Advertisement

Tumours associated with BAP1 mutations

  • Rajmohan Murali
    Correspondence
    Address for correspondence: Department of Pathology, and Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, Box 20, 1275 York Avenue, New York, NY 10065, USA
    Affiliations
    Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, USA

    Department of Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, USA
    Search for articles by this author
  • Thomas Wiesner
    Affiliations
    Department of Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, USA

    Department of Dermatology, Medical University ofGraz, Austria, Australia
    Search for articles by this author
  • Richard A. Scolyer
    Affiliations
    Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Australia

    Department of Discipline of Pathology, Sydney Medical School, The University of Sydney, Camperdown, Australia

    Melanoma Institute Australia, North Sydney, NSW, Australia
    Search for articles by this author
      This paper is only available as a PDF. To read, Please Download here.

      Summary

      BAP1 (BRCA1-Associated Protein 1) was initially identified as a protein that binds to BRCA1. BAP1 is a tumour suppressor that is believed to mediate its effects through chromatin modulation, transcriptional regulation, and possibly via the ubiquitin-proteasome system and the DNA damage response pathway. Germline mutations of BAP1 confer increased susceptibility for the developmentofseveral tumours, including uveal melanoma, epithelioid atypical Spitz tumours, cutaneous melanoma, and mesothelioma. However, the complete tumour spectrum associated with germline BAP1 mutations is not yet known. Somatic BAP1 mutations are seen in cutaneous melanocytic tumours (epithelioid atypical Spitz tumours and melanoma), uveal melanoma, mesothelioma, clear cell renal cell carcinoma, and other tumours. Here, we review the current state of knowledge about the functional roles of BAP1, and summarise data on tumours associated with BAP1 mutations. Awareness of these tumours will help pathologists and clinicians to identify patients with a high likelihood of harbouring germline or somatic BAP1 mutations. We recommend that pathologists consider testing for BAP1 mutations in epithelioid atypical Spitz tumours and uveal melanomas, or when other BAP1-associated tumours occur in individual patients. Tumour tissues may be screened for BAP1 mutations/loss/inactivation by immunohistochemistry (IHC) (demonstrated by loss of nuclear staining in tumour cells). Confirmatory sequencing may be considered in tumours that exhibit BAP1 loss by IHC and in those with equivocal IHC results. If a BAP1 mutation is confirmed in a tumour, the patient’s treating physician should be informed of the possibility of a BAP1 germline mutation, so they can consider whether genetic counselling and further testing of the patient and investigation of their family is appropriate. Recognition and evaluation of larger numbers of BAP1-associated tumours will also be necessary to facilitate identification of additional distinct clinico-pathological characteristics or other genotype-phenotype correlations that may have prognostic and management implications.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Pathology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Jensen D.E.
        • Proctor M.
        • Marquis S.T.
        • et al.
        BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression.
        Oncogene. 1998; 16: 1097-1112
        • Angeloni D.
        Molecular analysis of deletions in human chromosome 3p21 and the role of resident cancer genes in disease.
        Brief Funct Genomic Proteomic. 2007; 6: 19-39
        • Bott M.
        • Brevet M.
        • Taylor B.S.
        • et al.
        The nuclear deubiquitinase BAP1 is commonly inactivated by somatic mutations and 3p21. 1 losses in malignant pleural mesothelioma.
        Nat Genet. 2011; 43: 668-672
        • Ventii K.H.
        • Devi N.S.
        • Friedrich K.L.
        • et al.
        BRCA1-associated protein-1 is a tumor suppressor that requires deubiquitinating activity and nuclear localization.
        Cancer Res. 2008; 68: 6953-6962
        • Harbour J.W.
        • Onken M.D.
        • Roberson E.D.
        • et al.
        Frequent mutation ofBAP1 in metastasizing uveal melanomas.
        Science. 2010; 330: 1410-1413
        • Knudson Jr, A.G.
        Mutation and cancer: statistical study of retinoblastoma.
        Proc Natl Acad Sci USA. 1971; 68: 820-823
        • Nishikawa H.
        • Wu W.
        • Koike A.
        • et al.
        BRCA1-associated protein 1 interferes with BRCA1/BARD1 RING heterodimer activity.
        Cancer Res. 2009; 69: 111-119
        • Sowa M.E.
        • Bennett E.J.
        • Gygi S.P.
        • Harper J.W.
        Defining the human deubiquitinating enzyme interaction landscape.
        Cell. 2009; 138: 389-403
        • Misaghi S.
        • Ottosen S.
        • Izrael-Tomasevic A.
        • et al.
        Association of C-terminal ubiquitin hydrolase BRCA1-associated protein 1 with cell cycle regulator host cell factor 1.
        Mol Cell Biol. 2009; 29: 2181-2192
        • Eletr Z.M.
        • Wilkinson K.D.
        An emerging model for BAP1’s role in regulating cell cycle progression.
        Cell Biochem Biophys. 2011; 60: 3-11
        • Machida Y.J.
        • Machida Y.
        • Vashisht A.A.
        • et al.
        The deubiquitinating enzyme BAP1 regulates cell growth via interaction with HCF-1.
        J Biol Chem. 2009; 284: 34179-34188
        • Tyagi S.
        • Chabes A.L.
        • Wysocka J.
        • Herr W.
        E2F activation of S phase promoters via association with HCF-1 and the MLL family of histone H3K4 methyltransferases.
        Mol Cell. 2007; 27: 107-119
        • Narayanan A.
        • Ruyechan W.T.
        • Kristie T.M.
        The coactivator host cell factor-1 mediates Set1 and MLL1 H3K4 trimethylation at herpesvirus immediate early promoters for initiation of infection.
        Proc Natl Acad Sci USA. 2007; 104: 10835-10840
        • Yu H.
        • Mashtalir N.
        • Daou S.
        • et al.
        The ubiquitin carboxyl hydrolase BAP1 forms a ternary complex with YY1 and HCF-1 and is a critical regulator of gene expression.
        Mol Cell Biol. 2010; 30: 5071-5085
        • Kristie T.M.
        • Liang Y.
        • Vogel J.L.
        Control of alpha-herpesvirus IE gene expression by HCF-1 coupled chromatin modification activities.
        Biochim Biophys Acta. 2010; 1799: 257-265
        • Gieni R.S.
        • Ismail I.H.
        • Campbell S.
        • Hendzel M.J.
        Polycomb group proteins in the DNA damage response: a link between radiation resistance and ‘stem-ness’.
        Cell Cycle. 2011; 10: 883-894
        • Zhu P.
        • Zhou W.
        • Wang J.
        • et al.
        A histone H2A deubiquitinase complex coordinating histone acetylation and H1 dissociation in transcriptional regulation.
        Mol Cell. 2007; 27: 609-621
        • Wang H.
        • Wang L.
        • Erdjument-Bromage H.
        • et al.
        Role of histone H2A ubiquitination in Polycomb silencing.
        Nature. 2004; 431: 873-878
        • de Napoles M.
        • Mermoud J.E.
        • Wakao R.
        • et al.
        Polycomb group proteins Ring1A/B link ubiquitylation of histone H2A to heritable gene silencing and X inactivation.
        Dev Cell. 2004; 7: 663-676
        • Scheuermann J.C.
        • de Ayala Alonso A.G.
        • Oktaba K.
        • et al.
        Histone H2A deubiquitinase activity of the Polycomb repressive complex PR-DUB.
        Nature. 2010; 465: 243-247
        • Negishi M.
        • Saraya A.
        • Miyagi S.
        • et al.
        Bmi1 cooperates with Dnmt1-associated protein 1 in gene silencing.
        Biochem Biophys Res Commun. 2007; 353: 992-998
        • Vire E.
        • Brenner C.
        • Deplus R.
        • et al.
        The Polycomb group protein EZH2 directly controls DNA methylation.
        Nature. 2006; 439: 871-874
        • O’Hagan H.M.
        • Mohammad H.P.
        • Baylin S.B.
        Double strand breaks can initiate gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous promoter CpG island.
        PLoS Genet. 2008; 4: e1000155
        • Reynolds P.A.
        • Sigaroudinia M.
        • Zardo G.
        • et al.
        Tumor suppressor p16INK4A regulates polycomb-mediated DNA hypermethylation in human mammary epithelial cells.
        J Biol Chem. 2006; 281: 24790-24802
        • Venkitaraman A.R.
        Cancer susceptibility and the functions of BRCA1 and BRCA2.
        Cell. 2002; 108: 171-182
        • Greenberg R.A.
        • Sobhian B.
        • Pathania S.
        • et al.
        Multifactorial contributions to an acute DNA damage response by BRCA1/BARD1-containing complexes.
        Genes Dev. 2006; 20: 34-46
        • Hashizume R.
        • Fukuda M.
        • Maeda I.
        • et al.
        The RING heterodimer BRCA1-BARD1 is a ubiquitin ligase inactivated by a breast cancer-derived mutation.
        J Biol Chem. 2001; 276: 14537-14540
        • Jensen D.E.
        Rauscher FJ 3rd. BAP1, a candidate tumor suppressor protein that interacts with BRCA1.
        Ann NY Acad Sci. 1999; 886: 191-194
        • Mallery D.L.
        • Vandenberg C.J.
        • Hiom K.
        Activation of the E3 ligase function of the BRCA1/BARD1 complex by polyubiquitin chains.
        EMBO J. 2002; 21: 6755-6762
        • Yoshikawa Y.
        • Sato A.
        • Tsujimura T.
        • et al.
        Frequent inactivation of the BAP1 gene in epithelioid-type malignant mesothelioma.
        Cancer Sci. 2012; 103: 868-874
      1. COSMIC: catalogue of somatic mutations in cancer. Cited 5 Sept 2012. http://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=BAP1

        • Ladanyi M.
        • Zauderer M.G.
        • Krug L.M.
        • et al.
        New strategies in pleural mesothelioma: BAP1 and NF2 as novel targets for therapeutic development and risk assessment.
        Clin Cancer Res. 2012; 18: 4485-4490
        • Wiesner T.
        • Murali R.
        • Fried I.
        • et al.
        A distinct subset of atypical Spitz tumors is characterized by BRAF mutation and loss of BAP1 expression.
        Am J Surg Pathol. 2012; 36: 818-830
        • Wiesner T.
        • Obenauf A.C.
        • Murali R.
        • et al.
        Germline mutations in BAP1 predispose to melanocytic tumors.
        Nat Genet. 2011; 43: 1018-1021
        • Pena-Llopis S.
        • Vega-Rubin-de-Celis S.
        • Liao A.
        • et al.
        BAP1 loss defines a new class of renal cell carcinoma.
        Nat Genet. 2012; 44: 751-759
        • Abdel-Rahman M.H.
        • Pilarski R.
        • Cebulla C.M.
        • et al.
        Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, menin-gioma, and other cancers.
        J Med Genet. 2011; 48: 856-859
        • Wadt K.
        • Choi J.
        • Chung J.Y.
        • et al.
        A cryptic BAP1 splice mutation in a family with uveal and cutaneous melanoma, and paraganglioma.
        Pigment Cell Melanoma Res. 2012; 25: 815-818
        • Gill M.
        • Renwick N.
        • Silvers D.N.
        • Celebi J.T.
        Lack of BRAF mutations in Spitz nevi.
        J Invest Dermatol. 2004; 122: 1325-1326
        • Mihic-Probst D.
        • Perren A.
        • Schmid S.
        • et al.
        Absence of BRAF gene mutations differentiates spitz nevi from malignant melanoma.
        Anticancer Res. 2004; 24: 2415-2418
        • Palmedo G.
        • Hantschke M.
        • Rutten A.
        • et al.
        The T1796A mutation of the BRAF gene is absent in Spitz nevi.
        J Cutan Pathol. 2004; 31: 266-270
        • Scolyer R.A.
        • Zhuang L.
        • Palmer A.A.
        • et al.
        Combined naevus: a benign lesion frequently misdiagnosed both clinically and pathologically as melanoma.
        Pathology. 2004; 36: 419-427
        • Ludgate M.W.
        • Fullen D.R.
        • Lee J.
        • et al.
        The atypical Spitz tumor of uncertain biologic potential: a series of 67 patients from a single institution.
        Cancer. 2009; 115: 631-641
        • Barnhill R.L.
        • Argenyi Z.B.
        • From L.
        • et al.
        Atypical Spitz nevi/tumors: lack of consensus for diagnosis, discrimination from melanoma, and prediction of outcome.
        Hum Pathol. 1999; 30: 513-520
        • Carbone M.
        • Korb Ferris L.
        • Baumann F.
        • et al.
        BAP1 cancer syndrome: malignant mesothelioma, uveal and cutaneous melanoma, and MBAITs.
        J Transl Med. 2012; 10: 179
        • Njauw C.N.
        • Kim I.
        • Piris A.
        • et al.
        Germline BAP1 inactivation is preferentially associated with metastatic ocular melanoma and cutaneous-ocular melanoma families.
        PLoS One. 2012; 7: e35295
        • Cerroni L.
        • Barnhill R.
        • Elder D.
        • et al.
        Melanocytic tumors of uncertain malignant potential: results of a tutorial held at the XXIX Symposium of the International Society of Dermatopathology in Graz, October 2008.
        Am J Surg Pathol. 2010; 34: 314-326
        • Bastian B.C.
        • LeBoit P.E.
        • Pinkel D.
        Mutations and copy number increase of HRAS in Spitz nevi with distinctive histopathological features.
        Am J Pathol. 2000; 157: 967-972
        • Long G.V.
        • Wilmott J.S.
        • Capper D.
        • et al.
        , Immunohistochemistry is highly sensitive and specific for the detection of V600E BRAF mutation in melanoma.
        in: Am J Surg Pathol. 2012 (Sep 28: (Epub ahead of print))
        • Wiesner T.
        • Fried I.
        • Ulz P.
        • et al.
        Towards an improved definition of the tumor spectrum associated with BAP1 germline mutations.
        J Clin Oncol. 2012; 30: e337-e340
        • Carbone M.
        • Ly B.H.
        • Dodson R.F.
        • et al.
        Malignant mesothelioma: facts, myths, and hypotheses.
        J Cell Physiol. 2012; 227: 44-58
        • Carbone M.
        • Emri S.
        • Dogan A.U.
        • et al.
        A mesothelioma epidemic in Cappadocia: scientific developments and unexpected social outcomes.
        Nat Rev Cancer. 2007; 7: 147-154
        • Taguchi T.
        • Jhanwar S.C.
        • Siegfried J.M.
        • et al.
        Recurrent deletions of specific chromosomal sites in 1p, 3p, 6q, and 9p in human malignant mesothelioma.
        Cancer Res. 1993; 53: 4349-4355
        • Yoshikawa Y.
        • Sato A.
        • Tsujimura T.
        • et al.
        Frequent deletion of 3p21. 1 region carrying semaphorin 3G and aberrant expression of the genes participating in semaphorin signaling in the epithelioid type of malignant mesothelioma cells.
        Int J Oncol. 2011; 39: 1365-1374
        • Testa J.R.
        • Cheung M.
        • Pei J.
        • et al.
        Germline BAP1 mutations predispose to malignant mesothelioma.
        Nat Genet. 2011; 43: 1022-1025
        • van den Berg A.
        • Dijkhuizen T.
        • Draaijers T.G.
        • et al.
        Analysis of multiple renal cell adenomas and carcinomas suggests allelic loss at 3p21 to be a prerequisite for malignant development.
        Genes Chromosomes Cancer. 1997; 19: 228-232
        • Dalgliesh G.L.
        • Furge K.
        • Greenman C.
        • et al.
        Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes.
        Nature. 2010; 463: 360-363
        • Duns G.
        • van den Berg E.
        • van DuivenbodeI.
        • et al.
        Histone methyltransferase gene SETD2 is a novel tumor suppressor gene in clear cell renal cell carcinoma.
        Cancer Res. 2010; 70: 4287-4291
        • Duns G.
        • Hofstra R.M.
        • Sietzema J.G.
        • et al.
        Targeted exome sequencing in clear cell renal cell carcinoma tumors suggests aberrant chromatin regulation as a crucial step in ccRCC development.
        Hum Mutat. 2012; 33: 1059-1062
        • Guo G.
        • Gui Y.
        • Gao S.
        • et al.
        Frequent mutations of genes encoding ubiquitin-mediated proteolysis pathway components in clear cell renal cell carcinoma.
        Nat Genet. 2012; 44: 17-19
        • Coupier I.
        • Cousin P.Y.
        • Hughes D.
        • et al.
        BAP1 and breast cancer risk.
        Fam Cancer. 2005; 4: 273-277
        • Guenard F.
        • Labrie Y.
        • Ouellette G.
        • et al.
        Genetic sequence variations of BRCA1-interacting genes AURKA, BAP1, BARD1 and DHX9 in French Canadian families with high risk of breast cancer.
        J Hum Genet. 2009; 54: 152-161
        • Je E.M.
        • Lee S.H.
        • Yoo N.J.
        Somatic mutation of a tumor suppressor gene BAP1 is rare in breast, prostate, gastric and colorectal cancers.
        APMIS. 2012; 120: 855-856
        • Forbes S.A.
        • Bhamra G.
        • Bamford S.
        • et al.
        The Catalogue of Somatic Mutations in Cancer (COSMIC).
        in: Curr Protoc Hum Genet. 2008 (Ch 10, Unit 10.11)
        • Forbes S.A.
        • Bindal N.
        • Bamford S.
        • et al.
        COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer.
        Nucleic Acids Res. 2011; 39 (Database issue): D945-D950
        • Stephens P.J.
        • Tarpey P.S.
        • Davies H.
        • et al.
        The landscape of cancer genes and mutational processes in breast cancer.
        Nature. 2012; 486: 400-404
        • Buchhagen D.L.
        • Qiu L.
        • Etkind P.
        Homozygous deletion, rearrangement and hypermethylation implicate chromosome region 3p14. 3-3p21.3 in sporadic breast-cancer development.
        Int J Cancer. 1994; 57: 473-479
        • Thiberville L.
        • Bourguignon J.
        • Metayer J.
        • et al.
        Frequency and prognostic evaluation of 3p21-22 allelic losses in non-small-cell lung cancer.
        Int J Cancer. 1995; 64: 371-377
        • Wood L.D.
        • Parsons D.W.
        • Jones S.
        • et al.
        The genomic landscapes of human breast and colorectal cancers.
        Science. 2007; 318: 1108-1113
        • Gelsi-Boyer V.
        • Trouplin V.
        • Adelaide J.
        • et al.
        Mutations of polycomb-associated gene ASXL1 in myelodysplastic syndromes and chronic mye-lomonocytic leukaemia.
        Br J Haematol. 2009; 145: 788-800
        • Boultwood J.
        • Perry J.
        • Pellagatti A.
        • et al.
        Frequent mutation of the polycomb-associated gene ASXL1 in the myelodysplastic syndromes and in acute myeloid leukemia.
        Leukemia. 2010; 24: 1062-1065
        • Dey A.
        • Seshasayee D.
        • Noubade R.
        • et al.
        Loss of the tumor suppressor BAP1 causes myeloid transformation.
        Science. 2012; 337: 1541-1546
      2. OMIM: #614327. Tumor predisposition syndrome. 12 Apr 2012 (cited 5 Sep 2012). http://omim.org/entry/614327

        • Guney I.
        • Wu S.
        • Sedivy J.M.
        Reduced c-Myc signaling triggers telomere-independent senescence by regulating Bmi-1 and p16(INK4a).
        Proc Natl Acad Sci USA. 2006; 103: 3645-3650
        • Silva J.
        • Garcia J.M.
        • Pena C.
        • et al.
        Implication of polycomb members Bmi-1, Mel-18, and Hpc-2 in the regulation of p16INK4a, p14ARF, h-TERT, and c-Myc expression in primary breast carcinomas.
        Clin Cancer Res. 2006; 12: 6929-6936
        • Wang E.
        • Bhattacharyya S.
        • Szabolcs A.
        • et al.
        Enhancing chemotherapy response with Bmi-1 silencing in ovarian cancer.
        PLoS One. 2011; 6: e17918
        • Yong A.S.
        • Stephens N.
        • Weber G.
        • et al.
        Improved outcome following allogeneic stem cell transplantation in chronic myeloid leukemia is associated with higher expression of BMI-1 and immune responses to BMI-1 protein.
        Leukemia. 2011; 25: 629-637
        • Kemp C.D.
        • Rao M.
        • Xi S.
        • et al.
        Polycomb repressor complex-2 is a novel target for mesothelioma therapy.
        Clin Cancer Res. 2012; 18: 77-90
        • Fan T.
        • Jiang S.
        • Chung N.
        • et al.
        EZH2-dependent suppression of a cellular senescence phenotype in melanoma cells by inhibition of p21/CDKN1A expression.
        Mol Cancer Res. 2011; 9: 418-429
        • Gonzalez M.A.
        • Ben-Dor I.
        • Gaglia Jr, M.A.
        • et al.
        Qualitative comparison of coronary angiograms between 4 French catheters with an advanced cardiovascular injection system and 6 French catheters with manual injection.
        Catheter Cardiovasc Interv. 2012; 79: 843-848
        • Cao L.
        • Bombard J.
        • Cintron K.
        • et al.
        BMI1 as a novel target for drug discovery in cancer.
        J Cell Biochem. 2011; 112: 2729-2741
        • Liu L.
        • Andrews L.G.
        • Tollefsbol T.O.
        Loss of the human polycomb group protein BMI1 promotes cancer-specific cell death.
        Oncogene. 2006; 25: 4370-4375
        • Bommi P.V.
        • Dimri M.
        • Sahasrabuddhe A.A.
        • et al.
        The polycomb group protein BMI1 is a transcriptional target of HDAC inhibitors.
        Cell Cycle. 2010; 9: 2663-2673
        • Landreville S.
        • Agapova O.A.
        • Matatall K.A.
        • et al.
        Histone deacetylase inhibitors induce growth arrest and differentiation in uveal melanoma.
        Clin Cancer Res. 2012; 18: 408-416
        • Gottlicher M.
        • Minucci S.
        • Zhu P.
        • et al.
        Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells.
        EMBO J. 2001; 20: 6969-6978
        • Tan J.
        • Cang S.
        • Ma Y.
        • et al.
        Novel histone deacetylase inhibitors in clinical trials as anti-cancer agents.
        J Hematol Oncol. 2010; 3: 5
        • Rocca A.
        • Minucci S.
        • Tosti G.
        • et al.
        A phase I-II study of the histone deacetylase inhibitor valproic acid plus chemoimmuno-therapy in patients with advanced melanoma.
        Br J Cancer. 2009; 100: 28-36
        • Mendes-Pereira A.M.
        • Sims D.
        • Dexter T.
        • et al.
        Genome-wide functional screen identifies a compendium of genes affecting sensitivity to tamoxifen.
        Proc Natl Acad Sci USA. 2012; 109: 2730-2735
      3. NCBI. NCBI Reference Sequence: NP_004647.1. ubiquitin carboxyl-term-inal hydrolase. BAP1 [Homo sapiens]. Cited 19 Sep 2012. http://www.ncbi.nlm.nih.gov/protein/4757836?report=graph