1932

Abstract

Diffuse pleural mesothelioma (DPM) is a highly aggressive malignant neoplasm arising from the mesothelial cells lining the pleural surfaces. While DPM is a well-recognized disease linked to asbestos exposure, recent advances have expanded our understanding of molecular pathogenesis and transformed our clinical practice. This comprehensive review explores the current concepts and emerging trends in DPM, including risk factors, pathobiology, histologic subtyping, and therapeutic management, with an emphasis on a multidisciplinary approach to this complex disease.

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2024-01-24
2024-05-01
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Literature Cited

  1. 1.
    Ribak J, Lilis R, Suzuki Y, Penner L, Selikoff IJ. 1988. Malignant mesothelioma in a cohort of asbestos insulation workers: clinical presentation, diagnosis, and causes of death. Br. J. Ind. Med. 45:318287
    [Google Scholar]
  2. 2.
    Røe OD, Stella GM. 2015. Malignant pleural mesothelioma: history, controversy and future of a manmade epidemic. Eur. Respir. Rev. 24:13511531
    [Google Scholar]
  3. 3.
    Craighead JE. 2011. Epidemiology of mesothelioma and historical background. Recent Results Cancer Res. 189:1325
    [Google Scholar]
  4. 4.
    Wagner JC, Sleggs CA, Marchand P. 1960. Diffuse pleural mesothelioma and asbestos exposure in the North Western Cape Province. Br. J. Ind. Med. 17:426071
    [Google Scholar]
  5. 5.
    Wagner JC. 1991. The discovery of the association between blue asbestos and mesotheliomas and the aftermath. Br. J. Ind. Med. 48:6399403
    [Google Scholar]
  6. 6.
    Hmeljak J, Sanchez-Vega F, Hoadley KA, Shih J, Stewart C et al. 2018. Integrative molecular characterization of malignant pleural mesothelioma. Cancer Discov. 8:12154965
    [Google Scholar]
  7. 7.
    Bueno R, Stawiski EW, Goldstein LD, Durinck S, De Rienzo A et al. 2016. Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations. Nat. Genet. 48:440716
    [Google Scholar]
  8. 8.
    Zauderer MG, Martin A, Egger J, Rizvi H, Offin M et al. 2021. The use of a next-generation sequencing-derived machine-learning risk-prediction model (OncoCast-MPM) for malignant pleural mesothelioma: a retrospective study. Lancet Digit. Health 3:9e56576
    [Google Scholar]
  9. 9.
    Robinson BWS, Lake RA. 2005. Advances in malignant mesothelioma. N. Engl. J. Med. 353:151591603
    [Google Scholar]
  10. 10.
    Tsao AS, Lindwasser OW, Adjei AA, Adusumilli PS, Beyers ML et al. 2018. Current and future management of malignant mesothelioma: a consensus report from the National Cancer Institute Thoracic Malignancy Steering Committee, International Association for the Study of Lung Cancer, and Mesothelioma Applied Research Foundation. J. Thorac. Oncol. 13:11165567
    [Google Scholar]
  11. 11.
    Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. 2018. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68:6394424
    [Google Scholar]
  12. 12.
    Huang J, Chan SC, Pang WS, Chow SH, Lok V et al. 2023. Global incidence, risk factors, and temporal trends of mesothelioma: a population-based study. J. Thorac. Oncol. 18:792802
    [Google Scholar]
  13. 13.
    Carbone M, Adusumilli PS, Alexander HR, Baas P, Bardelli F et al. 2019. Mesothelioma: scientific clues for prevention, diagnosis, and therapy. CA Cancer J. Clin. 69:540229
    [Google Scholar]
  14. 14.
    Bellini A, Dell'amore A, Terzi S, Zambello G, Zuin A et al. 2021. Relapse patterns and tailored treatment strategies for malignant pleural mesothelioma recurrence after multimodality therapy. J. Clin. Med. 10:51134
    [Google Scholar]
  15. 15.
    Meirson T, Pentimalli F, Cerza F, Baglio G, Gray SG et al. 2022. Comparison of 3 randomized clinical trials of frontline therapies for malignant pleural mesothelioma. JAMA Netw. Open 5:3e221490
    [Google Scholar]
  16. 16.
    Lacourt A, Gramond C, Rolland P, Ducamp S, Audignon S et al. 2014. Occupational and non-occupational attributable risk of asbestos exposure for malignant pleural mesothelioma. Thorax 69:653239
    [Google Scholar]
  17. 17.
    Andujar P, Lacourt A, Brochard P, Pairon JC, Jaurand MC, Jean D. 2016. Five years update on relationships between malignant pleural mesothelioma and exposure to asbestos and other elongated mineral particles. J. Toxicol. Environ. Health. B Crit. Rev. 19:5–615172
    [Google Scholar]
  18. 18.
    IARC Work. Group Eval. Carcinog. Risks Hum 2012. Arsenic, metals, fibres, and dusts. IARC Monogr. Eval. Carcinog. Risks Humans 100:Part C11465
    [Google Scholar]
  19. 19.
    Pira E, Donato F, Maida L, Discalzi G. 2018. Exposure to asbestos: past, present and future. J. Thorac. Dis. 10:Suppl. 2S23745
    [Google Scholar]
  20. 20.
    Hodgson JT, Darnton A. 2000. The quantitative risks of mesothelioma and lung cancer in relation to asbestos exposure. Ann. Occup. Hyg. 44:565601
    [Google Scholar]
  21. 21.
    Xu A, Zhou H, Yu DZ, Hei TK. 2002. Mechanisms of the genotoxicity of crocidolite asbestos in mammalian cells: implication from mutation patterns induced by reactive oxygen species. Environ. Health Perspect. 110:1010038
    [Google Scholar]
  22. 22.
    Shukla A, Gulumian M, Hei TK, Kamp D, Rahman Q, Mossman BT. 2003. Multiple roles of oxidants in the pathogenesis of asbestos-induced diseases. Free Radic. Biol. Med. 34:9111729
    [Google Scholar]
  23. 23.
    Yang H, Bocchetta M, Kroczynska B, Elmishad AG, Chen Y et al. 2006. TNF-α inhibits asbestos-induced cytotoxicity via a NF-κB-dependent pathway, a possible mechanism for asbestos-induced oncogenesis. PNAS 103:2710397402
    [Google Scholar]
  24. 24.
    Carbone M, Baris YI, Bertino P, Brass B, Comertpay S et al. 2011. Erionite exposure in North Dakota and Turkish villages with mesothelioma. PNAS 108:331361823
    [Google Scholar]
  25. 25.
    Carbone M, Kanodia S, Chao A, Miller A, Wali A et al. 2016. Consensus report of the 2015 Weinman International Conference on Mesothelioma. J. Thorac. Oncol. 11:8124662
    [Google Scholar]
  26. 26.
    Attanoos RL, Churg A, Galateau-Salle F, Gibbs AR, Roggli VL. 2018. Malignant mesothelioma and its non-asbestos causes. Arch. Pathol. Lab. Med. 142:675360
    [Google Scholar]
  27. 27.
    Paoletti L, Batisti D, Bruno C, Di Paola M, Gianfagna A et al. 2000. Unusually high incidence of malignant pleural mesothelioma in a town of eastern Sicily: an epidemiological and environmental study. Arch. Environ. Health 55:639298
    [Google Scholar]
  28. 28.
    Comba P, Gianfagna A, Paoletti L. 2003. Pleural mesothelioma cases in Biancavilla are related to a new fluoro-edenite fibrous amphibole. Arch. Environ. Health 58:422932
    [Google Scholar]
  29. 29.
    Farioli A, Ottone M, Morganti AG, Compagnone G, Romani F et al. 2016. Radiation-induced mesothelioma among long-term solid cancer survivors: a longitudinal analysis of SEER database. Cancer Med. 5:595059
    [Google Scholar]
  30. 30.
    Kodama Y, Hoshi S, Minami M, Kiso M, Takezawa T et al. 2008. Malignant mesothelioma associated with chronic empyema with elevation of serum CYFRA19: a case report. Biosci. Trends 2:625054
    [Google Scholar]
  31. 31.
    Engels EA, Katki HA, Nielsen NM, Winther JF, Hjalgrim H et al. 2003. Cancer incidence in Denmark following exposure to poliovirus vaccine contaminated with simian virus 40. J. Natl. Cancer Inst. 95:753239
    [Google Scholar]
  32. 32.
    Strickler HD, Goedert JJ, Devesa SS, Lahey J, Fraumeni JF, Rosenberg PS. 2003. Trends in U.S. pleural mesothelioma incidence rates following simian virus 40 contamination of early poliovirus vaccines. J. Natl. Cancer Inst. 95:13845
    [Google Scholar]
  33. 33.
    Manfredi JJ, Dong J, Liu WJ, Resnick-Silverman L, Qiao R et al. 2005. Evidence against a role for SV40 in human mesothelioma. Cancer Res. 65:726029
    [Google Scholar]
  34. 34.
    López-Ríos F, Illei PB, Rusch V, Ladanyi M. 2004. Evidence against a role for SV40 infection in human mesotheliomas and high risk of false-positive PCR results owing to presence of SV40 sequences in common laboratory plasmids. Lancet 364:9440115766
    [Google Scholar]
  35. 35.
    Panou V, Gadiraju M, Wolin A, Weipert CM, Skarda E et al. 2018. Frequency of germline mutations in cancer susceptibility genes in malignant mesothelioma. J. Clin. Oncol. 36:28286371
    [Google Scholar]
  36. 36.
    Ohar JA, Cheung M, Talarchek J, Howard SE, Howard TD et al. 2016. Germline BAP1 mutational landscape of asbestos-exposed malignant mesothelioma patients with family history of cancer. Cancer Res. 76:220615
    [Google Scholar]
  37. 37.
    Wiesner T, Obenauf AC, Murali R, Fried I, Griewank KG et al. 2011. Germline mutations in BAP1 predispose to melanocytic tumors. Nat. Genet. 43:10101822
    [Google Scholar]
  38. 38.
    Carbone M, Ferris LK, Baumann F, Napolitano A, Lum CA et al. 2012. BAP1 cancer syndrome: malignant mesothelioma, uveal and cutaneous melanoma, and MBAITs. J. Transl. Med. 10:179
    [Google Scholar]
  39. 39.
    Popova T, Hebert L, Jacquemin V, Gad S, Caux-Moncoutier V et al. 2013. Germline BAP1 mutations predispose to renal cell carcinomas. Am. J. Hum. Genet. 92:697480
    [Google Scholar]
  40. 40.
    Wadt KAW, Aoude LG, Johansson P, Solinas A, Pritchard A et al. 2015. A recurrent germline BAP1 mutation and extension of the BAP1 tumor predisposition spectrum to include basal cell carcinoma. Clin. Genet. 88:326772
    [Google Scholar]
  41. 41.
    Abdel-Rahman MH, Pilarski R, Cebulla CM, Massengill JB, Christopher BN et al. 2011. Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers. J. Med. Genet. 48:1285659
    [Google Scholar]
  42. 42.
    Betti M, Aspesi A, Sculco M, Matullo G, Magnani C, Dianzani I. 2019. Genetic predisposition for malignant mesothelioma: a concise review. Mutat. Res. Rev. Mutat. Res. 781:110
    [Google Scholar]
  43. 43.
    Betti M, Aspesi A, Biasi A, Casalone E, Ferrante D et al. 2016. CDKN2A and BAP1 germline mutations predispose to melanoma and mesothelioma. Cancer Lett. 378:212030
    [Google Scholar]
  44. 44.
    Betti M, Casalone E, Ferrante D, Aspesi A, Morleo G et al. 2017. Germline mutations in DNA repair genes predispose asbestos-exposed patients to malignant pleural mesothelioma. Cancer Lett. 405:3845
    [Google Scholar]
  45. 45.
    Sauter JL, Dacic S, Galateau-Salle F, Attanoos RL, Butnor KJ et al. 2022. The 2021 WHO classification of tumors of the pleura: advances since the 2015 classification. J. Thorac. Oncol. 17:560822
    [Google Scholar]
  46. 46.
    WHO Classif. Tumours Ed. Board, ed. 2021. Thoracic Tumours Lyon, France: Int. Agency Res. Cancer. , 5th ed..
  47. 47.
    Brcic L, Kern I. 2020. Clinical significance of histologic subtyping of malignant pleural mesothelioma. Transl. Lung Cancer Res. 9:392433
    [Google Scholar]
  48. 48.
    Zhuo M, Zheng Q, Chi Y, Jia B, Zhao J et al. 2019. Survival analysis via nomogram of surgical patients with malignant pleural mesothelioma in the Surveillance, Epidemiology, and End Results database. Thorac. Cancer 10:51193202
    [Google Scholar]
  49. 49.
    Flores RM, Routledge T, Seshan VE, Dycoco J, Zakowski M et al. 2008. The impact of lymph node station on survival in 348 patients with surgically resected malignant pleural mesothelioma: implications for revision of the American Joint Committee on Cancer staging system. J. Thorac. Cardiovasc. Surg. 136:360510
    [Google Scholar]
  50. 50.
    Meyerhoff RR, Yang CFJ, Speicher PJ, Gulack BC, Hartwig MG et al. 2015. Impact of mesothelioma histologic subtype on outcomes in the Surveillance, Epidemiology, and End Results database. J. Surg. Res. 196:12332
    [Google Scholar]
  51. 51.
    Rusch VW. 2012. Extrapleural pneumonectomy and extended pleurectomy/decortication for malignant pleural mesothelioma: the Memorial Sloan-Kettering Cancer Center approach. Ann. Cardiothorac. Surg. 1:452331
    [Google Scholar]
  52. 52.
    Rusch VW, Giroux D. 2012. Do we need a revised staging system for malignant pleural mesothelioma? Analysis of the IASLC database. Ann. Cardiothorac. Surg. 1:443848
    [Google Scholar]
  53. 53.
    Rusch VW, Giroux D, Kennedy C, Ruffini E, Cangir AK et al. 2012. Initial analysis of the international association for the study of lung cancer mesothelioma database. J. Thorac. Oncol. 7:11163139
    [Google Scholar]
  54. 54.
    Rusch VW, Rimner A, Krug LM. 2014. The challenge of malignant pleural mesothelioma: new directions. J. Thorac. Oncol. 9:327172
    [Google Scholar]
  55. 55.
    Rusch VW, Venkatraman ES. 1999. Important prognostic factors in patients with malignant pleural mesothelioma, managed surgically. Ann. Thorac. Surg. 68:51799804
    [Google Scholar]
  56. 56.
    Van Meerbeeck JP, Gaafar R, Manegold C, Van Klaveren RJ, Van Marck EA et al. 2005. Randomized phase III study of cisplatin with or without raltitrexed in patients with malignant pleural mesothelioma: an intergroup study of the European Organisation for Research and Treatment of Cancer Lung Cancer Group and the National Cancer Institute of Canada. J. Clin. Oncol. 23:28688189
    [Google Scholar]
  57. 57.
    Nicholson AG, Sauter JL, Nowak AK, Kindler HL, Gill RR et al. 2020. EURACAN/IASLC proposals for updating the histologic classification of pleural mesothelioma: towards a more multidisciplinary approach. J. Thorac. Oncol. 15:12949
    [Google Scholar]
  58. 58.
    Kadota K, Suzuki K, Sima CS, Rusch VW, Adusumilli PS, Travis WD. 2011. Pleomorphic epithelioid diffuse malignant pleural mesothelioma: a clinicopathological review and conceptual proposal to reclassify as biphasic or sarcomatoid mesothelioma. J. Thorac. Oncol. 6:5896904
    [Google Scholar]
  59. 59.
    Bilecz A, Stockhammer P, Theegarten D, Kern I, Jakopovic M et al. 2020. Comparative analysis of prognostic histopathologic parameters in subtypes of epithelioid pleural mesothelioma. Histopathology 77:15566
    [Google Scholar]
  60. 60.
    Rosen LE, Karrison T, Ananthanarayanan V, Gallan AJ, Adusumilli PS et al. 2018. Nuclear grade and necrosis predict prognosis in malignant epithelioid pleural mesothelioma: a multi-institutional study. Mod. Pathol. 31:4598606
    [Google Scholar]
  61. 61.
    Kadota K, Suzuki K, Colovos C, Sima CS, Rusch VW et al. 2012. A nuclear grading system is a strong predictor of survival in epitheloid diffuse malignant pleural mesothelioma. Mod. Pathol. 25:226071
    [Google Scholar]
  62. 62.
    Zhang YZ, Brambilla C, Molyneaux PL, Rice A, Robertus JL et al. 2020. Utility of nuclear grading system in epithelioid malignant pleural mesothelioma in biopsy-heavy setting: an external validation study of 563 cases. Am. J. Surg. Pathol. 44:334756
    [Google Scholar]
  63. 63.
    Zhang YZ, Brambilla C, Molyneaux PL, Rice A, Robertus JL et al. 2020. Presence of pleomorphic features but not growth patterns improves prognostic stratification of epithelioid malignant pleural mesothelioma by 2-tier nuclear grade. Histopathology 77:342336
    [Google Scholar]
  64. 64.
    Ordóñez NG. 2012. Pleomorphic mesothelioma: report of 10 cases. Mod. Pathol. 25:7101122
    [Google Scholar]
  65. 65.
    Galateau-Sallé F, Attanoos R, Gibbs AR, Burke L, Astoul P et al. 2007. Lymphohistiocytoid variant of malignant mesothelioma of the pleura: a series of 22 cases. Am. J. Surg. Pathol. 31:571116
    [Google Scholar]
  66. 66.
    Kawai T, Hiroi S, Nakanishi K, Takagawa K, Haba R et al. 2010. Lymphohistiocytoid mesothelioma of the pleura. Pathol. Int. 60:856674
    [Google Scholar]
  67. 67.
    Ordóñez NG. 2006. Mesothelioma with rhabdoid features: an ultrastructural and immunohistochemical study of 10 cases. Mod. Pathol. 19:337383
    [Google Scholar]
  68. 68.
    Galateau Salle F, Le Stang N, Tirode F, Courtiol P, Nicholson AG et al. 2020. Comprehensive molecular and pathologic evaluation of transitional mesothelioma assisted by deep learning approach: a multi-institutional study of the International Mesothelioma Panel from the MESOPATH Reference Center. J. Thorac. Oncol. 15:6103753
    [Google Scholar]
  69. 69.
    Courtiol P, Maussion C, Moarii M, Pronier E, Pilcer S et al. 2019. Deep learning-based classification of mesothelioma improves prediction of patient outcome. Nat. Med. 25:10151925
    [Google Scholar]
  70. 70.
    Hashimoto K, Okuma Y, Hosomi Y, Hishima T. 2016. Malignant mesothelioma of the pleura with desmoplastic histology: a case series and literature review. BMC Cancer 16:1718
    [Google Scholar]
  71. 71.
    Arulananda S, Thapa B, Walkiewicz M, Zapparoli GV, Williams DS et al. 2018. Mismatch repair protein defects and microsatellite instability in malignant pleural mesothelioma. J. Thorac. Oncol. 13:10158894
    [Google Scholar]
  72. 72.
    Mangiante L, Alcala N, Sexton-Oates A, Di Genova A, Gonzalez-Perez A et al. 2023. Multiomic analysis of malignant pleural mesothelioma identifies molecular axes and specialized tumor profiles driving intertumor heterogeneity. Nat. Genet. 55:460718
    [Google Scholar]
  73. 73.
    Huang SXL, Jaurand MC, Kamp DW, Whysner J, Hei TK. 2011. Role of mutagenicity in asbestos fiber-induced carcinogenicity and other diseases. J. Toxicol. Environ. Health B Crit. Rev. 14:1–4179245
    [Google Scholar]
  74. 74.
    Malakoti F, Targhazeh N, Abadifard E, Zarezadeh R, Samemaleki S et al. 2022. DNA repair and damage pathways in mesothelioma development and therapy. Cancer Cell Int. 22:1176
    [Google Scholar]
  75. 75.
    Jensen DE, Proctor M, Marquis ST, Gardner HP, Ha SI et al. 1998. BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression. Oncogene 16:91097112
    [Google Scholar]
  76. 76.
    Harbour JW, Onken MD, Roberson EDO, Duan S, Cao L et al. 2010. Frequent mutation of BAP1 in metastasizing uveal melanomas. Science 330:6009141013
    [Google Scholar]
  77. 77.
    Bott M, Brevet M, Taylor BS, Shimizu S, Ito T et al. 2011. The nuclear deubiquitinase BAP1 is commonly inactivated by somatic mutations and 3p21.1 losses in malignant pleural mesothelioma. Nat. Genet. 43:766872
    [Google Scholar]
  78. 78.
    Misaghi S, Ottosen S, Izrael-Tomasevic A, Arnott D, Lamkanfi M et al. 2009. Association of C-terminal ubiquitin hydrolase BRCA1-associated protein 1 with cell cycle regulator host cell factor 1. Mol. Cell. Biol. 29:8218192
    [Google Scholar]
  79. 79.
    Peng H, Cassel J, McCracken DS, Prokop JW, Sementino E et al. 2021. Kinetic characterization of ASXL1/2-mediated allosteric regulation of the BAP1 deubiquitinase. Mol. Cancer Res. 19:71099112
    [Google Scholar]
  80. 80.
    Conway E, Rossi F, Fernandez-Perez D, Ponzo E, Ferrari KJ et al. 2021. BAP1 enhances Polycomb repression by counteracting widespread H2AK119ub1 deposition and chromatin condensation. Mol. Cell 81:1735263541.e8
    [Google Scholar]
  81. 81.
    Lafave LM, Béguelin W, Koche R, Teater M, Spitzer B et al. 2015. Loss of BAP1 function leads to EZH2-dependent transformation. Nat. Med. 21:11134449
    [Google Scholar]
  82. 82.
    Lee HS, Lee SA, Hur SK, Seo JW, Kwon J. 2014. Stabilization and targeting of INO80 to replication forks by BAP1 during normal DNA synthesis. Nat. Commun. 5:5128
    [Google Scholar]
  83. 83.
    Yu H, Mashtalir N, Daou S, Hammond-Martel I, Ross J et al. 2010. 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. 30:21507185
    [Google Scholar]
  84. 84.
    Zhang Y, Shi J, Liu X, Feng L, Gong Z et al. 2018. BAP1 links metabolic regulation of ferroptosis to tumour suppression. Nat. Cell Biol. 20:10118192
    [Google Scholar]
  85. 85.
    Carbone M, Harbour JW, Brugarolas J, Bononi A, Pagano I et al. 2020. Biological mechanisms and clinical significance of BAP1 mutations in human cancer. Cancer Discov. 10:8110320
    [Google Scholar]
  86. 86.
    Urso L, Cavallari I, Sharova E, Ciccarese F, Pasello G, Ciminale V. 2020. Metabolic rewiring and redox alterations in malignant pleural mesothelioma. Br. J. Cancer 122:15261
    [Google Scholar]
  87. 87.
    Bononi A, Giorgi C, Patergnani S, Larson D, Verbruggen K et al. 2017. BAP1 regulates IP3R3-mediated Ca2+ flux to mitochondria suppressing cell transformation. Nature 546:765954953
    [Google Scholar]
  88. 88.
    Righi L, Duregon E, Vatrano S, Izzo S, Giorcelli J et al. 2016. BRCA1-associated protein 1 (BAP1) immunohistochemical expression as a diagnostic tool in malignant pleural mesothelioma classification: a large retrospective study. J. Thorac. Oncol. 11:11200617
    [Google Scholar]
  89. 89.
    Emi M, Yoshikawa Y, Sato C, Sato A, Sato H et al. 2015. Frequent genomic rearrangements of BRCA1 associated protein-1 (BAP1) gene in Japanese malignant mesothelioma-characterization of deletions at exon level. J. Hum. Genet. 60:1064749
    [Google Scholar]
  90. 90.
    Yoshikawa Y, Emi M, Hashimoto-Tamaoki T, Ohmuraya M, Sato A et al. 2016. High-density array-CGH with targeted NGS unmask multiple noncontiguous minute deletions on chromosome 3p21 in mesothelioma. PNAS 113:471343237
    [Google Scholar]
  91. 91.
    De Rienzo A, Chirieac LR, Hung YP, Severson DT, Freyaldenhoven S et al. 2021. Large-scale analysis of BAP1 expression reveals novel associations with clinical and molecular features of malignant pleural mesothelioma. J. Pathol. 253:16879
    [Google Scholar]
  92. 92.
    Pastorino S, Yoshikawa Y, Pass HI, Emi M, Nasu M et al. 2018. A subset of mesotheliomas with improved survival occurring in carriers of BAP1 and other germline mutations. J. Clin. Oncol. 36:35348594
    [Google Scholar]
  93. 93.
    Kadariya Y, Cheung M, Xu J, Pei J, Sementino E et al. 2016. Bap1 is a bona fide tumor suppressor: genetic evidence from mouse models carrying heterozygous germline Bap1 mutations. Cancer Res. 76:9283644
    [Google Scholar]
  94. 94.
    Xue J, Patergnani S, Giorgi C, Suarez J, Goto K et al. 2020. Asbestos induces mesothelial cell transformation via HMGB1-driven autophagy. PNAS 117:412554352
    [Google Scholar]
  95. 95.
    Novelli F, Bononi A, Wang Q, Bai F, Patergnani S et al. 2021. BAP1 forms a trimer with HMGB1 and HDAC1 that modulates gene × environment interaction with asbestos. PNAS 118:48e2111946118
    [Google Scholar]
  96. 96.
    Baas R, van der Wal FJ, Bleijerveld OB, van Attikum H, Sixma TK. 2021. Proteomic analysis identifies novel binding partners of BAP1. PLOS ONE 16:9e0257688
    [Google Scholar]
  97. 97.
    Kukuyan AM, Sementino E, Kadariya Y, Menges CW, Cheung M et al. 2019. Inactivation of Bap1 cooperates with losses of Nf2 and Cdkn2a to drive the development of pleural malignant mesothelioma in conditional mouse models. Cancer Res. 79:16411323
    [Google Scholar]
  98. 98.
    Zhang M, Luo JL, Sun Q, Harber J, Dawson AG et al. 2021. Clonal architecture in mesothelioma is prognostic and shapes the tumour microenvironment. Nat. Commun. 12:11751
    [Google Scholar]
  99. 99.
    Singh A, Busacca S, Gaba A, Sheaff M, Poile C et al. 2023. BAP1 loss induces mitotic defects in mesothelioma cells through BRCA1-dependent and independent mechanisms. Oncogene 42:857285
    [Google Scholar]
  100. 100.
    Nishikawa H, Wu W, Koike A, Kojima R, Gomi H et al. 2009. BRCA1-associated protein 1 interferes with BRCA1/BARD1 RING heterodimer activity. Cancer Res. 69:111119
    [Google Scholar]
  101. 101.
    Ghafoor A, Mian I, Wagner C, Mallory Y, Agra MG et al. 2021. Phase 2 study of olaparib in malignant mesothelioma and correlation of efficacy with germline or somatic mutations in BAP1 gene. JTO Clin. Res. Rep. 2:10100231
    [Google Scholar]
  102. 102.
    Dudnik E, Bar J, Moore A, Gottfried T, Moskovitz M et al. 2021. BAP1-altered malignant pleural mesothelioma: outcomes with chemotherapy, immune check-point inhibitors and poly(ADP-ribose) polymerase inhibitors. Front. Oncol. 11:603223
    [Google Scholar]
  103. 103.
    Rathkey D, Khanal M, Murai J, Zhang J, Sengupta M et al. 2020. Sensitivity of mesothelioma cells to PARP inhibitors is not dependent on BAP1 but is enhanced by temozolomide in cells with high-Schlafen 11 and low-O6-methylguanine-DNA methyltransferase expression. J. Thorac. Oncol. 15:584359
    [Google Scholar]
  104. 104.
    Ishii Y, Kolluri KK, Pennycuick A, Zhang X, Nigro E et al. 2021. BAP1 and YY1 regulate expression of death receptors in malignant pleural mesothelioma. J. Biol. Chem. 297:5101223
    [Google Scholar]
  105. 105.
    Murrone A, Cantini L, Pecci F, Cognigni V, Copparoni C et al. 2021. BRCA-associated protein 1 (BAP1) and miR-31 combination predicts outcomes in epithelioid malignant pleural mesothelioma. J. Thorac. Dis. 13:10574151
    [Google Scholar]
  106. 106.
    Bononi A, Wang Q, Zolondick AA, Bai F, Steele-Tanji M et al. 2023. BAP1 is a novel regulator of HIF-1α. PNAS 120:4e2217840120
    [Google Scholar]
  107. 107.
    Liu CJ, Tsai MM, Hung PS, Kao SY, Liu TY et al. 2010. miR-31 ablates expression of the HIF regulatory factor FIH to activate the HIF pathway in head and neck carcinoma. Cancer Res. 70:4163544
    [Google Scholar]
  108. 108.
    Liu JY, Souroullas GP, Diekman BO, Krishnamurthy J, Hall BM et al. 2019. Cells exhibiting strong p16INK4a promoter activation in vivo display features of senescence. PNAS 116:7260311
    [Google Scholar]
  109. 109.
    Zhao R, Choi BY, Lee MH, Bode AM, Dong Z. 2016. Implications of genetic and epigenetic alterations of CDKN2A (p16INK4a) in cancer. EBioMedicine 8:3039
    [Google Scholar]
  110. 110.
    Ezhevsky SA, Nagahara H, Vocero-Akbani AM, Gius DR, Wei MC, Dowdy SF. 1997. Hypo-phosphorylation of the retinoblastoma protein (pRb) by cyclin D:Cdk4/6 complexes results in active pRb. PNAS 94:2010699704
    [Google Scholar]
  111. 111.
    Byeon IJL, Li J, Ericson K, Selby TL, Tevelev A et al. 1998. Tumor suppressor p16INK4A: determination of solution structure and analyses of its interaction with cyclin-dependent kinase 4. Mol. Cell 1:342131
    [Google Scholar]
  112. 112.
    Jeffrey PD, Tong L, Pavletich NP. 2000. Structural basis of inhibition of CDK-cyclin complexes by INK4 inhibitors. Genes Dev. 14:24311525
    [Google Scholar]
  113. 113.
    Russo AA, Tong L, Lee JO, Jeffrey PD, Pavletich NP. 1998. Structural basis for inhibition of the cyclin-dependent kinase Cdk6 by the tumour suppressor p16INK4a. Nature 395:669923743
    [Google Scholar]
  114. 114.
    Zhang Y, Xiong Y, Yarbrough WG. 1998. ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell 92:672534
    [Google Scholar]
  115. 115.
    Sherr CJ. 2006. Divorcing ARF and p53: an unsettled case. Nat. Rev. Cancer 6:966373
    [Google Scholar]
  116. 116.
    Illei PB, Rusch VW, Zakowski MF, Ladanyi M. 2003. Homozygous deletion of CDKN2A and codeletion of the methylthioadenosine phosphorylase gene in the majority of pleural mesotheliomas. Clin. Cancer Res. 9:210813
    [Google Scholar]
  117. 117.
    Hida T, Hamasaki M, Matsumoto S, Sato A, Tsujimura T et al. 2017. Immunohistochemical detection of MTAP and BAP1 protein loss for mesothelioma diagnosis: comparison with 9p21 FISH and BAP1 immunohistochemistry. Lung Cancer 104:98105
    [Google Scholar]
  118. 118.
    Hwang HC, Sheffield BS, Rodriguez S, Thompson K, Tse CH et al. 2016. Utility of BAP1 immunohistochemistry and p16 (CDKN2A) FISH in the diagnosis of malignant mesothelioma in effusion cytology specimens. Am. J. Surg. Pathol. 40:112026
    [Google Scholar]
  119. 119.
    Marshall K, Jackson S, Jones J, Holme J, Lyons J et al. 2020. Homozygous deletion of CDKN2A in malignant mesothelioma: diagnostic utility, patient characteristics and survival in a UK mesothelioma centre. Lung Cancer 150:195200
    [Google Scholar]
  120. 120.
    Frizelle SP, Grim J, Zhou J, Gupta P, Curiel DT et al. 1998. Re-expression of p16INK4a in mesothelioma cells results in cell cycle arrest, cell death, tumor suppression and tumor regression. Oncogene 16:24308795
    [Google Scholar]
  121. 121.
    Altomare DA, Menges CW, Xu J, Pei J, Zhang L et al. 2011. Losses of both products of the Cdkn2a/Arf locus contribute to asbestos-induced mesothelioma development and cooperate to accelerate tumorigenesis. PLOS ONE 6:4e18828
    [Google Scholar]
  122. 122.
    Fennell DA, King A, Mohammed S, Greystoke A, Anthony S et al. 2022. Abemaciclib in patients with p16ink4A-deficient mesothelioma (MiST2): a single-arm, open-label, phase 2 trial. Lancet. Oncol. 23:337481
    [Google Scholar]
  123. 123.
    Zhou C, Shen Z, Ye D, Li Q, Deng H et al. 2018. The association and clinical significance of CDKN2A promoter methylation in head and neck squamous cell carcinoma: a meta-analysis. Cell. Physiol. Biochem. 50:386882
    [Google Scholar]
  124. 124.
    Lou-Qian Z, Rong Y, Ming L, Xin Y, Feng J, Lin X. 2013. The prognostic value of epigenetic silencing of p16 gene in NSCLC patients: a systematic review and meta-analysis. PLOS ONE 8:1e54970
    [Google Scholar]
  125. 125.
    Collisson EA, Campbell JD, Brooks AN, Berger AH, Lee W et al. 2014. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511:751154350
    [Google Scholar]
  126. 126.
    Hiltbrunner S, Fleischmann Z, Sokol ES, Zoche M, Felley-Bosco E, Curioni-Fontecedro A. 2022. Genomic landscape of pleural and peritoneal mesothelioma tumours. Br. J. Cancer 127:1119972005
    [Google Scholar]
  127. 127.
    Hirao T, Bueno R, Chen CJ, Gordon GJ, Heilig E, Kelsey KT. 2002. Alterations of the p16INK4 locus in human malignant mesothelial tumors. Carcinogenesis 23:7112730
    [Google Scholar]
  128. 128.
    Wu D, Hiroshima K, Matsumoto S, Nabeshima K, Yusa T et al. 2013. Diagnostic usefulness of p16/CDKN2A FISH in distinguishing between sarcomatoid mesothelioma and fibrous pleuritis. Am. J. Clin. Pathol. 139:13946
    [Google Scholar]
  129. 129.
    Destro A, Ceresoli GL, Baryshnikova E, Garassino I, Zucali PA et al. 2008. Gene methylation in pleural mesothelioma: correlations with clinico-pathological features and patient's follow-up. Lung Cancer 59:336976
    [Google Scholar]
  130. 130.
    Kobayashi N, Toyooka S, Yanai H, Soh J, Fujimoto N et al. 2008. Frequent p16 inactivation by homozygous deletion or methylation is associated with a poor prognosis in Japanese patients with pleural mesothelioma. Lung Cancer 62:112025
    [Google Scholar]
  131. 131.
    Chapel DB, Dubuc AM, Hornick JL, Sholl LM. 2021. Correlation of methylthioadenosine phosphorylase (MTAP) protein expression with MTAP and CDKN2A copy number in malignant pleural mesothelioma. Histopathology 78:7103242
    [Google Scholar]
  132. 132.
    Wong L, Zhou J, Anderson D, Kratzke RA. 2002. Inactivation of p16INK4a expression in malignant mesothelioma by methylation. Lung Cancer 38:213136
    [Google Scholar]
  133. 133.
    Okazaki Y, Misawa N, Akatsuka S, Kohyama N, Sekido Y et al. 2020. Frequent homozygous deletion of Cdkn2a/2b in tremolite-induced malignant mesothelioma in rats. Cancer Sci. 111:4118092
    [Google Scholar]
  134. 134.
    Kettunen E, Savukoski S, Salmenkivi K, Böhling T, Vanhala E et al. 2019. CDKN2A copy number and p16 expression in malignant pleural mesothelioma in relation to asbestos exposure. BMC Cancer 19:507
    [Google Scholar]
  135. 135.
    Dagogo-Jack I, Madison RW, Lennerz JK, Chen K-T, Hopkins JF et al. 2022. Molecular characterization of mesothelioma: impact of histologic type and site of origin on molecular landscape. JCO Precis. Oncol. 6:e2100422
    [Google Scholar]
  136. 136.
    López-Ríos F, Chuai S, Flores R, Shimizu S, Ohno T et al. 2006. Global gene expression profiling of pleural mesotheliomas: overexpression of aurora kinases and P16/CDKN2A deletion as prognostic factors and critical evaluation of microarray-based prognostic prediction. Cancer Res. 66:6297079
    [Google Scholar]
  137. 137.
    Wu L, Amjad S, Yun H, Mani S, de Perrot M. 2022. A panel of emerging EMT genes identified in malignant mesothelioma. Sci. Rep. 12:1007
    [Google Scholar]
  138. 138.
    Wu L, Yoshihara K, Yun H, Karim S, Shokri N et al. 2023. Prognostic value of EMT gene signature in malignant mesothelioma. Int. J. Mol. Sci. 24:54264
    [Google Scholar]
  139. 139.
    Shi WK, Li YH, Bai XS, Lin GL 2022. The cell cycle-associated protein CDKN2A may promotes colorectal cancer cell metastasis by inducing epithelial-mesenchymal transition. Front. Oncol. 12:834235
    [Google Scholar]
  140. 140.
    Schubert NA, Van Hooff SR, Schild L, Ober K, Hortensius M et al. 2021. Loss of p16INK4a in neuro-blastoma cells induces shift to an immature state with mesenchymal characteristics and increases sensitivity to EGFR inhibitors. bioRxiv 2021.10.27.465137. https://doi.org/10.1101/2021.10.27.465137
  141. 141.
    Nastase A, Mandal A, Lu SK, Anbunathan H, Morris-Rosendahl D et al. 2021. Integrated genomics point to immune vulnerabilities in pleural mesothelioma. Sci. Rep. 11:119138
    [Google Scholar]
  142. 142.
    Barbarino M, Cesari D, Bottaro M, Luzzi L, Namagerdi A et al. 2020. PRMT5 silencing selectively affects MTAP-deleted mesothelioma: in vitro evidence of a novel promising approach. J. Cell. Mol. Med. 24:10556577
    [Google Scholar]
  143. 143.
    Mavrakis KJ, McDonald ER 3rd, Schlabach MR, Billy E, Hoffman GR et al. 2016. Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to dependence on PRMT5. Science 351:6278120813
    [Google Scholar]
  144. 144.
    Subhi AL, Diegelman P, Porter CW, Tang B, Lu ZJ et al. 2003. Methylthioadenosine phosphorylase regulates ornithine decarboxylase by production of downstream metabolites. J. Biol. Chem. 278:504986873
    [Google Scholar]
  145. 145.
    Grard M, Chatelain C, Delaunay T, Pons-Tostivint E, Bennouna J, Fonteneau JF. 2021. Homozygous co-deletion of type I interferons and CDKN2A genes in thoracic cancers: potential consequences for therapy. Front. Oncol. 11:695770
    [Google Scholar]
  146. 146.
    Okayasu R, Takahashi S, Yamada S, Hei TK, Ullrich RL. 1999. Asbestos and DNA double strand breaks. Cancer Res. 59:2298300
    [Google Scholar]
  147. 147.
    Ohkuri T, Ghosh A, Kosaka A, Zhu J, Ikeura M et al. 2014. STING contributes to antiglioma immunity via triggering type I IFN signals in the tumor microenvironment. Cancer Immunol. Res. 2:121199208
    [Google Scholar]
  148. 148.
    MacKenzie KJ, Carroll P, Martin CA, Murina O, Fluteau A et al. 2017. cGAS surveillance of micronuclei links genome instability to innate immunity. Nature 548:766846165
    [Google Scholar]
  149. 149.
    Ye Z, Dong H, Li Y, Ma T, Huang H et al. 2018. Prevalent homozygous deletions of type I interferon and defensin genes in human cancers associate with immunotherapy resistance. Clin. Cancer Res. 24:143299308
    [Google Scholar]
  150. 150.
    Christmas TI, Manning LS, Garlepp MJ, Musk AW, Robinson BW. 1993. Effect of interferon-α2a on malignant mesothelioma. J. Interferon Res. 13:1912
    [Google Scholar]
  151. 151.
    Sterman DH, Alley E, Stevenson JP, Friedberg J, Metzger S et al. 2016. Pilot and feasibility trial evaluating immuno-gene therapy of malignant mesothelioma using intrapleural delivery of adenovirus-IFNα combined with chemotherapy. Clin. Cancer Res. 22:153791800
    [Google Scholar]
  152. 152.
    Delaunay T, Achard C, Boisgerault N, Grard M, Petithomme T et al. 2020. Frequent homozygous deletions of type I interferon genes in pleural mesothelioma confer sensitivity to oncolytic measles virus. J. Thorac. Oncol. 15:582742
    [Google Scholar]
  153. 153.
    Rouleau GA, Merel P, Lutchman M, Sanson M, Zucman J et al. 1993. Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2. Nature 363:642951521
    [Google Scholar]
  154. 154.
    Trofatter JA, MacCollin MM, Rutter JL, Murrell JR, Duyao MP et al. 1993. A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor. Cell 72:5791800. Erratum. 1993 Cell 75:4826
    [Google Scholar]
  155. 155.
    McClatchey AI, Giovannini M. 2005. Membrane organization and tumorigenesis—the NF2 tumor suppressor, Merlin. Genes Dev. 19:19226577
    [Google Scholar]
  156. 156.
    Okada T, You L, Giancotti FG. 2007. Shedding light on Merlin's wizardry. Trends Cell Biol. 17:522229
    [Google Scholar]
  157. 157.
    Ladanyi M, Zauderer MG, Krug LM, Ito T, McMillan R et al. 2012. New strategies in pleural mesothelioma: BAP1 and NF2 as novel targets for therapeutic development and risk assessment. Clin. Cancer Res. 18:17448590
    [Google Scholar]
  158. 158.
    Bretscher A, Edwards K, Fehon RG. 2002. ERM proteins and merlin: integrators at the cell cortex. Nat. Rev. Mol. Cell Biol. 3:858699
    [Google Scholar]
  159. 159.
    Shimizu T, Seto A, Maita N, Hamada K, Tsukita S et al. 2002. Structural basis for neurofibromatosis type 2. Crystal structure of the merlin FERM domain. J. Biol. Chem. 277:121033236
    [Google Scholar]
  160. 160.
    Petrilli AM, Fernández-Valle C. 2016. Role of Merlin/NF2 inactivation in tumor biology. Oncogene 35:553748
    [Google Scholar]
  161. 161.
    Rong R, Surace EI, Haipek CA, Gutmann DH, Ye K. 2004. Serine 518 phosphorylation modulates merlin intramolecular association and binding to critical effectors important for NF2 growth suppression. Oncogene 23:52844754
    [Google Scholar]
  162. 162.
    Kissil JL, Johnson KC, Eckman MS, Jacks T. 2002. Merlin phosphorylation by p21-activated kinase 2 and effects of phosphorylation on merlin localization. J. Biol. Chem. 277:121039499
    [Google Scholar]
  163. 163.
    Xiao GH, Beeser A, Chernoff J, Testa JR. 2002. p21-activated kinase links Rac/Cdc42 signaling to merlin. J. Biol. Chem. 277:288386
    [Google Scholar]
  164. 164.
    Bianchi AB, Mitsunaga SI, Cheng JQ, Klein WM, Jhanwar SC et al. 1995. High frequency of inactivating mutations in the neurofibromatosis type 2 gene (NF2) in primary malignant mesotheliomas. PNAS 92:241085458
    [Google Scholar]
  165. 165.
    Sekido Y, Pass HI, Bader S, Mew DJ, Christman MF et al. 1995. Neurofibromatosis type 2 (NF2) gene is somatically mutated in mesothelioma but not in lung cancer. Cancer Res. 55:6122731
    [Google Scholar]
  166. 166.
    Meiller C, Montagne F, Hirsch TZ, Caruso S, de Wolf J et al. 2021. Multi-site tumor sampling highlights molecular intra-tumor heterogeneity in malignant pleural mesothelioma. Genome Med. 13:113
    [Google Scholar]
  167. 167.
    Quetel L, Meiller C, Assié JB, Blum Y, Imbeaud S et al. 2020. Genetic alterations of malignant pleural mesothelioma: association with tumor heterogeneity and overall survival. Mol. Oncol. 14:6120723
    [Google Scholar]
  168. 168.
    Blum Y, Meiller C, Quetel L, Elarouci N, Ayadi M et al. 2019. Dissecting heterogeneity in malignant pleural mesothelioma through histo-molecular gradients for clinical applications. Nat. Commun. 10:1333
    [Google Scholar]
  169. 169.
    Fleury-Feith J, Lecomte C, Renier A, Matrat M, Kheuang L et al. 2003. Hemizygosity of Nf2 is associated with increased susceptibility to asbestos-induced peritoneal tumours. Oncogene 22:243799805
    [Google Scholar]
  170. 170.
    Altomare DA, Vaslet CA, Skele KL, De Rienzo A, Devarajan K et al. 2005. A mouse model recapitulating molecular features of human mesothelioma. Cancer Res. 65:18809095
    [Google Scholar]
  171. 171.
    Nguyen R, Reczek D, Bretscher A. 2001. Hierarchy of merlin and ezrin N- and C-terminal domain interactions in homo- and heterotypic associations and their relationship to binding of scaffolding proteins EBP50 and E3KARP. J. Biol. Chem. 276:10762129
    [Google Scholar]
  172. 172.
    McClatchey AI, Fehon RG. 2009. Merlin and the ERM proteins—regulators of receptor distribution and signaling at the cell cortex. Trends Cell Biol. 19:5198206
    [Google Scholar]
  173. 173.
    Zhang N, Bai H, David KK, Dong J, Zheng Y et al. 2010. The Merlin/NF2 tumor suppressor functions through the YAP oncoprotein to regulate tissue homeostasis in mammals. Dev. Cell 19:12738
    [Google Scholar]
  174. 174.
    Hamaratoglu F, Willecke M, Kango-Singh M, Nolo R, Hyun E et al. 2006. The tumour-suppressor genes NF2/Merlin and Expanded act through Hippo signalling to regulate cell proliferation and apoptosis. Nat. Cell Biol. 8:12736
    [Google Scholar]
  175. 175.
    Zhao B, Wei X, Li W, Udan RS, Yang Q et al. 2007. Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev. 21:274761
    [Google Scholar]
  176. 176.
    Cho E, Feng Y, Rauskolb C, Maitra S, Fehon R, Irvine KD. 2006. Delineation of a Fat tumor suppressor pathway. Nat. Genet. 38:10114250
    [Google Scholar]
  177. 177.
    Li W, You L, Cooper J, Schiavon G, Pepe-Caprio A et al. 2010. Merlin/NF2 suppresses tumorigenesis by inhibiting the E3 ubiquitin ligase CRL4DCAF1 in the nucleus. Cell 140:447790
    [Google Scholar]
  178. 178.
    Murakami H, Mizuno T, Taniguchi T, Fujii M, Ishiguro F et al. 2011. LATS2 is a tumor suppressor gene of malignant mesothelioma. Cancer Res. 71:387383
    [Google Scholar]
  179. 179.
    Zoncu R, Efeyan A, Sabatini DM. 2011. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat. Rev. Mol. Cell Biol. 12:2135
    [Google Scholar]
  180. 180.
    Okada T, Lopez-Lago M, Giancotti FG. 2005. Merlin/NF-2 mediates contact inhibition of growth by suppressing recruitment of Rac to the plasma membrane. J. Cell Biol. 171:236171
    [Google Scholar]
  181. 181.
    Rong R, Tang X, Gutmann DH, Ye K. 2004. Neurofibromatosis 2 (NF2) tumor suppressor merlin inhibits phosphatidylinositol 3-kinase through binding to PIKE-L. PNAS 101:52182005
    [Google Scholar]
  182. 182.
    López-Lago MA, Okada T, Murillo MM, Socci N, Giancotti FG. 2009. Loss of the tumor suppressor gene NF2, encoding merlin, constitutively activates integrin-dependent mTORC1 signaling. Mol. Cell. Biol. 29:15423549
    [Google Scholar]
  183. 183.
    James MF, Han S, Polizzano C, Plotkin SR, Manning BD et al. 2009. NF2/merlin is a novel negative regulator of mTOR complex 1, and activation of mTORC1 is associated with meningioma and schwannoma growth. Mol. Cell. Biol. 29:15425061
    [Google Scholar]
  184. 184.
    Ou SHI, Moon J, Garland LL, Mack PC, Testa JR et al. 2015. SWOG S0722: phase II study of mTOR inhibitor everolimus (RAD001) in advanced malignant pleural mesothelioma (MPM). J. Thorac. Oncol. 10:238791
    [Google Scholar]
  185. 185.
    Brevet M, Shimizu S, Bott MJ, Shukla N, Zhou Q et al. 2011. Coactivation of receptor tyrosine kinases in malignant mesothelioma as a rationale for combination targeted therapy. J. Thorac. Oncol. 6:586474
    [Google Scholar]
  186. 186.
    Zhang YL, Sun JW, Xie YY, Zhou Y, Liu P et al. 2018. Setd2 deficiency impairs hematopoietic stem cell self-renewal and causes malignant transformation. Cell Res. 28:447690
    [Google Scholar]
  187. 187.
    Hu M, Sun XJ, Zhang YL, Kuang Y, Hu CQ et al. 2010. Histone H3 lysine 36 methyltransferase Hypb/Setd2 is required for embryonic vascular remodeling. PNAS 107:7295661
    [Google Scholar]
  188. 188.
    Zhou Y, Yan X, Feng X, Bu J, Dong Y et al. 2018. Setd2 regulates quiescence and differentiation of adult hematopoietic stem cells by restricting RNA polymerase II elongation. Haematologica 103:7111023
    [Google Scholar]
  189. 189.
    Faber PW, Barnes GT, Srinidhi J, Chen J, Gusella JF, MacDonald ME. 1998. Huntingtin interacts with a family of WW domain proteins. Hum. Mol. Genet. 7:9146374
    [Google Scholar]
  190. 190.
    Edmunds JW, Mahadevan LC, Clayton AL. 2008. Dynamic histone H3 methylation during gene induction: HYPB/Setd2 mediates all H3K36 trimethylation. EMBO J. 27:240620
    [Google Scholar]
  191. 191.
    Neri F, Rapelli S, Krepelova A, Incarnato D, Parlato C et al. 2017. Intragenic DNA methylation prevents spurious transcription initiation. Nature 543:76437277
    [Google Scholar]
  192. 192.
    Carvalho S, Vítor AC, Sridhara SC, Filipa BM, Ana CR et al. 2014. SETD2 is required for DNA double-strand break repair and activation of the p53-mediated checkpoint. eLife 3:e02482
    [Google Scholar]
  193. 193.
    Li F, Mao G, Tong D, Huang J, Gu L et al. 2013. The histone mark H3K36me3 regulates human DNA mismatch repair through its interaction with MutSα. Cell 153:3590600
    [Google Scholar]
  194. 194.
    Kanu N, Grönroos E, Martinez P, Burrell RA, Yi Goh X et al. 2015. SETD2 loss-of-function promotes renal cancer branched evolution through replication stress and impaired DNA repair. Oncogene 34:465699708
    [Google Scholar]
  195. 195.
    Skucha A, Ebner J, Grebien F. 2019. Roles of SETD2 in leukemia—transcription, DNA-damage, and beyond. Int. J. Mol. Sci. 20:51029
    [Google Scholar]
  196. 196.
    Chen R, Zhao WQ, Fang C, Yang X, Ji M. 2020. Histone methyltransferase SETD2: a potential tumor suppressor in solid cancers. J. Cancer 11:11334956
    [Google Scholar]
  197. 197.
    Fontebasso AM, Schwartzentruber J, Khuong-Quang DA, Liu XY, Sturm D et al. 2013. Mutations in SETD2 and genes affecting histone H3K36 methylation target hemispheric high-grade gliomas. Acta Neuropathol. 125:565969
    [Google Scholar]
  198. 198.
    Hacker KE, Fahey CC, Shinsky SA, Chiang YCJ, DiFiore JV et al. 2016. Structure/function analysis of recurrent mutations in SETD2 protein reveals a critical and conserved role for a SET domain residue in maintaining protein stability and histone H3 Lys-36 trimethylation. J. Biol. Chem. 291:402128395
    [Google Scholar]
  199. 199.
    Carrozza MJ, Li B, Florens L, Suganuma T, Swanson SK et al. 2005. Histone H3 methylation by Set2 directs deacetylation of coding regions by Rpd3S to suppress spurious intragenic transcription. Cell 123:458192
    [Google Scholar]
  200. 200.
    Lickwar CR, Rao B, Shabalin AA, Nobel AB, Strahl BD, Lieb JD. 2009. The Set2/Rpd3S pathway suppresses cryptic transcription without regard to gene length or transcription frequency. PLOS ONE 4:3e4886
    [Google Scholar]
  201. 201.
    Gibson MD, Gatchalian J, Slater A, Kutateladze TG, Poirier MG. 2017. PHF1 Tudor and N-terminal domains synergistically target partially unwrapped nucleosomes to increase DNA accessibility. Nucleic Acids Res. 45:7376776
    [Google Scholar]
  202. 202.
    Baubec T, Colombo DF, Wirbelauer C, Schmidt J, Burger L et al. 2015. Genomic profiling of DNA methyltransferases reveals a role for DNMT3B in genic methylation. Nature 520:754624347
    [Google Scholar]
  203. 203.
    Cai L, Rothbart SB, Lu R, Xu B, Chen WY et al. 2013. An H3K36 methylation-engaging Tudor motif of polycomb-like proteins mediates PRC2 complex targeting. Mol. Cell 49:357182
    [Google Scholar]
  204. 204.
    Bhattacharya S, Levy MJ, Zhang N, Li H, Florens L et al. 2021. The methyltransferase SETD2 couples transcription and splicing by engaging mRNA processing factors through its SHI domain. Nat. Commun. 12:1443
    [Google Scholar]
  205. 205.
    De Almeida SF, Grosso AR, Koch F, Fenouil R, Carvalho S et al. 2011. Splicing enhances recruitment of methyltransferase HYPB/Setd2 and methylation of histone H3 Lys36. Nat. Struct. Mol. Biol. 18:997783
    [Google Scholar]
  206. 206.
    Pfister SX, Ahrabi S, Zalmas LP, Sarkar S, Aymard F et al. 2014. SETD2-dependent histone H3K36 trimethylation is required for homologous recombination repair and genome stability. Cell Rep. 7:6200618
    [Google Scholar]
  207. 207.
    Guo S, Fang J, Xu W, Ortega J, Liu CY et al. 2022. Interplay between H3K36me3, methyltransferase SETD2, and mismatch recognition protein MutSα facilitates processing of oxidative DNA damage in human cells. J. Biol. Chem. 298:7102102
    [Google Scholar]
  208. 208.
    Park IY, Powell RT, Tripathi DN, Dere R, Ho TH et al. 2016. Dual chromatin and cytoskeletal remodeling by SETD2. Cell 166:495062
    [Google Scholar]
  209. 209.
    Forde PM, Anagnostou V, Sun Z, Dahlberg SE, Kindler HL et al. 2021. Durvalumab with platinum-pemetrexed for unresectable pleural mesothelioma: survival, genomic and immunologic analyses from the phase 2 PrE0505 trial. Nat. Med. 27:11191020
    [Google Scholar]
  210. 210.
    Creaney J, Patch AM, Addala V, Sneddon SA, Nones K et al. 2022. Comprehensive genomic and tumour immune profiling reveals potential therapeutic targets in malignant pleural mesothelioma. Genome Med. 14:58
    [Google Scholar]
  211. 211.
    Hung YP, Dong F, Dubuc AM, Dal Cin P, Bueno R, Chirieac LR. 2020. Molecular characterization of localized pleural mesothelioma. Mod. Pathol. 33:227180
    [Google Scholar]
  212. 212.
    Kang HC, Kim HK, Lee S, Mendez P, Kim JW et al. 2016. Whole exome and targeted deep sequencing identify genome-wide allelic loss and frequent SETDB1 mutations in malignant pleural mesotheliomas. Oncotarget 7:7832131
    [Google Scholar]
  213. 213.
    Husain AN, Colby TV, Ordóñez NG, Allen TC, Attanoos RL et al. 2018. Guidelines for pathologic diagnosis of malignant mesothelioma: 2017 update of the consensus statement from the International Mesothelioma Interest Group. Arch. Pathol. Lab. Med. 142:189108
    [Google Scholar]
  214. 214.
    Naso JR, Tsuji S, Churg A. 2020. HEG1 is a highly specific and sensitive marker of epithelioid malignant mesothelioma. Am. J. Surg. Pathol. 44:8114348
    [Google Scholar]
  215. 215.
    Tsuji S, Washimi K, Kageyama T, Yamashita M, Yoshihara M et al. 2017. HEG1 is a novel mucin-like membrane protein that serves as a diagnostic and therapeutic target for malignant mesothelioma. Sci. Rep. 7:45768
    [Google Scholar]
  216. 216.
    Chapel DB, Hornick JL, Barlow J, Bueno R, Sholl LM. 2022. Clinical and molecular validation of BAP1, MTAP, P53, and Merlin immunohistochemistry in diagnosis of pleural mesothelioma. Mod. Pathol. 35:10138397
    [Google Scholar]
  217. 217.
    Zuccatosta L, Bizzarro T, Rossi G, Gallo G, Gasparini S, Ambrosini-Spaltro A. 2023. Immunohistochemistry for Claudin-4 and BAP1 in the differential diagnosis between sarcomatoid carcinoma and sarcomatoid mesothelioma. Diagnostics 13:2249
    [Google Scholar]
  218. 218.
    Sun T, Wang X, Wang M, Minerowicz C, Sanchez H et al. 2022. Somatic mutation of BAP1 can lead to expression loss in non-small cell lung carcinoma: next generation sequencing and IHC analysis in a large single institute cohort. Int. J. Surg. Pathol. 30:551219
    [Google Scholar]
  219. 219.
    Brcic L, Le Stang N, Gallob F, Pissaloux D, Sequeiros R et al. 2023. A combination of MTAP and p16 immunohistochemistry can substitute for CDKN2A fluorescence in situ hybridization in diagnosis and prognosis of pleural mesotheliomas. Arch. Pathol. Lab. Med. 147:331322
    [Google Scholar]
  220. 220.
    Hamasaki M, Matsumoto S, Abe S, Hamatake D, Kamei T et al. 2016. Low homozygous/high heterozygous deletion status by p16 FISH correlates with a better prognostic group than high homozygous deletion status in malignant pleural mesothelioma. Lung Cancer 99:15561
    [Google Scholar]
  221. 221.
    Dacic S, Kothmaier H, Land S, Shuai Y, Halbwedl I et al. 2008. Prognostic significance of p16/cdkn2a loss in pleural malignant mesotheliomas. Virchows Arch. 453:662735
    [Google Scholar]
  222. 222.
    Chapel DB, Schulte JJ, Berg K, Churg A, Dacic S et al. 2020. MTAP immunohistochemistry is an accurate and reproducible surrogate for CDKN2A fluorescence in situ hybridization in diagnosis of malignant pleural mesothelioma. Mod. Pathol. 33:224554
    [Google Scholar]
  223. 223.
    Illei PB, Ladanyi M, Rusch VW, Zakowski MF. 2003. The use of CDKN2A deletion as a diagnostic marker for malignant mesothelioma in body cavity effusions. Cancer 99:15156
    [Google Scholar]
  224. 224.
    Lo Iacono M, Monica V, Righi L, Grosso F, Libener R et al. 2015. Targeted next-generation sequencing of cancer genes in advanced stage malignant pleural mesothelioma: a retrospective study. J. Thorac. Oncol. 10:349299
    [Google Scholar]
  225. 225.
    Sheffield BS, Lorette J, Shen Y, Marra MA, Churg A. 2016. Immunohistochemistry for NF2, LATS1/2, and YAP/TAZ fails to separate benign from malignant mesothelial proliferations. Arch. Pathol. Lab. Med. 140:5391
    [Google Scholar]
  226. 226.
    Li Y, Yang S-R, Chen Y-B, Adusumilli PS, Bialik A et al. 2023. Neurofibromatosis type 2-yes-associated protein and transcriptional coactivator with PDZ-binding motif dual immunohistochemistry is a reliable marker for the detection of neurofibromatosis type 2 alterations in diffuse pleural mesothelioma. Mod. Pathol. 36:3100030
    [Google Scholar]
  227. 227.
    Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E et al. 2003. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J. Clin. Oncol. 21:14263644
    [Google Scholar]
  228. 228.
    Zalcman G, Mazieres J, Margery J, Greillier L, Audigier-Valette C et al. 2016. Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial. Lancet 387:10026140514
    [Google Scholar]
  229. 229.
    Zauderer MG. 2016. A new standard for malignant pleural mesothelioma. Lancet 387:10026135254
    [Google Scholar]
  230. 230.
    Baas P, Scherpereel A, Nowak AK, Fujimoto N, Peters S et al. 2021. First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial. Lancet 397:1027237586
    [Google Scholar]
  231. 231.
    Offin M, Rusch VW, Rimner A, Adusumilli PS, Zauderer MG. 2022. Evolving landscape of initial treatments for patients with malignant pleural mesotheliomas: clinical trials to clinical practice. Oncologist 27:861014
    [Google Scholar]
  232. 232.
    Muller S, Lai WV, Adusumilli PS, Desmeules P, Frosina D et al. 2020. V-domain Ig-containing suppressor of T-cell activation (VISTA), a potentially targetable immune checkpoint molecule, is highly expressed in epithelioid malignant pleural mesothelioma. Mod. Pathol. 33:230311
    [Google Scholar]
  233. 233.
    Ceresoli GL, Zucali PA, Favaretto AG, Grossi F, Bidoli P et al. 2006. Phase II study of pemetrexed plus carboplatin in malignant pleural mesothelioma. J. Clin. Oncol. 24:9144348
    [Google Scholar]
  234. 234.
    Castagneto B, Botta M, Aitini E, Spigno F, Degiovanni D et al. 2008. Phase II study of pemetrexed in combination with carboplatin in patients with malignant pleural mesothelioma (MPM). Ann. Oncol. 19:237073
    [Google Scholar]
  235. 235.
    Santoro A, O'Brien ME, Stahel RA, Nackaerts K, Baas P et al. 2008. Pemetrexed plus cisplatin or pemetrexed plus carboplatin for chemonaïve patients with malignant pleural mesothelioma: results of the International Expanded Access Program. J. Thorac. Oncol. 3:775663
    [Google Scholar]
  236. 236.
    Zauderer MG, Kass SL, Woo K, Sima CS, Ginsberg MS, Krug LM. 2014. Vinorelbine and gemcitabine as second- or third-line therapy for malignant pleural mesothelioma. Lung Cancer 84:327174
    [Google Scholar]
  237. 237.
    Adusumilli PS, Zauderer MG, Rivière I, Solomon SB, Rusch VW et al. 2021. A phase I trial of regional mesothelin-targeted CAR T-cell therapy in patients with malignant pleural disease, in combination with the anti-PD-1 agent pembrolizumab. Cancer Discov. 11:11274863
    [Google Scholar]
  238. 238.
    Ghosn M, Cheema W, Zhu A, Livschitz J, Maybody M et al. 2022. Image-guided interventional radiological delivery of chimeric antigen receptor (CAR) T cells for pleural malignancies in a phase I/II clinical trial. Lung Cancer 165:19
    [Google Scholar]
  239. 239.
    Chintala NK, Restle D, Quach H, Saini J, Bellis R et al. 2021. CAR T-cell therapy for pleural mesothelioma: rationale, preclinical development, and clinical trials. Lung Cancer 157:4859
    [Google Scholar]
  240. 240.
    Kindler HL, Novello S, Bearz A, Ceresoli GL, Aerts JGJV et al. 2022. Anetumab ravtansine versus vinorelbine in patients with relapsed, mesothelin-positive malignant pleural mesothelioma (ARCS-M): a randomised, open-label phase 2 trial. Lancet. Oncol. 23:454052
    [Google Scholar]
  241. 241.
    Krug LM, Dao T, Brown AB, Maslak P, Travis W et al. 2010. WT1 peptide vaccinations induce CD4 and CD8 T cell immune responses in patients with mesothelioma and non-small cell lung cancer. Cancer Immunol. Immunother. 59:10146779
    [Google Scholar]
  242. 242.
    Zauderer MG, Tsao AS, Dao T, Panageas K, Lai WV et al. 2017. A randomized phase II trial of adjuvant galinpepimut-S, WT-1 analogue peptide vaccine, after multimodality therapy for patients with malignant pleural mesothelioma. Clin. Cancer Res. 23:24748389
    [Google Scholar]
  243. 243.
    Louw A, Panou V, Szejniuk WM, Meristoudis C, Chai SM et al. 2022. BAP1 loss by immunohistochemistry predicts improved survival to first-line platinum and pemetrexed chemotherapy for patients with pleural mesothelioma: a validation study. J. Thorac. Oncol. 17:792130
    [Google Scholar]
  244. 244.
    Oehl K, Vrugt B, Wagner U, Kirschner MB, Meerang M et al. 2021. Alterations in BAP1 are associated with cisplatin resistance through inhibition of apoptosis in malignant pleural mesothelioma. Clin. Cancer Res. 27:8227791
    [Google Scholar]
  245. 245.
    Bahnasy AA, El-Din RS, Sabri NA, Abdel-Rahman CA, El Bastawisy A 2018. BAP1 gene mutations in Egyptian patients with advanced sporadic malignant pleural mesothelioma (MPM): relation with clinical outcomes and survival. Cancer Genet. 228:8392
    [Google Scholar]
  246. 246.
    Pandey GK, Landman N, Neikes HK, Hulsman D, Lieftink C et al. 2023. Genetic screens reveal new targetable vulnerabilities in BAP1-deficient mesothelioma. Cell Rep. Med. 4:2100915
    [Google Scholar]
  247. 247.
    Zauderer MG, Szlosarek PW, Le Moulec S, Popat S, Taylor P et al. 2022. EZH2 inhibitor tazemetostat in patients with relapsed or refractory, BAP1-inactivated malignant pleural mesothelioma: a multicentre, open-label, phase 2 study. Lancet. Oncol. 23:675867
    [Google Scholar]
  248. 248.
    Fennell DA, King A, Mohammed S, Branson A, Brookes C et al. 2021. Rucaparib in patients with BAP1-deficient or BRCA1-deficient mesothelioma (MiST1): an open-label, single-arm, phase 2a clinical trial. Lancet. Respir. Med. 9:6593600
    [Google Scholar]
  249. 249.
    Osmanbeyoglu HU, Palmer D, Sagan A, Sementino E, Becich MJ, Testa JR. 2022. Isolated BAP1 genomic alteration in malignant pleural mesothelioma predicts distinct immunogenicity with implications for immunotherapeutic response. Cancers 14:225626
    [Google Scholar]
  250. 250.
    Shrestha R, Nabavi N, Lin YY, Mo F, Anderson S et al. 2019. BAP1 haploinsufficiency predicts a distinct immunogenic class of malignant peritoneal mesothelioma. Genome Med. 11:8
    [Google Scholar]
  251. 251.
    Ladanyi M, Sanchez Vega F, Zauderer M. 2019. Loss of BAP1 as a candidate predictive biomarker for immunotherapy of mesothelioma. Genome Med. 11:18
    [Google Scholar]
  252. 252.
    Tang B, Lee HO, An SS, Cai KQ, Kruger WD. 2018. Specific targeting of MTAP-deleted tumors with a combination of 2′-fluoroadenine and 5′-methylthioadenosine. Cancer Res. 78:15438695
    [Google Scholar]
  253. 253.
    Zauderer MG, Alley EW, Bendell J, Capelletto E, Bauer TM et al. 2021. Phase 1 cohort expansion study of LY3023414, a dual PI3K/mTOR inhibitor, in patients with advanced mesothelioma. Investig. New Drugs 39:4108188
    [Google Scholar]
  254. 254.
    Dolly SO, Wagner AJ, Bendell JC, Kindler HL, Krug LM et al. 2016. Phase I study of apitolisib (GDC-0980), dual phosphatidylinositol-3-kinase and mammalian target of rapamycin kinase inhibitor, in patients with advanced solid tumors. Clin. Cancer Res. 22:12287484
    [Google Scholar]
  255. 255.
    Cooper J, Xu Q, Zhou L, Pavlovic M, Ojeda V et al. 2017. Combined inhibition of NEDD8-activating enzyme and mTOR suppresses NF2 loss-driven tumorigenesis. Mol. Cancer Ther. 16:81693704
    [Google Scholar]
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