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Pulmonary Malignancies (2): Mesothelioma—What Are the Roles of Genetic Factors in the Pathogenesis of Mesothelioma?

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Clinical Relevance of Genetic Factors in Pulmonary Diseases

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Abstract

Malignant pleural mesothelioma is a highly lethal and aggressive tumor, and its incidence is increasing because of widespread asbestos exposure in the last 50 years. Malignant mesothelioma is characterized by a long latency period of 40 years between initial exposure to asbestos and tumor development, indicating that multiple somatic genetic alterations contribute to its carcinogenesis. Molecular genetic studies have identified multiple chromosomal alterations in most mesothelioma tumor tissues and cell lines. In addition, these studies have identified several key genetic alterations. Mutation rates in CDKN2A, NF2, and BAP1, which are cancer suppressor genes, are high in mesothelioma cells. Moreover, diagnosis of a new familial cancer predisposition syndrome associated with germline BAP1 mutation indicates the importance of genetic factors in mesothelioma susceptibility. In this chapter, we have summarized the clinicopathological aspects of mesothelioma and have discussed the roles of genetic factors in the development of malignant pleural mesothelioma.

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References

  1. Risberg B, Nickels J, Wågermark J. Familial clustering of malignant mesothelioma. Cancer. 1980;45:2422–7.

    Article  CAS  PubMed  Google Scholar 

  2. Hammar SP, Bockus D, Remington F, Freidman S, LaZerte G. Familial mesothelioma: a report of two families. Hum Pathol. 1989;20:107–12.

    Article  CAS  PubMed  Google Scholar 

  3. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Gemba K, Fujimoto N, Kato K, Aoe K, Takeshima Y, Inai K, et al. National survey of malignant mesothelioma and asbestos exposure in Japan. Cancer Sci. 2012;103:483–90.

    Article  CAS  PubMed  Google Scholar 

  6. Tossavainen A. Global use of asbestos and the incidence of mesothelioma. Int J Occup Environ Health. 2004;10:22–5.

    Article  PubMed  Google Scholar 

  7. Myojin T, Azuma K, Okumura J, Uchiyama I. Future trends of mesothelioma mortality in Japan based on risk function. Ind Health. 2012;50:197–204.

    Article  PubMed  Google Scholar 

  8. Ault JG, Cole RW, Jensen CG, Jensen LC, Bachert LA, Rieder CL. Behavior of crocidolite asbestos during mitosis in living vertebrate lung epithelial cells. Cancer Res. 1995;55:792–8.

    PubMed  CAS  Google Scholar 

  9. Altomare DA, Testa JR. Cytogenetic and molecular genetic changes in malignant mesothelioma. In: O’Byne K, Rusch V, editors. Malignant pleural mesothelioma. Oxford: Oxford University Press; 2006. p. 239–50.

    Google Scholar 

  10. King JE, Hasleton PS. The epidemiology and etiology of malignant mesothelioma. In: O’Byne K, Rusch V, editors. Malignant pleural mesothelioma. Oxford: Oxford University Press; 2006. p. 1–18.

    Google Scholar 

  11. Taguchi T, Jhanwar SC, Siegfried JM, Keller SM, Testa JR. Recurrent deletions of specific chromosomal sites in 1p, 3p, 6q, and 9p in human malignant mesothelioma. Cancer Res. 1993;53:4349–55.

    PubMed  CAS  Google Scholar 

  12. Bjorkqvist AM, Tammilehto L, Anttila S, Mattson K, Knuutila S. Recurrent DNA copy number changes in 1q, 4q, 6q, 9p, 13q, 14q and 22q detected by comparative genomic hybridization in malignant mesothelioma. Br J Cancer. 1997;75:523–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lindholm PM, Salmenkivi K, Vauhkonen H, Nicholson AG, Anttila S, Kinnula VL, et al. Gene copy number analysis in malignant pleural mesothelioma using oligonucleotide array CGH. Cytogenet Genome Res. 2007;119(1–2):46–52.

    Article  CAS  PubMed  Google Scholar 

  14. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Yoshikawa Y, Sato A, Tsujimura T, Morinaga T, Fukuoka K, Yamada S, et al. Frequent deletion of 3p21.1 region carrying semaphorin 3G and aberrant expression of the genes participating in semaphorin signaling in the epithelioid type of malignant mesothelioma cells. Int J Oncol. 2011;39:1365–74.

    PubMed  CAS  Google Scholar 

  16. Chirac P, Maillet D, Lepretre F, Isaac S, Glehen O, Figeac M, et al. Genomic copy number alterations in 33 malignant peritoneal mesothelioma analyzed by comparative genomic hybridization array. Hum Pathol. 2016;55:72–82.

    Article  CAS  PubMed  Google Scholar 

  17. Yoshikawa Y, Emi M, Hashimoto-Tamaoki T, Ohmuraya M, Sato A, Tsujimura T, et al. High-density array-CGH with targeted NGS unmask multiple noncontiguous minute deletions on chromosome 3p21 in mesothelioma. Proc Natl Acad Sci U S A. 2016;113:13432–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Stephens PJ, Greenman CD, Fu B, Yang F, Bignell GR, Mudie LJ, et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell. 2011;144:27–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Bolognesi C, Filiberti R, Neri M, Perrone E, Landini E, Canessa PA, et al. High frequency of micronuclei in peripheral blood lymphocytes as index of susceptibility to pleural malignant mesothelioma. Cancer Res. 2002;62:5418–9.

    PubMed  CAS  Google Scholar 

  20. Zhang CZ, Spektor A, Cornils H, Francis JM, Jackson EK, Liu S, et al. Chromothripsis from DNA damage in micronuclei. Nature. 2015;522(7555):179–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kobayashi N, Toyooka S, Yanai H, Soh J, Fujimoto N, Yamamoto H, et al. Frequent p16 inactivation by homozygous deletion or methylation is associated with a poor prognosis in Japanese patients with pleural mesothelioma. Lung Cancer. 2008;62:120–5.

    Article  PubMed  Google Scholar 

  22. Sharpless NE, Bardeesy N, Lee KH, Carrasco D, Castrillon DH, Aguirre AJ, et al. Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis. Nature. 2001;413(6851):86–91.

    Article  CAS  PubMed  Google Scholar 

  23. Hu Q, Akatsuka S, Yamashita Y, Ohara H, Nagai H, Okazaki Y, et al. Homozygous deletion of CDKN2A/2B is a hallmark of iron-induced high-grade rat mesothelioma. Lab Investig. 2010;90(3):360–73.

    Article  CAS  PubMed  Google Scholar 

  24. Nabeshima K, Matsumoto S, Hamasaki M, Hida T, Kamei T, Hiroshima K, et al. Use of p16 FISH for differential diagnosis of mesothelioma in smear preparations. Diagn Cytopathol. 2016;44:774–80.

    Article  PubMed  Google Scholar 

  25. Hamasaki M, Matsumoto S, Abe S, Hamatake D, Kamei T, Hiroshima K, et al. 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. 2016;99:155–61.

    Article  PubMed  Google Scholar 

  26. Bianchi AB, Mitsunaga SI, Cheng JQ, Klein WM, Jhanwar SC, Seizinger B, et al. High frequency of inactivating mutations in the neurofibromatosis type 2 gene (NF2) in primary malignant mesotheliomas. Proc Natl Acad Sci U S A. 1995;92:10854–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Sekido Y, Pass HI, Bader S, Mew DJ, Christman MF, Gazdar AF, et al. Neurofibromatosis type 2 (NF2) gene is somatically mutated in mesothelioma but not in lung cancer. Cancer Res. 1995;55:1227–31.

    PubMed  CAS  Google Scholar 

  28. McClatchey AI, Saotome I, Ramesh V, Gusella JF, Jacks T. The Nf2 tumor suppressor gene product is essential for extraembryonic development immediately prior to gastrulation. Genes Dev. 1997;11:1253–65.

    Article  CAS  PubMed  Google Scholar 

  29. McClatchey AI, Saotome I, Mercer K, Crowley D, Gusella JF, Bronson RT, et al. Mice heterozygous for a mutation at the Nf2 tumor suppressor locus develop a range of highly metastatic tumors. Genes Dev. 1998;12(8):1121–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Fleury-Feith J, Lecomte C, Renier A, Matrat M, Kheuang L, Abramowski V, et al. Hemizygosity of Nf2 is associated with increased susceptibility to asbestos-induced peritoneal tumours. Oncogene. 2003;22(24):3799–805.

    Article  CAS  PubMed  Google Scholar 

  31. Kakiuchi T, Takahara T, Kasugai Y, Arita K, Yoshida N, Karube K, et al. Modeling mesothelioma utilizing human mesothelial cells reveals involvement of phospholipase-C beta 4 in YAP-active mesothelioma cell proliferation. Carcinogenesis. 2016. pii: bgw084.

    Google Scholar 

  32. Murakami H, Mizuno T, Taniguchi T, Fujii M, Ishiguro F, Fukui T, et al. LATS2 is a tumor suppressor gene of malignant mesothelioma. Cancer Res. 2011;71:873–83.

    Article  CAS  PubMed  Google Scholar 

  33. Tranchant R, Quetel L, Tallet A, Meiller C, Renier A, de Koning L, et al. Co-occurring mutations of tumor suppressor genes, LATS2 and NF2, in malignant pleural mesothelioma. Clin Cancer Res. 2016. https://doi.org/10.1158/1078-0432.CCR-16-1971.

  34. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Yoshikawa Y, Sato A, Tsujimura T, Emi M, Morinaga T, Fukuoka K, et al. Frequent inactivation of the BAP1 gene in epithelioid-type malignant mesothelioma. Cancer Sci. 2012;103:868–74.

    Article  CAS  PubMed  Google Scholar 

  36. Zauderer MG, Bott M, McMillan R, Sima CS, Rusch V, Krug LM, et al. Clinical characteristics of patients with malignant pleural mesothelioma harboring somatic BAP1 mutations. J Thorac Oncol. 2013;8:1430–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Nasu M, Emi M, Pastorino S, Tanji M, Powers A, Luk H, et al. High incidence of somatic BAP1 alterations in sporadic malignant mesothelioma. J Thorac Oncol. 2015;10:565–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Emi M, Yoshikawa Y, Sato C, Sato A, Sato H, Kato T, et al. Frequent genomic rearrangements of BRCA1 associated protein-1 (BAP1) gene in Japanese malignant mesothelioma-characterization of deletions at exon level. J Hum Genet. 2015;60:647–9.

    Article  CAS  PubMed  Google Scholar 

  39. Cigognetti M, Lonardi S, Fisogni S, Balzarini P, Pellegrini V, Tironi A, et al. BAP1 (BRCA1-associated protein 1) is a highly specific marker for differentiating mesothelioma from reactive mesothelial proliferations. Mod Pathol. 2015;28:1043–57.

    Article  CAS  Google Scholar 

  40. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Carbone M, Flores EG, Emi M, Johnson TA, Tsunoda T, Behner D, et al. Combined genetic and genealogic studies uncover a large BAP1 cancer syndrome kindred tracing back nine generations to a common ancestor from the 1700s. PLoS Genet. 2015;11(12):e1005633. https://doi.org/10.1371/journal.pgen.1005633. eCollection 2015

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Nishikawa H, Wu W, Koike A, Kojima R, Gomi H, Fukuda M, et al. BRCA1-associated protein 1 interferes with BRCA1/BARD1 RING heterodimer activity. Cancer Res. 2009;69:111–9.

    Article  CAS  PubMed  Google Scholar 

  43. Scheuermann JC, de Ayala Alonso AG, Oktaba K, Ly-Hartig N, McGinty RK, Fraterman S, et al. Histone H2A deubiquitinase activity of the Polycomb repressive complex PR-DUB. Nature. 2010;465(7295):243–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Dey A, Seshasayee D, Noubade R, French DM, Liu J, Chaurushiya MS, et al. Loss of the tumor suppressor BAP1 causes myeloid transformation. Science. 2012;337(6101):1541–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Xu J, Kadariya Y, Cheung M, Pei J, Talarchek J, Sementino E, et al. Germline mutation of Bap1 accelerates development of asbestos-induced malignant mesothelioma. Cancer Res. 2014;74:4388–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Guo G, Chmielecki J, Goparaju C, Heguy A, Dolgalev I, Carbone M, et al. Whole-exome sequencing reveals frequent genetic alterations in BAP1, NF2, CDKN2A, and CUL1 in malignant pleural mesothelioma. Cancer Res. 2015;75:264–9.

    Article  CAS  PubMed  Google Scholar 

  47. 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.

    Article  CAS  PubMed  Google Scholar 

  48. Garraway LA, Lander ES. Lessons from the cancer genome. Cell. 2013;153:17–37.

    Article  CAS  PubMed  Google Scholar 

  49. De Rienzo A, Richards WG, Yeap BY, Coleman MH, Sugarbaker PE, Chirieac LR, et al. Sequential binary gene ratio tests define a novel molecular diagnostic strategy for malignant pleural mesothelioma. Clin Cancer Res. 2013;19:2493–502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Bruno R, Ali G, Giannini R, Proietti A, Lucchi M, Chella A, et al. Malignant pleural mesothelioma and mesothelial hyperplasia: a new molecular tool for the differential diagnosis. Oncotarget. 2017;8:2758–70.

    PubMed  Google Scholar 

  51. Ivanov SV, Goparaju CM, Lopez P, Zavadil J, Toren-Haritan G, Rosenwald S, et al. Pro-tumorigenic effects of miR-31 loss in mesothelioma. J Biol Chem. 2010;285:22809–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kubo T, Toyooka S, Tsukuda K, Sakaguchi M, Fukazawa T, Soh J, et al. Epigenetic silencing of microRNA-34b/c plays an important role in the pathogenesis of malignant pleural mesothelioma. Clin Cancer Res. 2011;17:4965–74.

    Article  CAS  PubMed  Google Scholar 

  53. Reid G, Pel ME, Kirschner MB, Cheng YY, Mugridge N, Weiss J, et al. Restoring expression of miR-16: a novel approach to therapy for malignant pleural mesothelioma. Ann Oncol. 2013;24:3128–35.

    Article  CAS  PubMed  Google Scholar 

  54. Williams M, Kirschner MB, Cheng YY, Hanh J, Weiss J, Mugridge N, et al. miR-193a-3p is a potential tumor suppressor in malignant pleural mesothelioma. Oncotarget. 2015;6:23480–95.

    PubMed  PubMed Central  Google Scholar 

  55. Weber DG, Johnen G, Bryk O, Jockel KH, Bruning T. Identification of miRNA-103 in the cellular fraction of human peripheral blood as a potential biomarker for malignant mesothelioma—a pilot study. PLoS One. 2012;7(1):e30221.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Tomasetti M, Staffolani S, Nocchi L, Neuzil J, Strafella E, Manzella N, et al. Clinical significance of circulating miR-126 quantification in malignant mesothelioma patients. Clin Biochem. 2012;45(7–8):575–81.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Center for Respiratory Medicine, Otemae Hospital, Osaka, Japan

    Takashi Nakano

  2. Division of Respiratory Diseases, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan

    Eisuke Shibata & Kozo Kuribayashi

  3. Department of Genetics, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan

    Yoshie Yoshikawa & Masaki Ohmuraya

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  1. Takashi Nakano
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  2. Eisuke Shibata
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  3. Kozo Kuribayashi
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  4. Yoshie Yoshikawa
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  5. Masaki Ohmuraya
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Correspondence to Takashi Nakano .

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  1. Yokohama City University, Yokohama, Kanagawa, Japan

    Takeshi Kaneko

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Nakano, T., Shibata, E., Kuribayashi, K., Yoshikawa, Y., Ohmuraya, M. (2018). Pulmonary Malignancies (2): Mesothelioma—What Are the Roles of Genetic Factors in the Pathogenesis of Mesothelioma?. In: Kaneko, T. (eds) Clinical Relevance of Genetic Factors in Pulmonary Diseases. Respiratory Disease Series: Diagnostic Tools and Disease Managements. Springer, Singapore. https://doi.org/10.1007/978-981-10-8144-6_12

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  • DOI: https://doi.org/10.1007/978-981-10-8144-6_12

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