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Immunohistochemical Assessment of BAP1 Protein in Mucoepidermoid Carcinomas

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Abstract

Mucoepidermoid carcinomas are common malignant salivary gland tumors. Despite recent advances in diagnosis and treatment, there has not been much improvement in outcome of these patients, necessitating identification of novel targeted therapeutic agents. Genomic profiling of mucoepidermoid carcinomas has recently revealed aberrations in BAP1 gene. Therefore, we conducted this study to identify BAP1 loss by immunohistochemistry in these tumors. Mucoepidermoid carcinoma cases were retrieved; hematoxylin-and-eosin stained sections were reviewed. Immunohistochemistry for BAP1 was performed. Forty cases were assessed, including 25 salivary gland and 15 pulmonary mucoepidermoid carcinomas. There were 19 cases in the parotid (76%), two in submandibular gland (8%), and remaining 16% from minor salivary gland locations. Ten (40%) were low grade, nine (36%) were intermediate grade, and six (24%) were high grade mucoepidermoid carcinomas. Thirteen (86.7%) pulmonary mucoepidermoid carcinomas were tracheobronchial, while two (13.3%) were intraparenchymal; all were low grade mucoepidermoid carcinomas. On immunohistochemistry, BAP1 nuclear staining was retained in all cases (100%), irrespective of tumor location or grade. Therapeutic connotations necessitate the identification of readily applicable techniques to detect BAP1 loss in mucoepidermoid carcinomas. Using immunohistochemistry, loss of BAP1 staining was not seen in any of our cases, suggesting insensitivity of BAP1 IHC to detect aberrations at genomic level in these tumors. Analysis of BAP1 alterations by targeted sequencing may therefore be performed prior to excluding the possibility of response to BAP1-targeted therapeutics based on immunohistochemistry alone.

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References

  1. Kato S, Elkin SK, Schwaederle M et al (2015) Genomic landscape of salivary gland tumors. Oncotarget 6:25631–25645

    PubMed  PubMed Central  Google Scholar 

  2. Wahlberg P, Anderson H, Biorklund A et al (2002) Carcinoma of the parotid and submandibular glands—a study of survival in 2465 patients. Oral Oncol 38:706–713

    Article  PubMed  Google Scholar 

  3. Jones AV, Craig GT, Speight PM et al (2008) The range and demo-graphics of salivary gland tumours diagnosed in a UK population. Oral Oncol 44:407–417

    Article  PubMed  CAS  Google Scholar 

  4. Wang K, McDermott JD, Schrock AB et al (2017) Comprehensive genomic profiling of salivary mucoepidermoid carcinomas reveals frequent BAP1, PIK3CA, and other actionable genomic alterations. Ann Oncol 28:748–753

    Article  PubMed  CAS  Google Scholar 

  5. Brandwein MS, Ivanov K, Wallace DI et al (2001) Mucoepidermoid carcinoma: a clinicopathologic study of 80 patients with special reference to histological grading. Am J Surg Pathol 25:835–845

    Article  PubMed  CAS  Google Scholar 

  6. Chen MM, Roman SA, Sosa JA et al (2014) Histologic grade as prognostic indicator for mucoepidermoid carcinoma: a population-level analysis of 2400 patients. Head Neck 36:158–163

    Article  PubMed  CAS  Google Scholar 

  7. Hsieh CC, Sun YH, Lin SW et al (2017) Surgical outcomes of pulmonary mucoepidermoid carcinoma: a review of 41 cases. PLoS ONE 12:e0176918

    Article  PubMed  PubMed Central  Google Scholar 

  8. Kalhor N, Moran CA (2018) Pulmonary mucoepidermoid carcinoma: diagnosis and treatment. Expert Rev Respir Med 12:249–255

    Article  PubMed  CAS  Google Scholar 

  9. Salem A, Bell D, Sepesi B et al (2017) Clinicopathologic and genetic features of primary bronchopulmonary mucoepidermoid carcinoma: the MD Anderson Cancer Center experience and comprehensive review of the literature. Virchows Arch 470:619–626

    Article  PubMed  CAS  Google Scholar 

  10. Saade RE, Bell D, Garcia J et al (2016) Role of CRTC1/MAML2 translocation in the prognosis and clinical outcomes of mucoepidermoid carcinoma. JAMA Otolaryngol Head Neck Surg 142:234–240

    Article  PubMed  Google Scholar 

  11. Jee KJ, Persson M, Heikinheimo K et al (2013) Genomic profiles and CRTC1-MAML2 fusion distinguish different subtypes of mucoepidermoid carcinoma. Mod Pathol 26:213–222

    Article  PubMed  CAS  Google Scholar 

  12. Kang H, Tan M, Bishop JA et al (2017) Whole-exome sequencing of salivary gland mucoepidermoid carcinoma. Clin Cancer Res 23:283–288

    Article  PubMed  CAS  Google Scholar 

  13. Ross JS, Gay LM, Wang K et al (2017) Comprehensive genomic profiles of metastatic and relapsed salivary gland carcinomas are associated with tumor type and reveal new routes to targeted therapies. Ann Oncol 28:2539–2546

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. White AE, Harper JW (2012) Cancer Emerging anatomy of the BAP1 tumor suppressor system. Science 337:1463–1464

    Article  PubMed  CAS  Google Scholar 

  15. Harbour JW, Onken MD, Roberson ED et al (2010) Frequent mutation of BAP1 in metastasizing uveal melanomas. Science 330:1410–1413

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Testa JR, Cheung M, Pei J et al (2011) Germline BAP1 mutations predispose to malignant mesothelioma. Nat Genet 43:1022–1025

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Bott M, Brevet M, Taylor BS et al (2011) The nuclear deubiquitinase BAP1 is commonly inactivated by somatic mutations and 3p21.1 losses in malignant pleural mesothelioma. Nat Genet 43:668–672

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Cancer Genome Atlas Research Network (2013) Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 499:43–49

    Article  Google Scholar 

  19. Nasu M, Emi M, Pastorino S et al (2015) High incidence of somatic BAP1 alterations in sporadic malignant mesothelioma. J Thorac Oncol 10:565–576

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Shankar GM, Abedalthagafi M, Vaubel RA et al (2017) Germline and somatic BAP1 mutations in high-grade rhabdoid meningiomas. Neuro Oncol 19:535–545

    Article  PubMed  CAS  Google Scholar 

  21. Piris A, Mihm MC Jr, Hoang MP (2015) BAP1 and BRAFV600E expression in benign and malignant melanocytic proliferations. Hum Pathol 46:239–245

    Article  PubMed  CAS  Google Scholar 

  22. Loeser H, Waldschmidt D, Kuetting F et al (2017) Somatic BRCA1-associated protein 1 (BAP1) loss is an early and rare event in esophageal adenocarcinoma. Mol Clin Oncol 7:225–228

    PubMed  PubMed Central  CAS  Google Scholar 

  23. Cigognetti M, Lonardi S, Fisogni S et al (2015) BAP1 (BRCA1-associated protein 1) is a highly specific marker for differentiating mesothelioma from reactive mesothelial proliferations. Mod Pathol 28:1043–1057

    Article  PubMed  CAS  Google Scholar 

  24. Joseph NM, Chen YY, Nasr A et al (2017) Genomic profiling of malignant peritoneal mesothelioma reveals recurrent alterations in epigenetic regulatory genes BAP1, SETD2, and DDX3X. Mod Pathol 30:246–254

    Article  PubMed  CAS  Google Scholar 

  25. Churg A, Sheffield BS, Galateau-Salle F (2016) New markers for separating benign from malignant mesothelial proliferations: Are we there yet? Arch Pathol Lab Med 140:318–321

    Article  PubMed  CAS  Google Scholar 

  26. Carbone M, Shimizu D, Napolitano A et al (2016) Positive nuclear BAP1 immunostaining helps differentiate non-small cell lung carcinomas from malignant mesothelioma. Oncotarget 7:59314–59321

    Article  PubMed  PubMed Central  Google Scholar 

  27. Tang J, Xi S, Wang G et al (2013) Prognostic significance of BRCA1-associated protein 1 in colorectal cancer. Med Oncol 30:541

    Article  PubMed  Google Scholar 

  28. Shen C, Wang Y, Wei P et al (2016) BRCA1-associated protein 1 deficiency in lung adenocarcinoma predicts poor outcome and increased tumor invasion. BMC Cancer 16:670

    Article  PubMed  PubMed Central  Google Scholar 

  29. Minardi D, Lucarini G, Milanese G et al (2016) Loss of nuclear BAP1 protein expression is a marker of poor prognosis in patients with clear cell renal cell carcinoma. Urol Oncol 34:11–18

    Article  Google Scholar 

  30. A Trial of Niraparib in BAP1 and Other DNA Damage Response (DDR) Deficient Neoplasms (2017). Retrieved from http://clinicaltrials.gov/ct2. Identification No. NCT03207347

  31. Study of the EZH2 Inhibitor Tazemetostat in Malignant Mesothelioma (2016). Retrieved from http://clinicaltrials.gov/ct2. Identification No. NCT02860286

  32. Koopmans AE, Verdijk RM, Brouwer RW et al (2014) Clinical significance of immunohistochemistry for detection of BAP1 mutations in uveal melanoma. Mod Pathol 27:1321–1330

    Article  PubMed  CAS  Google Scholar 

  33. Badlani J, Gupta R, Balasubramanian D et al (2018) Primary salivary gland malignancies: a review of clinicopathological evolution, molecular mechanisms and management. ANZ J Surg 88:152–157

    Article  PubMed  Google Scholar 

  34. Martins C, Cavaco B, Tonon G et al (2004) A study of MECT1-MAML2 in mucoepidermoid carcinoma and Warthin’s tumor of salivary glands. J Mol Diagn 6:205–210

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Tonon G, Modi S, Wu L et al (2003) t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway. Nat Genet 33:208–213

    Article  PubMed  CAS  Google Scholar 

  36. Okabe M, Miyabe S, Nagatsuka H et al (2006) MECT1-MAML2 fusion transcript defines a favorable subset of mucoepidermoid carcinoma. Clin Cancer Res 12:3902–3907

    Article  PubMed  CAS  Google Scholar 

  37. Schwarz S, Stiegler C, Müller M et al (2011) Salivary gland mucoepidermoid carcinoma is a clinically, morphologically and genetically heterogeneous entity: a clinicopathological study of 40 cases with emphasis on grading, histological variants and presence of the t(11;19) translocation. Histopathology 58:557–570

    Article  PubMed  Google Scholar 

  38. Behboudi A, Enlund F, Winnes M et al (2006) Molecular classification of mucoepidermoid carcinomas-prognostic significance of the MECT1-MAML2 fusion oncogene. Genes Chromosomes Cancer 45:470–481

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Deepali Jain.

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Kakkar, A., Guleria, P., Madan, K. et al. Immunohistochemical Assessment of BAP1 Protein in Mucoepidermoid Carcinomas. Indian J Otolaryngol Head Neck Surg 71, 33–37 (2019). https://doi.org/10.1007/s12070-018-1549-3

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  • DOI: https://doi.org/10.1007/s12070-018-1549-3

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