BAP1

Synonyms: BRCA1 Associated Protein 1, Ubiquitin carboxyl-terminal hydrolase BAP1, Ubiquitin carboxyl-terminal hydrolase like-2 (UCHL2), Human cerebral protein 6 (hucep 6), Human cerebral protein-13 (hucep-13)

by Jan Klos

Background

BAP1 is an enzyme encoded by gene located on a short arm of chr. 3 (3p21.31-p21.2). It forms a catalytic subunit of the Polycomb complex, controlling homeobox genes, by regulating the amount of Histone H2A bound to their promoters in nucleosomes. BAP1 associates also with other factors involved in chromatin modulation and transcriptional regulation during progression of the cell cycle as well as DNA damage response/repair. High levels of mutated BAP1 protein upregulate heat shock proteins especially Hsp90. The antibody reacts with normal protein giving a distinct nuclear staining but it does not react with the mutated BAP1 protein, so the negative nuclear staining indicates strongly mutation of BAP1 gene. Immunohistochemistry with properly calibrated staining protocol is a cost effective method of detecting biallelic BAP1 mutations (loss of reactivity), with positive and negative predictive values of 100% and 98.6% respectively. Few missense mutations that inactivate protein without alteration of the epitope may however not be detected with IHC.

Staining in normal cells

All normal cells are stained positive.

Staining in tumors

BAP1 is mutated only in several cancers or is commonly lost because of chromosomal deletion in various tumors, including  malignant mesothelioma (> 60%), uveal melanoma (~50% particularly metastasizing), ~50% intrahepatic cholangiocarcinoma and esophageal squamous cell carcinoma, ~10-20%  renal cell carcinoma, cutaneous desmoplastic melanoma, atypical Spitzoid tumors  and <10% hepatocellular carcinoma. Negative staining is seen rarely in small cell and non-small cell lung cancers, pancreas adenocarcinoma, breast carcinoma and basal cell carcinomas. Positive immunohistochemical staining reflecting normal BAP1 status is seen in other tumors.
Germline mutations of BAP1 gene causes genetic predisposition (autosomal dominant hereditary tumor predisposition syndrome) to mesothelioma, uveal melanoma and melanocytic skin tumors often resembling atypical Spitz tumors (combined BAP1 loss and positive BRAFV600E staining is seen in ~70% of BAP1 tumor syndrome-associated melanocytic lesions), multiple basal cell carcinomas as well as some other types of cancer.

Staining pattern

Staining pattern is nuclear.

Applications

  • Supporting diagnosis of mesothelioma in cytology (preferably cell block) and histology – negative nuclear staining is a strong argument for malignancy. Conflicting results are reported regarding correlation between result of staining and prognosis. Remember that positive staining in mesothelial cells does not exclude mesothelioma.
  • Loss of nuclear staining is associated with more aggressive clinical course in uveal melanomas.
  • Differential diagnosis of metastatic uveal melanoma (almost 80% negative staining) from metastatic cutaneous melanoma (>5% negative staining).
  • Loss of nuclear staining seen in some melanotic tumors (BAP inactivated nevus/melanocytoma, BAPoma) correlates with “aggressive” morphology.
  • Screening for BAP1 tumor syndrome – immunoprofile BAP1-/BRAFV600E+  appears to be a present in ~70% of melanocytic lesions associated with this syndrome.
  • Loss of nuclear staining supports diagnosis of intrahepatic cholangiocarcinoma (~50% negative) vs. pancreatic adenocarcinoma (99% positive staining).
  • In clear cell carcinoma of kidney ~10% cases show absent nuclear staining which correlates with worse prognosis.
  • Cytoplasmic perinuclear staining (Golgi like) seen in some tumors is of uncertain diagnostic relevance in the presence of positive nuclear staining.

Selected references

  1. Cheung M, Testa JR. BAP1, a tumor suppressor gene driving malignant mesothelioma.  Transl Lung Cancer Res. 2017 Jun;6(3):270-278. doi: 10.21037/tlcr.2017.05.03.
  2. Hida T, Hamasaki M, Matsumoto S, et al. BAP1 immunohistochemistry and p16 FISH results in combination provide higher confidence in malignant pleural mesothelioma diagnosis: ROC analysis of the two tests.  Pathol Int. 2016 Oct;66(10):563-570. doi: 10.1111/pin.12453. Epub 2016 Sep 11.
  3. Farquhar N, Thornton S, Coupland SE, et al. Patterns of BAP1 protein expression provide insights into prognostic significance and the biology of uveal melanoma. J Pathol Clin Res. 2017 Nov 13;4(1):26-38. doi: 10.1002/cjp2.86. eCollection 2018 Jan.
  4. de la Fouchardière A, Cabaret O, Savin L, et al. Germline BAP1 mutations predispose also to multiple basal cell carcinomas. Clin Genet. 2015 Sep;88(3):273-7. doi: 10.1111/cge.12472. Epub 2014 Sep 8.PMID: 25080371
  5. Masoomian B, Shields JA, Shields CL. Overview of BAP1 cancer predisposition syndrome and the relationship to uveal melanoma.  J Curr Ophthalmol. 2018 Mar 22;30(2):102-109. doi: 10.1016/j.joco.2018.02.005. eCollection 2018 Jun.
  6. Mori T1, Sumii M1, Fujishima F2, et al. Somatic alteration and depleted nuclear expression of BAP1 in human esophageal squamous cell carcinoma. Cancer Sci. 2015 Sep;106(9):1118-29. doi: 10.1111/cas.12722. Epub 2015 Aug 10.
  7. Liu J, Liao X, Gu Y, et al. Role of p16 deletion and BAP1 loss in the diagnosis of malignant mesothelioma. J Thorac Dis. 2018 Sep;10(9):5522-5530. doi: 10.21037/jtd.2018.08.59.
  8. Pillappa R1, Maleszewski JJ1, Sukov WR1, et al. Loss of BAP1 Expression in Atypical Mesothelial Proliferations Helps to Predict Malignant Mesothelioma. Am J Surg Pathol. 2018 Feb;42(2):256-263. doi: 10.1097/PAS.0000000000000976.
  9. Piris A1, Mihm MC Jr2, et al. BAP1 and BRAFV600E expression in benign and  malignant  melanocytic proliferations. Hum Pathol. 2015 Feb;46(2):239-45. doi: 10.1016/j.humpath.2014.10.015. Epub 2014 Nov 4.
  10. Stålhammar G. BAP1. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/stainsBAP1.html. Accessed February 6th, 2021.
  11. Wang A, Papneja A, Hyrcza M, et al. Gene of the month: BAP1. J Clin Pathol. 2016 Sep;69(9):750-3. doi: 10.1136/jclinpath-2016-203866. Epub 2016 May 27.