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Loss of BAP1 in Pheochromocytomas and Paragangliomas Seems Unrelated to Genetic Mutations

Abstract

Breast cancer–associated protein 1 (BAP1) gene is a broad-spectrum tumor suppressor. Indeed, its loss of expression, due to biallelic inactivating mutations or deletions, has been described in several types of tumors including melanoma, malignant mesothelioma, renal cell carcinoma, and others. There are so far only two reports of BAP1-mutated paraganglioma, suggesting the possible involvement of this gene in paraganglioma (PGL) and pheochromocytoma (PCC) pathogenesis. We assessed BAP1 expression by immunohistochemistry (IHC) in a cohort of 56 PCC/PGL patients (and corresponding metastases, when available). Confirmatory Sanger sequencing (exons 1–17) of BAP1 has been performed in those samples which resulted negative by IHC. BAP1 nuclear expression was lost in 2/22 (9.1%) PGLs and in 12/34 (35.3%) PCCs, five of which harboring a germline mutation predisposing the development of such tumors (MENIN, MAX, SDHB, SDHD, and RET gene). Confirmatory Sanger sequencing revealed the wild-type BAP1 status of all the analyzed samples. No heterogeneity between primary and metastatic tissue was observed. This study documents that the loss of BAP1 nuclear expression is quite a frequent finding in PCC/PGL, suggesting a possible role of BAP1 in the pathogenesis of these tumors. Gene mutations do not seem to be involved in this loss of expression, at least in most cases. Other genetic and epigenetic mechanisms need to be further investigated.

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References

  1. 1.

    Lloyd RV, Osamura RY, Klöppel G, Rosai J (eds) (2017) WHO Classification of tumours of endocrine organs, 4th ed. IARC, Lyon, France

    Google Scholar 

  2. 2.

    Pillai S, Gopalan V, Smith RA, Lam AK-Y (2016) Updates on the genetics and the clinical impacts on phaeochromocytoma and paraganglioma in the new era. Crit Rev Oncol Hematol 100:190–208. https://doi.org/10.1016/j.critrevonc.2016.01.022

    Article  PubMed  Google Scholar 

  3. 3.

    Fishbein L, Leshchiner I, Walter V, Danilova L., Robertson A.G., Johnson A.R., Lichtenberg T.M., Murray B.A., Ghayee H.K., Else T., Ling S., Jefferys S.R., de Cubas A.A., Wenz B., Korpershoek E., Amelio A.L., Makowski L., Rathmell W.K., Gimenez-Roqueplo A.P., Giordano T.J., Asa S.L., Tischler A.S., Cancer Genome Atlas Research Network, Pacak K., Nathanson K.L., Wilkerson M.D. (2017) Comprehensive molecular characterization of pheochromocytoma and paraganglioma. Cancer Cell 31:181–193. https://doi.org/10.1016/j.ccell.2017.01.001

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Zhikrivetskaya SO, Snezhkina AV, Zaretsky AR, Alekseev BY, Pokrovsky AV, Golovyuk AL, Melnikova NV, Stepanov OA, Kalinin DV, Moskalev AA, Krasnov GS, Dmitriev AA, Kudryavtseva AV (2017) Molecular markers of paragangliomas/pheochromocytomas. Oncotarget 8:25756–25782. https://doi.org/10.18632/oncotarget.15201

    Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Carbone M, Yang H, Pass HI, Krausz T, Testa JR, Gaudino G (2013) BAP1 and cancer. Nat Rev Cancer 13:153–159. https://doi.org/10.1038/nrc3459

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    White AE, Harper JW (2012) Cancer. Emerging anatomy of the BAP1 tumor suppressor system. Science 337:1463–1464. https://doi.org/10.1126/science.1228463

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Carbone M, Ferris LK, Baumann F, Napolitano A, Lum CA, Flores EG, Gaudino G, Powers A, Bryant-Greenwood P, Krausz T, Hyjek E, Tate R, Friedberg J, Weigel T, Pass HI, Yang H (2012) BAP1 cancer syndrome: malignant mesothelioma, uveal and cutaneous melanoma, and MBAITs. J Transl Med 10:179. https://doi.org/10.1186/1479-5876-10-179

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Wang A, Papneja A, Hyrcza M, al-Habeeb A, Ghazarian D (2016) Gene of the month: BAP1. J Clin Pathol 69:750–753. https://doi.org/10.1136/jclinpath-2016-203866

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Wiesner T, Obenauf AC, Murali R, Fried I, Griewank KG, Ulz P, Windpassinger C, Wackernagel W, Loy S, Wolf I, Viale A, Lash AE, Pirun M, Socci ND, Rütten A, Palmedo G, Abramson D, Offit K, Ott A, Becker JC, Cerroni L, Kutzner H, Bastian BC, Speicher MR (2011) Germline mutations in BAP1 predispose to melanocytic tumors. Nat Genet 43:1018–1021. https://doi.org/10.1038/ng.910

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Watchorn RE, Calonje E, Taibjee SM (2018) Germline BRCA1-associated protein 1 mutation presenting as BAP1 inactivated melanocytic nevi in a child of a father with fatal paraganglioma. Pediatr Dermatol 35:e316–e318. https://doi.org/10.1111/pde.13553

    Article  PubMed  Google Scholar 

  11. 11.

    Wadt K, Choi J, Chung J-Y, Kiilgaard J, Heegaard S, Drzewiecki KT, Trent JM, Hewitt SM, Hayward NK, Gerdes AM, Brown KM (2012) A cryptic BAP1 splice mutation in a family with uveal and cutaneous melanoma, and paraganglioma. Pigment Cell Melanoma Res 25:815–818. https://doi.org/10.1111/pcmr.12006

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Peña-Llopis S, Vega-Rubín-de-Celis S, Liao A, Leng N, Pavía-Jiménez A, Wang S, Yamasaki T, Zhrebker L, Sivanand S, Spence P, Kinch L, Hambuch T, Jain S, Lotan Y, Margulis V, Sagalowsky AI, Summerour PB, Kabbani W, Wong SW, Grishin N, Laurent M, Xie XJ, Haudenschild CD, Ross MT, Bentley DR, Kapur P, Brugarolas J (2012) BAP1 loss defines a new class of renal cell carcinoma. Nat Genet 44:751–759. https://doi.org/10.1038/ng.2323

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Shankar GM, Abedalthagafi M, Vaubel RA, Merrill PH, Nayyar N, Gill CM, Brewster R, Bi WL, Agarwalla PK, Thorner AR, Reardon DA, al-Mefty O, Wen PY, Alexander BM, van Hummelen P, Batchelor TT, Ligon KL, Ligon AH, Meyerson M, Dunn IF, Beroukhim R, Louis DN, Perry A, Carter SL, Giannini C, Curry WT Jr, Cahill DP, Barker FG 2nd, Brastianos PK, Santagata S (2017) Germline and somatic BAP1 mutations in high-grade rhabdoid meningiomas. Neuro Oncology 19:535–545. https://doi.org/10.1093/neuonc/now235

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Jiao Y, Pawlik TM, Anders RA, Selaru FM, Streppel MM, Lucas DJ, Niknafs N, Guthrie VB, Maitra A, Argani P, Offerhaus GJA, Roa JC, Roberts LR, Gores GJ, Popescu I, Alexandrescu ST, Dima S, Fassan M, Simbolo M, Mafficini A, Capelli P, Lawlor RT, Ruzzenente A, Guglielmi A, Tortora G, de Braud F, Scarpa A, Jarnagin W, Klimstra D, Karchin R, Velculescu VE, Hruban RH, Vogelstein B, Kinzler KW, Papadopoulos N, Wood LD (2013) Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas. Nat Genet 45:1470–1473. https://doi.org/10.1038/ng.2813

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Luchini C, Veronese N, Yachida S, Cheng L, Nottegar A, Stubbs B, Solmi M, Capelli P, Pea A, Barbareschi M, Fassan M, Wood LD, Scarpa A (2016) Different prognostic roles of tumor suppressor gene BAP1 in cancer: a systematic review with meta-analysis. Genes Chromosomes Cancer 55:741–749. https://doi.org/10.1002/gcc.22381

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Snezhkina AV, Lukyanova EN, Kalinin DV, Pokrovsky AV, Dmitriev AA, Koroban NV, Pudova EA, Fedorova MS, Volchenko NN, Stepanov OA, Zhevelyuk EA, Kharitonov SL, Lipatova AV, Abramov IS, Golovyuk AV, Yegorov YE, Vishnyakova KS, Moskalev AA, Krasnov GS, Melnikova NV, Shcherbo DS, Kiseleva MV, Kaprin AD, Alekseev BY, Zaretsky AR, Kudryavtseva AV (2018) Exome analysis of carotid body tumor. BMC Med Genomics 11:17. https://doi.org/10.1186/s12920-018-0327-0

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Sauerbrei W, Taube SE, McShane LM, Cavenagh MM, Altman DG (2018) Reporting recommendations for tumor marker prognostic studies (REMARK): an abridged explanation and elaboration. J Natl Cancer Inst 110:803–811. https://doi.org/10.1093/jnci/djy088

    Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Sarcognato S, Gringeri E, Fassan M, di Giunta M, Maffeis V, Guzzardo V, Cillo U, Guido M (2019) Prognostic role of BAP-1 and PBRM-1 expression in intrahepatic cholangiocarcinoma. Virchows Arch 474:29–37. https://doi.org/10.1007/s00428-018-2478-y

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Elder DE, Massi D, Scolyer R, Willemze R (eds) (2018) WHO classification of skin tumours, 4th ed. IARC, Lyon, France

    Google Scholar 

  20. 20.

    cBioPortal (2019). https://www.cbioportal.org/ Accessed 19 July 2019

  21. 21.

    Shah AA, Bourne TD, Murali R (2013) BAP1 protein loss by immunohistochemistry: a potentially useful tool for prognostic prediction in patients with uveal melanoma. Pathology 45:651–656. https://doi.org/10.1097/PAT.0000000000000002

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Koopmans AE, Verdijk RM, Brouwer RWW, van den Bosch T, van den Berg M, Vaarwater J, Kockx CE, Paridaens D, Naus NC, Nellist M, van IJcken W, Kiliç E, de Klein A (2014) Clinical significance of immunohistochemistry for detection of BAP1 mutations in uveal melanoma. Mod Pathol 27:1321–1330. https://doi.org/10.1038/modpathol.2014.43

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Testa JR, Cheung M, Pei J, Below JE, Tan Y, Sementino E, Cox NJ, Dogan AU, Pass HI, Trusa S, Hesdorffer M, Nasu M, Powers A, Rivera Z, Comertpay S, Tanji M, Gaudino G, Yang H, Carbone M (2011) Germline BAP1 mutations predispose to malignant mesothelioma. Nat Genet 43:1022–1025. https://doi.org/10.1038/ng.912

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Nasu M, Emi M, Pastorino S, Tanji M, Powers A, Luk H, Baumann F, Zhang YA, Gazdar A, Kanodia S, Tiirikainen M, Flores E, Gaudino G, Becich MJ, Pass HI, Yang H, Carbone M (2015) High incidence of somatic BAP1 alterations in sporadic malignant mesothelioma. J Thorac Oncol 10:565–576. https://doi.org/10.1097/JTO.0000000000000471

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Murali R, Wiesner T, Scolyer RA (2013) Tumours associated with BAP1 mutations. Pathology 45:116–126. https://doi.org/10.1097/PAT.0b013e32835d0efb

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Abdel-Rahman MH, Pilarski R, Cebulla CM, Massengill JB, Christopher BN, Boru G, Hovland P, Davidorf FH (2011) Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers. J Med Genet 48:856–859. https://doi.org/10.1136/jmedgenet-2011-100156

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Kadariya Y, Cheung M, Xu J, Pei J, Sementino E, Menges CW, Cai KQ, Rauscher FJ, Klein-Szanto AJ, Testa JR (2016) Bap1 is a bona fide tumor suppressor: genetic evidence from mouse models carrying heterozygous germline Bap1 mutations. Cancer Res 76:2836–2844. https://doi.org/10.1158/0008-5472.CAN-15-3371

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Song H, Wang L, Lyu J, Wu Y, Guo W, Ren G (2017) Loss of nuclear BAP1 expression is associated with poor prognosis in oral mucosal melanoma. Oncotarget 8:29080–29090. https://doi.org/10.18632/oncotarget.16175

    Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Crona J, Backman S, Maharjan R, Mayrhofer M, Stålberg P, Isaksson A, Hellman P, Björklund P (2015) Spatiotemporal heterogeneity characterizes the genetic landscape of pheochromocytoma and defines early events in tumorigenesis. Clin Cancer Res 21:4451–4460. https://doi.org/10.1158/1078-0432.CCR-14-2854

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Farquhar N, Thornton S, Coupland SE, Coulson JM, Sacco JJ, Krishna Y, Heimann H, Taktak A, Cebulla CM, Abdel-Rahman MH, Kalirai H (2018) Patterns of BAP1 protein expression provide insights into prognostic significance and the biology of uveal melanoma. J Pathol Clin Res 4:26–38. https://doi.org/10.1002/cjp2.86

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Ewens KG, Lalonde E, Richards-Yutz J, Shields CL, Ganguly A (2018) Comparison of germline versus somatic BAP1 mutations for risk of metastasis in uveal melanoma. BMC Cancer 18:1172. https://doi.org/10.1186/s12885-018-5079-x, 1112

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Ascoli V, Cozzi I, Vatrano S, Izzo S, Giorcelli J, Romeo E, Carnovale-Scalzo C, Grillo LR, Facciolo F, Visca P, Papotti M, Righi L (2016) Mesothelioma families without inheritance of a BAP1 predisposing mutation. Cancer Genet 209:381–387. https://doi.org/10.1016/j.cancergen.2016.07.002

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Hirosawa T, Ishida M, Ishii K, Kanehara K, Kudo K, Ohnuma S, Kamei T, Motoi F, Naitoh T, Selaru FM, Unno M (2018) Loss of BAP1 expression is associated with genetic mutation and can predict outcomes in gallbladder cancer. PLoS ONE 13:e0206643. https://doi.org/10.1371/journal.pone.0206643

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    van de Nes JAP, Nelles J, Kreis S, Metz CH, Hager T, Lohmann DR, Zeschnigk M (2016) Comparing the prognostic value of BAP1 mutation pattern, chromosome 3 status, and BAP1 immunohistochemistry in uveal melanoma. Am J Surg Pathol 40:796–805. https://doi.org/10.1097/PAS.0000000000000645

    Article  PubMed  Google Scholar 

  35. 35.

    Royer-Bertrand B, Torsello M, Rimoldi D, el Zaoui I., Cisarova K., Pescini-Gobert R., Raynaud F., Zografos L., Schalenbourg A., Speiser D., Nicolas M., Vallat L., Klein R., Leyvraz S., Ciriello G., Riggi N., Moulin A.P., Rivolta C. (2016) Comprehensive genetic landscape of uveal melanoma by whole-genome sequencing. Am J Hum Genet 99:1190–1198. https://doi.org/10.1016/j.ajhg.2016.09.008

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Mashtalir N, Daou S, Barbour H, Sen NN, Gagnon J, Hammond-Martel I, Dar HH, Therrien M, Affar el B (2014) Autodeubiquitination protects the tumor suppressor BAP1 from cytoplasmic sequestration mediated by the atypical ubiquitin ligase UBE2O. Mol Cell 54:392–406. https://doi.org/10.1016/j.molcel.2014.03.002

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Ibragimova I, Maradeo ME, Dulaimi E, Cairns P (2013) Aberrant promoter hypermethylation of PBRM1, BAP1, SETD2, KDM6A and other chromatin-modifying genes is absent or rare in clear cell RCC. Epigenetics 8:486–493. https://doi.org/10.4161/epi.24552

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38.

    de Araújo ÉSS, Pramio DT, Kashiwabara AY, et al. (2015) DNA Methylation levels of melanoma risk genes are associated with clinical characteristics of melanoma patients. Biomed Res Int 2015:. https://doi.org/10.1155/2015/376423

    Article  Google Scholar 

  39. 39.

    Field MG, Kuznetsov JN, Bussies PL, et al. (2019) BAP1 loss is associated with DNA methylomic repatterning in highly aggressive Class 2 uveal melanomas. Clin Cancer Res https://doi.org/10.1158/1078-0432.CCR-19-0366

    Article  Google Scholar 

  40. 40.

    Hedayat AA, Lefferts JA, Atkinson AE, et al. (2019) BAP1-deficient tumor/nevus with germline aberration: a potential pitfall in assessing melanocytic neoplasms with single nucleotide polymorphism array. J Cutan Pathol https://doi.org/10.1111/cup.13488

    Article  Google Scholar 

  41. 41.

    Ge Y-Z, Xu L-W, Zhou C-C, Lu TZ, Yao WT, Wu R, Zhao YC, Xu X, Hu ZK, Wang M, Yang XB, Zhou LH, Zhong B, Xu Z, Li WC, Zhu JG, Jia RP (2017) A BAP1 Mutation-specific microRNA signature predicts clinical outcomes in clear cell renal cell carcinoma patients with wild-type BAP1. J Cancer 8:2643–2652. https://doi.org/10.7150/jca.20234

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Castro-Vega LJ, Letouzé E, Burnichon N, Buffet A, Disderot PH, Khalifa E, Loriot C, Elarouci N, Morin A, Menara M, Lepoutre-Lussey C, Badoual C, Sibony M, Dousset B, Libé R, Zinzindohoue F, Plouin PF, Bertherat J, Amar L, de Reyniès A, Favier J, Gimenez-Roqueplo AP (2015) Multi-omics analysis defines core genomic alterations in pheochromocytomas and paragangliomas. Nat Commun 6:6044. https://doi.org/10.1038/ncomms7044

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Yu M, Liang H, Fu Z, Wang X, Liao Z, Zhou Y, Liu Y, Wang Y, Hong Y, Zhou X, Yan X, Yu M, Ma M, Zhang W, Guo B, Zhang J, Zen K, Zhang CY, Wang T, Zhang Q, Chen X (2016) BAP1 suppresses lung cancer progression and is inhibited by miR-31. Oncotarget 7:13742–13753. https://doi.org/10.18632/oncotarget.7328

    Article  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Wang X-Y, Wang Z, Huang J-B, Ren XD, Ye D, Zhu WW, Qin LX (2017) Tissue-specific significance of BAP1 gene mutation in prognostic prediction and molecular taxonomy among different types of cancer. Tumour Biol 39:1010428317699111. https://doi.org/10.1177/1010428317699111

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Cigognetti M, Lonardi S, Fisogni S, Balzarini P, Pellegrini V, Tironi A, Bercich L, Bugatti M, Rossi G, Murer B, Barbareschi M, Giuliani S, Cavazza A, Marchetti G, Vermi W, Facchetti F (2015) BAP1 (BRCA1-associated protein 1) is a highly specific marker for differentiating mesothelioma from reactive mesothelial proliferations. Mod Pathol 28:1043–1057. https://doi.org/10.1038/modpathol.2015.65

    CAS  Article  PubMed  Google Scholar 

  46. 46.

    Walpole S, Pritchard AL, Cebulla CM, Pilarski R, Stautberg M, Davidorf FH, de la Fouchardière A, Cabaret O, Golmard L, Stoppa-Lyonnet D, Garfield E, Njauw CN, Cheung M, Turunen JA, Repo P, Järvinen RS, van Doorn R, Jager MJ, Luyten GPM, Marinkovic M, Chau C, Potrony M, Höiom V, Helgadottir H, Pastorino L, Bruno W, Andreotti V, Dalmasso B, Ciccarese G, Queirolo P, Mastracci L, Wadt K, Kiilgaard JF, Speicher MR, van Poppelen N, Kilic E, al-Jamal RT, Dianzani I, Betti M, Bergmann C, Santagata S, Dahiya S, Taibjee S, Burke J, Poplawski N, O'Shea SJ, Newton-Bishop J, Adlard J, Adams DJ, Lane AM, Kim I, Klebe S, Racher H, Harbour JW, Nickerson ML, Murali R, Palmer JM, Howlie M, Symmons J, Hamilton H, Warrier S, Glasson W, Johansson P, Robles-Espinoza CD, Ossio R, de Klein A, Puig S, Ghiorzo P, Nielsen M, Kivelä TT, Tsao H, Testa JR, Gerami P, Stern MH, Paillerets BB, Abdel-Rahman MH, Hayward NK (2018) Comprehensive study of the clinical phenotype of germline BAP1 variant-carrying families worldwide. J Natl Cancer Inst 110:1328–1341. https://doi.org/10.1093/jnci/djy171

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

The preliminary results of this study were presented at the 29th European Congress of Pathology that was held in Amsterdam, Netherland, on the 3th of September 2017. The authors are grateful to Simone Zorzi and Mattia Pegoraro for their technical assistance.

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VM and RC: conception and design of the study, acquisition, analysis and interpretation of data, writing and revision of the manuscript. LN: acquisition and analysis of data. VG: development of methodology, technical and material contribution. CM and LE: development of methodology, technical and material contribution, revision of the manuscript. FS: collection of data. MG: reagents, material, and analysis tool contribution. AF: conception and design of the study, revision of the manuscript, supervision of the study. All of the authors confirm that each of them qualifies for all the criteria of authorship.

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Correspondence to Ambrogio Fassina.

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Maffeis, V., Cappellesso, R., Nicolè, L. et al. Loss of BAP1 in Pheochromocytomas and Paragangliomas Seems Unrelated to Genetic Mutations. Endocr Pathol 30, 276–284 (2019). https://doi.org/10.1007/s12022-019-09595-0

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Keywords

  • BAP1
  • Immunohistochemistry
  • Sanger sequencing
  • Pheochromocytoma
  • Paraganglioma