immunohistochemistry

Gustav Stålhammar, M.D., Ph.D.
Page views in 2019: 39
Page views in 2020 to date: 5,977
Cite this page: Stålhammar G. BAP1. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/stainsBAP1.html. Accessed December 4th, 2020.
Definition / general
  • BAP1: BRCA1 Associated Protein-1, located on chromosome 3p21.1
  • Loss of BAP1 expression in tumor nuclei is associated with poor patient prognosis in several cancers
  • Loss of BAP1 expression can be used to differentiate certain malignant lesions from benign proliferations
Essential features
  • BAP1 is functionally a tumor suppressor (Proc Natl Acad Sci USA 2014;111:285)
  • BAP1 is a deubiquitinase that associates with multiprotein complexes that regulate key cellular pathways, including the cell cycle, cellular differentiation, cell death, gluconeogenesis and the DNA damage response (Nat Rev Cancer 2013;13:153)
  • Used by pathologists for:
    • Prognostication of uveal melanoma
    • Differentiation of metastatic uveal melanoma (at least 77% negative) from metastatic skin melanoma (5% negative) (Br J Cancer 2014;111:1373, Nat Genet 2011;43:1018)
    • Differentiation of mesothelioma from benign mesothelial proliferation
Terminology
  • BAP1
  • UCHL2
  • Hucep-6
  • HUCEP-13
Pathophysiology
  • Ubiquitin tag promotes breakdown of certain proteins
  • BAP1 removes ubiquitin tags, thereby inhibiting protein breakdown, which affects diverse cellular processes
  • BAP1 is thought to help inhibit cell proliferation and promote apoptosis of damaged cells
  • BAP1 protein is normally localized in the cell nucleus due to the presence of a nuclear localization sequence (NLS)
    • In the presence of a ubiquitin conjugating enzyme (UBE20), NLS will be covered with ubiquitin localizing the BAP1 protein in the cytoplasm
    • Wild type BAP1 protein has the capability to remove the ubiquitin and hence is able to enter back into the nucleus
    • Mutated BAP1 protein loses its autodeubiquitination property and remains in the cytoplasm (Ocul Oncol Pathol 2020;6:129)
  • BAP1 cytogenetic location: 3p21.1
  • Molecular location: base pairs 52,401,004 to 52,410,030 on chromosome 3
Diagrams / tables

Images hosted on other servers:

BAP1 protein localization

Missing Image Missing Image

BAP1 interactions

Clinical features
Interpretation
  • Nuclear staining: any visible nuclear staining above background is sufficient for positive classification
  • Degree of cytoplasmic staining is prognostically irrelevant but has shown some correlation with gene expression class 2 (aggressive tumors) (Ocul Oncol Pathol 2020;6:129)
Uses by pathologists
  • For prognostication of uveal melanoma: lack of BAP1 expression in tumor nuclei associated with significantly shorter metastasis free survival (Ophthalmology 2018;125:203)
  • For differentiation of metastatic uveal melanoma (at least 77% negative) from metastatic skin melanoma (5% negative) (Br J Cancer 2014;111:1373, Nat Genet 2011;43:1018)
  • For differentiation of mesothelioma from benign mesothelial proliferation: in biopsies initially interpreted as reactive mesothelial proliferation, BAP1 loss was 100% predictive of malignancy (Mod Pathol 2015;28:1043)
Prognostic factors
Microscopic (histologic) description
  • Recommended method for BAP1 scoring of uveal melanoma:
    • Make sure the stain works in both external controls (e.g. skin or BAP1 positive uveal melanoma tissue from previous cases) and internal controls (e.g. ganglion layer of retina, normal melanocytes in choroid or iris or optic nerve nuclei)
    • Under low magnification (40x), select the tumor area with most intense BAP1 staining
    • Within this area, use higher magnification to assess the percentage of tumor cells with nuclear stain
      • Count at least 100 cells in each of 3 high power fields (200x - 400x)
      • Use the mean score for classification:
        • If < 33% of tumor nuclei are positive, classify as BAP1 low
        • If ≥ 33% are positive, classify as BAP1 high
    • Some pathologists would argue that uveal melanomas usually have either complete absence of staining (0% positive tumor nuclei) or fully retained expression (100% positive tumor nuclei) and that mixed tumors (1 - 99% positive tumor nuclei) are exceptions (J Pathol Clin Res 2018;4:26)
  • Regarding melanocytic nevi:
    • Benign melanocytic nevi associated with BAP1 germline mutations are often spitzoid or epitheliod
      • These melanocytic tumors may have overlapping features with melanoma
      • Spitzoid tumors often lack epidermal hyperplasia, Kamino bodies, clefting
      • Many lesions are highly cellular, pleomorphic and can contain molecular aberrations occasionally identified in melanoma (Nat Genet 2011;43:1018)
Microscopic (histologic) images

Contributed by Gustav Stålhammar, M.D., Ph.D.
Positive tumor

Uveal melanoma, BAP1 positive

Negative tumor

Uveal melanoma, BAP1 negative

Mixed tumor

Uveal melanoma, BAP1 mixed

Positive staining - normal
Positive staining - disease
Negative staining
Molecular / cytogenetics description
Sample pathology report
  • Eye with uveal melanoma, enucleation:
    • BAP1 IHC: low expression (tumor proportion score 10%)
    • BAP1 IHC is a prognostic test in uveal melanoma. Classification is as follows: if < 33% of tumor nuclei are positive, classify as low. If ≥ 33% are positive, classify as high. The tumor proportion score is estimated by manual quantification or digital image analysis.
Board review style question #1

The photomicrograph shows BAP1 in uveal melanoma. Which of the following describes the use of BAP1 in this tumor?

  1. Biomarker used to determine medication treatment
  2. Differentiates melanoma from benign melanocytic lesions
  3. Loss of nuclear expression is associated with a poor prognosis
Board review answer #1
C. Loss of nuclear expression of BAP1 is associated with a poor prognosis

Comment Here

Reference: BAP1
Back to top
Image 01 Image 02