Can Mutations in the BAP1 Gene be Detected by Immunohisto-chemistry in Hereditary Kidney Cancers?

• Arunima Ghosh

  Translational Surgical Pathology, Laboratory of Pathology and Urologic Oncology Branch, NCI, NIH, Bethesda, MD, USA

• Karlena Lara-Otero

  Translational Surgical Pathology, Laboratory of Pathology and Urologic Oncology Branch, NCI, NIH, Bethesda, MD, USA

• Marston W. Linehan

  Translational Surgical Pathology, Laboratory of Pathology and Urologic Oncology Branch, NCI, NIH, Bethesda, MD, USA

• Maria J. Merino

  Translational Surgical Pathology, Laboratory of Pathology and Urologic Oncology Branch, NCI, NIH, Bethesda, MD, USA

  Background: Hereditary renal cell carcinoma (RCC) constitutes about 5% of all RCCs. The most common and well studied syndromes include, VHL, HLRCC, BHD, Familial Oncocytoma, RCC Papillary Type 1, TSC, RCC associated with Succinate dehydrogenase B (SHDB) mutations and others. Several genes, including VHL, MET, FLCN, FH and genes encoding the succinate dehydrogenase (SDH) subunits B/C/D have been identified as causative. However, the genetic basis of a significant percentage of familial RCC, some with clear cell morphology remain unknown. BAP1 (BRCA1 associated protein-1), a tumor suppressor gene that encodes a nuclear deubiquitinase, is inactivated in 15% of sporadic clear cell RCCs and its loss was associated with high tumor grade and poor prognosis. In this study, we investigated the possible role of this gene in the spectrum of RCC part of hereditary syndromes.

Materials and Methods: To elucidate the role of BAP1 in all the spectrum of hereditary RCC, we studied by IHC a panel of RCCs which covers the spectrum of kidney cancers and included 10 VHL tumors, 6 HLRCCs, 8 chromophobe, 5 Hereditary Papillary Type 1, 6 Oncocytomas, 3 BHD (hybrid), and 24 sporadic clear cell RCCs. To analyze the BAP1 expression in these tumors, formalin fixed paraffin embedded (FFPE) tissues were immunostained with mouse monoclonal anti-human BAP1 antibody (Clone C-4, Santa Cruz).

Results: We found that all the tumors except two showed positive nuclear staining for BAP1. The two negative cases that were negative for BAP1 were Clear cell type and belonged to two siblings. Molecular analysis in a prepublished study showed both patients harboring the p.L14H mutation.

Conclusion: Our study supports the hypothesis that BAP1 mutations can play a role in hereditary syndromes predominantly in clear cell tumors. Staining for BAP1 should be done when there is no definite known mutation in a clear cell cancer but the patient gives history of familial kidney cancer. The two related patients who had similar mutations had aggressive, metastatic disease, which suggests that probably BAP1 does play a role in hereditary RCC clear cell type.

Richards FM, Crossey PA, Phipps ME, Foster K, Latif F, Evans G, et al. Detailed mapping of germline deletions of the von Hippel-Lindau disease tumour suppressor gene. Hum Mol Genet 1994; 3(4): 595-8. http://dx.doi.org/10.1093/hmg/3.4.595

Richards FM, Maher ER, Latif F, Phipps ME, Tory K, Lush M, et al. Detailed genetic mapping of the von Hippel-Lindau disease tumour suppressor gene. J Med Genet 1993; 30(2): 104-7. http://dx.doi.org/10.1136/jmg.30.2.104

Richards FM, Phipps ME, Latif F, Yao M, Crossey PA, Foster K, et al. Mapping the Von Hippel-Lindau disease tumour suppressor gene: identification of germline deletions by pulsed field gel electrophoresis. Hum Mol Genet 1993; 2(7): 879-82. http://dx.doi.org/10.1093/hmg/2.7.879

Latif F, Tory K, Gnarra J, Yao M, Duh FM, Orcutt ML, et al. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 1993; 260(5112): 1317-20. http://dx.doi.org/10.1126/science.8493574

Khoo SK, Bradley M, Wong FK, Hedblad MA, Nordenskjold M, Teh BT. Birt-Hogg-Dube syndrome: mapping of a novel hereditary neoplasia gene to chromosome 17p12-q11.2. Oncogene 2001; 20(37): 5239-42. http://dx.doi.org/10.1038/sj.onc.1204703

Schmidt LS, Warren MB, Nickerson ML, Weirich G, Matrosova V, Toro JR, et al. Birt-Hogg-Dube syndrome, a genodermatosis associated with spontaneous pneumothorax and kidney neoplasia, maps to chromosome 17p11.2. Am J Hum Genet 2001; 69(4): 876-82. http://dx.doi.org/10.1086/323744

Nickerson ML, Warren MB, Toro JR, Matrosova V, Glenn G, Turner ML, et al. Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dube syndrome. Cancer Cell 2002; 2(2): 157-64. http://dx.doi.org/10.1016/S1535-6108(02)00104-6

Zbar B, Glenn G, Lubensky I, Choyke P, Walther MM, Magnusson G, et al. Hereditary papillary renal cell carcinoma: clinical studies in 10 families. J Urol 1995; 153(3 Pt 2): 907-12.

Zbar B, Tory K, Merino M, Schmidt L, Glenn G, Choyke P, et al. Hereditary papillary renal cell carcinoma. J Urol 1994; 151(3): 561-6.

Toro JR, Nickerson ML, Wei MH, Warren MB, Glenn GM, Turner ML, et al. Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America. Am J Hum Genet 2003; 73(1): 95-106. http://dx.doi.org/10.1086/376435

Alam NA, Rowan AJ, Wortham NC, Pollard PJ, Mitchell M, Tyrer JP, et al. Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency. Hum Mol Genet 2003; 12(11): 1241-52. http://dx.doi.org/10.1093/hmg/ddg148

Merino MJ, Torres-Cabala C, Pinto P, Linehan WM. The morphologic spectrum of kidney tumors in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome. Am J Surg Pathol 2007; 31(10): 1578-85. http://dx.doi.org/10.1097/PAS.0b013e31804375b8

Wei MH, Toure O, Glenn GM, Pithukpakorn M, Neckers L, Stolle C, et al. Novel mutations in FH and expansion of the spectrum of phenotypes expressed in families with hereditary leiomyomatosis and renal cell cancer. J Med Genet 2006; 43(1): 18-27. http://dx.doi.org/10.1136/jmg.2005.033506

Smit DL, Mensenkamp AR, Badeloe S, Breuning MH, Simon ME, van Spaendonck KY, et al. Hereditary leiomyomatosis and renal cell cancer in families referred for fumarate hydratase germline mutation analysis. Clin Genet 2011; 79(1): 49-59. http://dx.doi.org/10.1111/j.1399-0004.2010.01486.x

Ricketts C, Woodward ER, Killick P, Morris MR, Astuti D, Latif F, et al. Germline SDHB mutations and familial renal cell carcinoma. J Natl Cancer Inst 2008; 100(17): 1260-2. http://dx.doi.org/10.1093/jnci/djn254

Vanharanta S, Buchta M, McWhinney SR, Virta SK, Peczkowska M, Morrison CD, et al. Early-onset renal cell carcinoma as a novel extraparaganglial component of SDHB-associated heritable paraganglioma. Am J Hum Genet 2004; 74(1): 153-9. http://dx.doi.org/10.1086/381054

Morris MR, Maina E, Morgan NV, Gentle D, Astuti D, Moch H, et al. Molecular genetic analysis of FIH-1, FH, and SDHB candidate tumour suppressor genes in renal cell carcinoma. J Clin Pathol 2004; 57(7): 706-11. http://dx.doi.org/10.1136/jcp.2003.011767

Eletr ZM, Wilkinson KD. An emerging model for BAP1's role in regulating cell cycle progression. Cell Biochem Biophys 2011; 60(1-2): 3-11. http://dx.doi.org/10.1007/s12013-011-9184-6

Jensen DE, Proctor M, Marquis ST, Gardner HP, Ha SI, Chodosh LA, et al. BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression. Oncogene 1998; 16(9): 1097-112. http://dx.doi.org/10.1038/sj.onc.1201861

Ventii KH, Devi NS, Friedrich KL, Chernova TA, Tighiouart M, Van Meir EG, et al. BRCA1-associated protein-1 is a tumor suppressor that requires deubiquitinating activity and nuclear localization. Cancer Res 2008; 68(17): 6953-62. http://dx.doi.org/10.1158/0008-5472.CAN-08-0365

Bott M, Brevet M, Taylor BS, Shimizu S, Ito T, Wang L, et al. The nuclear deubiquitinase BAP1 is commonly inactivated by somatic mutations and 3p21.1 losses in malignant pleural mesothelioma. Nat Genet 2011; 43(7): 668-72. http://dx.doi.org/10.1038/ng.855

Harbour JW, Onken MD, Roberson ED, Duan S, Cao L, Worley LA, et al. Frequent mutation of BAP1 in metastasizing uveal melanomas. Science 2010; 330(6009): 1410-3. http://dx.doi.org/10.1126/science.1194472

Pena-Llopis S, Vega-Rubin-de-Celis S, Liao A, Leng N, Pavia-Jimenez A, Wang S, et al. BAP1 loss defines a new class of renal cell carcinoma. Nat Genet 2012; 44(7): 751-9. http://dx.doi.org/10.1038/ng.2323

Popova T, Hebert L, Jacquemin V, Gad S, Caux-Moncoutier V, Dubois-d'Enghien C, et al. Germline BAP1 mutations predispose to renal cell carcinomas. Am J Hum Genet 2013; 92(6): 974-80. http://dx.doi.org/10.1016/j.ajhg.2013.04.012

Kapur P, Pena-Llopis S, Christie A, Zhrebker L, Pavia-Jimenez A, Rathmell WK, et al. Effects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal-cell carcinoma: a retrospective analysis with independent validation. Lancet Oncol 2013; 14(2): 159-67. http://dx.doi.org/10.1016/S1470-2045(12)70584-3

Farley MN, Schmidt LS, Mester JL, Pena-Llopis S, Pavia-Jimenez A, Christie A, et al. A novel germline mutation in BAP1 predisposes to familial clear-cell renal cell carcinoma. Mol Cancer Res 2013; 11(9): 1061-71. http://dx.doi.org/10.1158/1541-7786.MCR-13-0111

Kapur P, Christie A, Raman JD, Then MT, Nuhn P, Buchner A, et al. BAP1 immunohistochemistry predicts outcomes in a multi-institutional cohort with clear cell renal cell carcinoma. J Urol 2014; 191(3): 603-10. http://dx.doi.org/10.1016/j.juro.2013.09.041

Abdel-Rahman MH, Pilarski R, Cebulla CM, Massengill JB, Christopher BN, Boru G, et al. Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers. J Med Genet 2011; 48(12): 856-9. http://dx.doi.org/10.1136/jmedgenet-2011-100156

Aoude LG, Vajdic CM, Kricker A, Armstrong B, Hayward NK. Prevalence of germline BAP1 mutation in a population-based sample of uveal melanoma cases. Pigment Cell Melanoma Res 2013; 26(2): 278-9. http://dx.doi.org/10.1111/pcmr.12046

Njauw CN, Kim I, Piris A, Gabree M, Taylor M, Lane AM, et al. Germline BAP1 inactivation is preferentially associated with metastatic ocular melanoma and cutaneous-ocular melanoma families. PLoS One 2012; 7(4): e35295. http://dx.doi.org/10.1371/journal.pone.0035295

Testa JR, Cheung M, Pei J, Below JE, Tan Y, Sementino E, et al. Germline BAP1 mutations predispose to malignant mesothelioma. Nat Genet 2011; 43(10): 1022-5. http://dx.doi.org/10.1038/ng.912

Hakimi AA, Ostrovnaya I, Reva B, Schultz N, Chen YB, Gonen M, et al. Adverse outcomes in clear cell renal cell carcinoma with mutations of 3p21 epigenetic regulators BAP1 and SETD2: a report by MSKCC and the KIRC TCGA research network. Clin Cancer Res 2013; 19(12): 3259-67. http://dx.doi.org/10.1158/1078-0432.CCR-12-3886

• PDF