Molecular characterization of localized pleural mesothelioma

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Localized pleural mesothelioma is a rare solitary circumscribed pleural tumor that is microscopically similar to diffuse malignant pleural mesothelioma. However, the molecular characteristics and nosologic relationship with its diffuse counterpart remain unknown. In a consecutive cohort of 1110 patients with pleural mesotheliomas diagnosed in 2005–2018, we identified six (0.5%) patients diagnosed with localized pleural mesotheliomas. We gathered clinical history, evaluated the histopathology, and in select cases performed karyotypic analysis and targeted next-generation sequencing. The cohort included three women and three men (median age 63; range 28–76), often presenting incidentally during radiologic evaluation for unrelated conditions. Neoadjuvant chemotherapy was administered in two patients. All tumors (median size 5.0 cm; range 2.7–13.5 cm) demonstrated gross circumscription (with microscopic invasion into lung, soft tissue, and/or rib in four cases), mesothelioma histology (four biphasic and two epithelioid types), and mesothelial immunophenotype. Of four patients with at least 6-month follow-up, three were alive (up to 8.9 years). Genomic characterization identified several subgroups: (1) BAP1 mutations with deletions of CDKN2A and NF2 in two tumors; (2) TRAF7 mutations in two tumors, including one harboring trisomies of chromosomes 3, 5, 7, and X; and (3) genomic near-haploidization, characterized by extensive loss of heterozygosity sparing chromosomes 5 and 7. Localized pleural mesotheliomas appear genetically heterogeneous and include BAP1-mutated, TRAF7-mutated, and near-haploid subgroups. While the BAP1-mutated subgroup is similar to diffuse malignant pleural mesotheliomas, the TRAF7-mutated subgroup overlaps genetically with adenomatoid tumors and well-differentiated papillary mesotheliomas, in which recurrent TRAF7 mutations have been described. Genomic near-haploidization, identified recently in a subset of diffuse malignant pleural mesotheliomas, suggests a novel mechanism in the pathogenesis of both localized pleural mesothelioma and diffuse malignant pleural mesothelioma. Our findings describe distinctive genetic features of localized pleural mesothelioma, with both similarities to and differences from diffuse malignant pleural mesothelioma.

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  1. 1.

    Churg A, Roggli V, Chirieac LR, Galateau-Salle F, Borczuk AC, Dacic S, et al. Tumours of the pleura. Mesothelial tumours. Localized malignant mesothelioma. In: Travis WD, Brambilla E, Burke A, Marx A, Nicholson AG, editors. World Health Organization Classification of tumors pathology and genetics of tumors of the lung, pleura, thymus, and heart. 4th edn. Lyon, France: IARC Press; 2015. p. 170.

  2. 2.

    Allen TC, Cagle PT, Churg AM, Colby TV, Gibbs AR, Hammar SP, et al. Localized malignant mesothelioma. Am J Surg Pathol. 2005;29:866–73.

  3. 3.

    Okike N, Bernatz PE, Woolner LB. Localized mesothelioma of the pleura: benign and malignant variants. J Thorac Cardiovasc Surg. 1978;75:363–72.

  4. 4.

    Crotty TB, Myers JL, Katzenstein AL, Tazelaar HD, Swensen SJ, Churg A. Localized malignant mesothelioma. A clinicopathologic and flow cytometric study. Am J Surg Pathol. 1994;18:357–63.

  5. 5.

    Nakano T, Hamanaka R, Oiwa K, Nakazato K, Masuda R, Iwazaki M. Localized malignant pleural mesothelioma. Gen Thorac Cardiovasc Surg. 2012;60:468–74.

  6. 6.

    Mann S, Khawar S, Moran C, Kalhor N. Revisiting localized malignant mesothelioma. Ann Diagn Pathol. 2019;39:74–7.

  7. 7.

    Bueno R, Stawiski EW, Goldstein LD, Durinck S, De Rienzo A, Modrusan Z, et al. Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations. Nat Genet. 2016;48:407–16.

  8. 8.

    Hmeljak J, Sanchez-Vega F, Hoadley KA, Shih J, Stewart C, Heiman D, et al. Integrative molecular characterization of malignant pleural mesothelioma. Cancer Discov. 2018;8:1548–65.

  9. 9.

    Ramkissoon SH, Bi WL, Schumacher SE, Ramkissoon LA, Haidar S, Knoff D, et al. Clinical implementation of integrated whole-genome copy number and mutation profiling for glioblastoma. Neuro Oncol. 2015;17:1344–55.

  10. 10.

    De Rienzo A, Archer MA, Yeap BY, Dao N, Sciaranghella D, Sideris AC, et al. Gender-specific molecular and clinical features underlie malignant pleural mesothelioma. Cancer Res. 2016;76:319–28.

  11. 11.

    Sholl LM, Do K, Shivdasani P, Cerami E, Dubuc AM, Kuo FC, et al. Institutional implementation of clinical tumor profiling on an unselected cancer population. JCI Insight. 2016;1:e87062.

  12. 12.

    Kolin DL, Dong F, Baltay M, Lindeman N, MacConaill L, Nucci MR, et al. SMARCA4-deficient undifferentiated uterine sarcoma (malignant rhabdoid tumor of the uterus): a clinicopathologic entity distinct from undifferentiated carcinoma. Mod Pathol. 2018;31:1442–56.

  13. 13.

    Chmielecki J, Crago AM, Rosenberg M, O’Connor R, Walker SR, Ambrogio L, et al. Whole-exome sequencing identifies a recurrent NAB2-STAT6 fusion in solitary fibrous tumors. Nat Genet. 2013;45:131–2.

  14. 14.

    Robinson DR, Wu YM, Kalyana-Sundaram S, Cao X, Lonigro RJ, Sung YS, et al. Identification of recurrent NAB2-STAT6 gene fusions in solitary fibrous tumor by integrative sequencing. Nat Genet. 2013;45:180–5.

  15. 15.

    Hung YP, Dong F, Watkins JC, Nardi V, Bueno R, Dal Cin P, et al. Identification of ALK rearrangements in malignant peritoneal mesothelioma. JAMA Oncol. 2018;4:235–8.

  16. 16.

    Desmeules P, Joubert P, Zhang L, Al-Ahmadie HA, Fletcher CD, Vakiani E, et al. A subset of malignant mesotheliomas in young adults are associated with recurrent EWSR1/FUS-ATF1 fusions. Am J Surg Pathol. 2017;41:980–8.

  17. 17.

    Goldblum J, Hart WR. Localized and diffuse mesotheliomas of the genital tract and peritoneum in women. A clinicopathologic study of nineteen true mesothelial neoplasms, other than adenomatoid tumors, multicystic mesotheliomas, and localized fibrous tumors. Am J Surg Pathol. 1995;19:1124–37.

  18. 18.

    Yousem SA, Flynn SD. Intrapulmonary localized fibrous tumor. Intraparenchymal so-called localized fibrous mesothelioma. Am J Clin Pathol. 1988;89:365–9.

  19. 19.

    Delgermaa V, Takahashi K, Park EK, Le GV, Hara T, Sorahan T. Global mesothelioma deaths reported to the World Health Organization between 1994 and 2008. Bull World Health Organ. 2011;89:716–24, 24A-24C.

  20. 20.

    Mazurek JM, Syamlal G, Wood JM, Hendricks SA, Weston A. Malignant mesothelioma mortality - United States, 1999–2015. MMWR Morb Mortal Wkly Rep. 2017;66:214–8.

  21. 21.

    Nelson DB, Rice DC, Niu J, Atay S, Vaporciyan AA, Antonoff M, et al. Long-term survival outcomes of cancer-directed surgery for malignant pleural mesothelioma: propensity score matching analysis. J Clin Oncol. 2017;35:3354–62.

  22. 22.

    Gotfried MH, Quan SF, Sobonya RE. Diffuse epithelial pleural mesothelioma presenting as a solitary lung mass. Chest. 1983;84:99–101.

  23. 23.

    Testa JR, Cheung M, Pei J, Below JE, Tan Y, Sementino E, et al. Germline BAP1 mutations predispose to malignant mesothelioma. Nat Genet. 2011;43:1022–5.

  24. 24.

    Wiesner T, Obenauf AC, Murali R, Fried I, Griewank KG, Ulz P, et al. Germline mutations in BAP1 predispose to melanocytic tumors. Nat Genet. 2011;43:1018–21.

  25. 25.

    Carlo MI, Mukherjee S, Mandelker D, Vijai J, Kemel Y, Zhang L, et al. Prevalence of germline mutations in cancer susceptibility genes in patients with advanced renal cell carcinoma. JAMA Oncol. 2018;4:1228–35.

  26. 26.

    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;43:668–72.

  27. 27.

    Joseph NM, Chen YY, Nasr A, Yeh I, Talevich E, Onodera C, et al. Genomic profiling of malignant peritoneal mesothelioma reveals recurrent alterations in epigenetic regulatory genes BAP1, SETD2, and DDX3X. Mod Pathol. 2017;30:246–54.

  28. 28.

    Harbour JW, Onken MD, Roberson ED, Duan S, Cao L, Worley LA, et al. Frequent mutation of BAP1 in metastasizing uveal melanomas. Science. 2010;330:1410–3.

  29. 29.

    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;44:751–9.

  30. 30.

    Chan-On W, Nairismagi ML, Ong CK, Lim WK, Dima S, Pairojkul C, et al. Exome sequencing identifies distinct mutational patterns in liver fluke-related and non-infection-related bile duct cancers. Nat Genet. 2013;45:1474–8.

  31. 31.

    Jiao Y, Pawlik TM, Anders RA, Selaru FM, Streppel MM, Lucas DJ, et al. Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas. Nat Genet. 2013;45:1470–3.

  32. 32.

    Clark VE, Erson-Omay EZ, Serin A, Yin J, Cotney J, Ozduman K, et al. Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO. Science. 2013;339:1077–80.

  33. 33.

    Reuss DE, Piro RM, Jones DT, Simon M, Ketter R, Kool M, et al. Secretory meningiomas are defined by combined KLF4 K409Q and TRAF7 mutations. Acta Neuropathol. 2013;125:351–8.

  34. 34.

    Clark VE, Harmanci AS, Bai H, Youngblood MW, Lee TI, Baranoski JF, et al. Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas. Nat Genet. 2016;48:1253–9.

  35. 35.

    Klein CJ, Wu Y, Jentoft ME, Mer G, Spinner RJ, Dyck PJ, et al. Genomic analysis reveals frequent TRAF7 mutations in intraneural perineuriomas. Ann Neurol. 2017;81:316–21.

  36. 36.

    Stevers M, Rabban JT, Garg K, Van Ziffle J, Onodera C, Grenert JP, et al. Well-differentiated papillary mesothelioma of the peritoneum is genetically defined by mutually exclusive mutations in TRAF7 and CDC42. Mod Pathol. 2019;32:88–99.

  37. 37.

    Yu W, Chan-On W, Teo M, Ong CK, Cutcutache I, Allen GE, et al. First somatic mutation of E2F1 in a critical DNA binding residue discovered in well-differentiated papillary mesothelioma of the peritoneum. Genome Biol. 2011;12:R96.

  38. 38.

    Goode B, Joseph NM, Stevers M, Van Ziffle J, Onodera C, Talevich E, et al. Adenomatoid tumors of the male and female genital tract are defined by TRAF7 mutations that drive aberrant NF-kB pathway activation. Mod Pathol. 2018;31:660–73.

  39. 39.

    Tamura D, Maeda D, Halimi SA, Okimura M, Kudo-Asabe Y, Ito S, et al. Adenomatoid tumour of the uterus is frequently associated with iatrogenic immunosuppression. Histopathology. 2018;73:1013–22.

  40. 40.

    Mandahl N, Johansson B, Mertens F, Mitelman F. Disease-associated patterns of disomic chromosomes in hyperhaploid neoplasms. Genes Chromosomes Cancer. 2012;51:536–44.

  41. 41.

    Bovee JV, van Royen M, Bardoel AF, Rosenberg C, Cornelisse CJ, Cleton-Jansen AM, et al. Near-haploidy and subsequent polyploidization characterize the progression of peripheral chondrosarcoma. Am J Pathol. 2000;157:1587–95.

  42. 42.

    Hallor KH, Staaf J, Bovee JV, Hogendoorn PC, Cleton-Jansen AM, Knuutila S, et al. Genomic profiling of chondrosarcoma: chromosomal patterns in central and peripheral tumors. Clin Cancer Res. 2009;15:2685–94.

  43. 43.

    Olsson L, Paulsson K, Bovee JV, Nord KH. Clonal evolution through loss of chromosomes and subsequent polyploidization in chondrosarcoma. PLoS ONE. 2011;6:e24977.

  44. 44.

    Holmfeldt L, Wei L, Diaz-Flores E, Walsh M, Zhang J, Ding L, et al. The genomic landscape of hypodiploid acute lymphoblastic leukemia. Nat Genet. 2013;45:242–52.

  45. 45.

    Corver WE, van Wezel T, Molenaar K, Schrumpf M, van den Akker B, van Eijk R, et al. Near-haploidization significantly associates with oncocytic adrenocortical, thyroid, and parathyroid tumors but not with mitochondrial DNA mutations. Genes Chromosomes Cancer. 2014;53:833–44.

  46. 46.

    Assie G, Letouze E, Fassnacht M, Jouinot A, Luscap W, Barreau O, et al. Integrated genomic characterization of adrenocortical carcinoma. Nat Genet. 2014;46:607–12.

  47. 47.

    Zheng S, Cherniack AD, Dewal N, Moffitt RA, Danilova L, Murray BA, et al. Comprehensive pan-genomic characterization of adrenocortical carcinoma. Cancer Cell. 2016;29:723–36.

  48. 48.

    Ganly I, Makarov V, Deraje S, Dong Y, Reznik E, Seshan V, et al. Integrated genomic analysis of Hurthle cell cancer reveals oncogenic drivers, recurrent mitochondrial mutations, and unique chromosomal landscapes. Cancer Cell. 2018;34:256–70.e5.

  49. 49.

    Arbajian E, Koster J, Vult von Steyern F, Mertens F. Inflammatory leiomyosarcoma is a distinct tumor characterized by near-haploidization, few somatic mutations, and a primitive myogenic gene expression signature. Mod Pathol. 2018;31:93–100.

  50. 50.

    Kang HC, Kim HK, Lee S, Mendez P, Kim JW, Woodard G, et al. Whole exome and targeted deep sequencing identify genome-wide allelic loss and frequent SETDB1 mutations in malignant pleural mesotheliomas. Oncotarget. 2016;7:8321–31.

  51. 51.

    Sukov WR, Ketterling RP, Wei S, Monaghan K, Blunden P, Mazzara P, et al. Nearly identical near-haploid karyotype in a peritoneal mesothelioma and a retroperitoneal malignant peripheral nerve sheath tumor. Cancer Genet Cytogenet. 2010;202:123–8.

  52. 52.

    Davoli T, Xu AW, Mengwasser KE, Sack LM, Yoon JC, Park PJ, et al. Cumulative haploinsufficiency and triplosensitivity drive aneuploidy patterns and shape the cancer genome. Cell. 2013;155:948–62.

  53. 53.

    Sandberg AA, Bridge JA. Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors. Mesothelioma. Cancer Genet Cytogenet. 2001;127:93–110.

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We thank Ms. Michele Baltay at the Center for Advanced Molecular Diagnostics at the Brigham and Women’s Hospital for technical support.

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Correspondence to Yin P. Hung.

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There is no disclosure from YPH, FD, AMD and PDC. RB has served on the Advisory boards for Myriad, Exosome Diagnostics, and CollaboRx and received support from the National Cancer Institute and investigator-initiated industry grants from Castle Biosciences, Exosome Diagnostics, Genentech-Roche, Gritstone, HTG, Merck, Myriad, Novartis, PamGene, Siemens, Verastem, MedGenome, and Epizyme. LRC undertakes medicolegal work related to mesothelioma. All financial disclosures listed above do not apply to the current study, which is not associated with a specific source of funding.

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