Skip to main content
SpringerLink
Log in

Molecular Characteristics

  • Chapter
  • First Online:
Diffuse Malignant Mesothelioma

  • 883 Accesses

Abstract

Exposure to asbestos is a major factor which is thought to predispose to development of most cases of malignant mesothelioma. The asbestos fibers are thought to elicit an inflammatory response and reactive oxygen species which may be involved in genetic mutation in the mesothelial cells and subsequent development of malignant mesothelioma. Karyotyping of mesothelioma cases have revealed very complex chromosomal abnormalities with both hypodiploid and hyperdiploid karyotypes; however, there are certain chromosomes or regions of some of the chromosomes which are more likely to contain losses or structural rearrangements. This chapter reviews common genetic abnormalities found in mesothelioma including deletion of chromosome 9p21, which contains the gene CDKN2A that encodes the cell cycle protein p16INK4a; deletion of chromosome 22 or 22q, which includes the neurofibromatosis 2 (NF2) gene that encodes the tumor suppressor protein Merlin; and deletion of chromosome 3p21, which includes the BAP1 gene which encodes BRCA-1-associated protein 1 (BAP1). The functions of each of these proteins and likely pathogenic mechanisms are reviewed. Other less common mutations will also be discussed. In addition, possible germ-line mutations (including BAP1) that increase risk of development of mesothelioma are reviewed.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 54.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Liu G, Cheresh P, Kamp DW. Molecular basis of asbestos-induced lung disease. Ann Rev Pathol. 2013;8:161–87.

    Article  CAS  Google Scholar 

  2. Gibas Z, Li FP, Antman KH, Bernal S, Stahel R, Sandberg AA. Chromosome changes in malignant mesothelioma. Cancer Genet Cytogenet. 1986;20:191–201.

    Article  CAS  PubMed  Google Scholar 

  3. Popescu NC, Chahinian AP, DiPaolo JA. Nonrandom chromosome alterations in human malignant mesothelioma. Cancer Res. 1988;48:142–7.

    CAS  PubMed  Google Scholar 

  4. Hagemeijer A, Versnel MA, Van Drunen E, et al. Cytogenetic analysis of malignant mesothelioma. Cancer Genet Cytogenet. 1990;47:1–28.

    Article  CAS  PubMed  Google Scholar 

  5. 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.

    CAS  PubMed  Google Scholar 

  6. 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. Brit J Cancer. 1997;75:523–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Krismann M, Muller KM, Jaworska M, Johnen G. Molecular cytogenetic differences between histological subtypes of malignant mesotheliomas: DNA cytometry and comparative genomic hybridization of 90 cases. J Pathol. 2002;197:363–71.

    Article  CAS  PubMed  Google Scholar 

  8. Lindholm PM, Salmenkivi K, Vauhkonen H, et al. Gene copy number analysis in malignant pleural mesothelioma using oligonucleotide array CGH. Cytogenet Genome Res. 2007;119:46–52.

    Article  CAS  PubMed  Google Scholar 

  9. Kamb A, Gruis NA, Weaver-Feldhaus J, et al. A cell cycle regulator potentially involved in genesis of many tumor types. Science. 1994;264:436–40.

    Article  CAS  PubMed  Google Scholar 

  10. Fountain JW, Karayiorgou M, Ernstoff MS, et al. Homozygous deletions within human chromosome band 9p21 in melanoma. Proc Natl Acad Sci U S A. 1992;89:10557–61.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Brambilla E, Moro D, Gazzeri S, Brambilla C. Alterations of expression of Rb, p16(INK4A) and cyclin D1 in non-small cell lung carcinoma and their clinical significance. J Pathol. 1999;188:351–60.

    Article  CAS  PubMed  Google Scholar 

  12. Moulton T, Samara G, Chung WY, et al. MTS1/p16/CDKN2 lesions in primary glioblastoma multiforme. Am J Pathol. 1995;146:613–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  13. Nielsen GP, Burns KL, Rosenberg AE, Louis DN. CDKN2A gene deletions and loss of p16 expression occur in osteosarcomas that lack RB alterations. Am J Pathol. 1998;153:159–63.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Serrano M, Hannon GJ, Beach D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature. 1993;366:704–7.

    Article  CAS  PubMed  Google Scholar 

  15. Nobori T, Takabayashi K, Tran P, et al. Genomic cloning of methylthioadenosine phosphorylase: a purine metabolic enzyme deficient in multiple different cancers. Proc Natl Acad Sci U S A. 1996;93:6203–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Cheng JQ, Jhanwar SC, Lu YY, Testa JR. Homozygous deletions within 9p21-p22 identify a small critical region of chromosomal loss in human malignant mesotheliomas. Cancer Res. 1993;53:4761–3.

    CAS  PubMed  Google Scholar 

  17. Cheng JQ, Jhanwar SC, Klein WM, et al. p16 alterations and deletion mapping of 9p21-p22 in malignant mesothelioma. Cancer Res. 1994;54:5547–51.

    CAS  PubMed  Google Scholar 

  18. Illei PB, Rusch VW, Zakowski MF, Ladanyi M. Homozygous deletion of CDKN2A and codeletion of the methylthioadenosine phosphorylase gene in the majority of pleural mesotheliomas. Clin Cancer Res. 2003;9:2108–13.

    CAS  PubMed  Google Scholar 

  19. Takeda M, Kasai T, Enomoto Y, et al. 9p21 deletion in the diagnosis of malignant mesothelioma, using fluorescence in situ hybridization analysis. Pathol Int. 2010;60:395–9.

    Article  PubMed  Google Scholar 

  20. Bott M, Brevet M, Taylor BS, et al. The nuclear deubiquitinase BAP1 is commonly inactivated by somatic mutations and 3p21.1 losses in malignant pleural mesothelioma. Nature Genet. 2011;43:668–72.

    Article  CAS  PubMed  Google Scholar 

  21. Takeda M, Kasai T, Enomoto Y, et al. Genomic gains and losses in malignant mesothelioma demonstrated by FISH analysis of paraffin-embedded tissues. J Clin Pathol. 2012;65:77–82.

    Article  CAS  PubMed  Google Scholar 

  22. Wu D, Hiroshima K, Matsumoto S, et al. Diagnostic usefulness of p16/CDKN2A FISH in distinguishing between sarcomatoid mesothelioma and fibrous pleuritis. Am J Clin Pathol. 2013;139:39–46.

    Article  CAS  PubMed  Google Scholar 

  23. Kobayashi N, Toyooka S, Yanai 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 

  24. Illei PB, Ladanyi M, Rusch VW, Zakowski MF. The use of CDKN2A deletion as a diagnostic marker for malignant mesothelioma in body cavity effusions. Cancer. 2003;99:51–6.

    Article  CAS  PubMed  Google Scholar 

  25. Quelle DE, Zindy F, Ashmun RA, Sherr CJ. Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Cell. 1995;83:993–1000.

    Article  CAS  PubMed  Google Scholar 

  26. Stone S, Jiang P, Dayananth P, et al. Complex structure and regulation of the P16 (MTS1) locus. Cancer Res. 1995;55:2988–94.

    CAS  PubMed  Google Scholar 

  27. Duro D, Bernard O, Della Valle V, Berger R, Larsen CJ. A new type of p16INK4/MTS1 gene transcript expressed in B-cell malignancies. Oncogene. 1995;11:21–9.

    CAS  PubMed  Google Scholar 

  28. Mao L, Merlo A, Bedi G, et al. A novel p16INK4A transcript. Cancer Res. 1995;55:2995–7.

    CAS  PubMed  Google Scholar 

  29. Ozenne P, Eymin B, Brambilla E, Gazzeri S. The ARF tumor suppressor: structure, functions and status in cancer. Int J Cancer. 2010;127:2239–47.

    Article  CAS  PubMed  Google Scholar 

  30. Kato J, Matsushime H, Hiebert SW, Ewen ME, Sherr CJ. Direct binding of cyclin D to the retinoblastoma gene product (pRb) and pRb phosphorylation by the cyclin D-dependent kinase CDK4. Genes Dev. 1993;7:331–42.

    Article  CAS  PubMed  Google Scholar 

  31. Kato JY, Sherr CJ. Inhibition of granulocyte differentiation by G1 cyclins D2 and D3 but not D1. Proc Natl Acad Sci U S A. 1993;90:11513–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Witkiewicz AK, Knudsen KE, Dicker AP, Knudsen ES. The meaning of p16(ink4a) expression in tumors: functional significance, clinical associations and future developments. Cell Cycle. 2011;10:2497–503.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Mor O, Yaron P, Huszar M, et al. Absence of p53 mutations in malignant mesotheliomas. Am J Respir Cell Mol Biol. 1997;16:9–13.

    Article  CAS  PubMed  Google Scholar 

  34. Kitamura F, Araki S, Tanigawa T, Miura H, Akabane H, Iwasaki R. Assessment of mutations of Ha- and Ki-ras oncogenes and the p53 suppressor gene in seven malignant mesothelioma patients exposed to asbestos–PCR-SSCP and sequencing analyses of paraffin-embedded primary tumors. Ind Health. 1998;36:52–6.

    Article  CAS  PubMed  Google Scholar 

  35. Andujar P, Pairon JC, Renier A, et al. Differential mutation profiles and similar intronic TP53 polymorphisms in asbestos-related lung cancer and pleural mesothelioma. Mutagenesis. 2013;28:323–31.

    Article  CAS  PubMed  Google Scholar 

  36. Weber JD, Taylor LJ, Roussel MF, Sherr CJ, Bar-Sagi D. Nucleolar Arf sequesters Mdm2 and activates p53. Nat Cell Biol. 1999;1:20–6.

    Article  CAS  PubMed  Google Scholar 

  37. Eischen CM, Weber JD, Roussel MF, Sherr CJ, Cleveland JL. Disruption of the ARF-Mdm2-p53 tumor suppressor pathway in Myc-induced lymphomagenesis. Genes Dev. 1999;13:2658–69.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Chen D, Kon N, Li M, Zhang W, Qin J, Gu W. ARF-BP1/Mule is a critical mediator of the ARF tumor suppressor. Cell. 2005;121:1071–83.

    Article  CAS  PubMed  Google Scholar 

  39. Xio S, Li D, Vijg J, Sugarbaker DJ, Corson JM, Fletcher JA. Codeletion of p15 and p16 in primary malignant mesothelioma. Oncogene. 1995;11:511–5.

    CAS  PubMed  Google Scholar 

  40. Krimpenfort P, Ijpenberg A, Song JY, et al. p15Ink4b is a critical tumour suppressor in the absence of p16Ink4a. Nature. 2007;448:943–6.

    Article  CAS  PubMed  Google Scholar 

  41. Bianchi AB, Mitsunaga SI, Cheng JQ, 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  PubMed Central  CAS  PubMed  Google Scholar 

  42. Thurneysen C, Opitz I, Kurtz S, Weder W, Stahel RA, Felley-Bosco E. Functional inactivation of NF2/merlin in human mesothelioma. Lung Cancer. 2009;64:140–7.

    Article  PubMed  Google Scholar 

  43. Rouleau GA, Merel P, Lutchman M, et al. Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2. Nature. 1993;363:515–21.

    Article  CAS  PubMed  Google Scholar 

  44. Trofatter JA, MacCollin MM, Rutter JL, et al. A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor. Cell. 1993;72:791–800.

    Article  CAS  PubMed  Google Scholar 

  45. McClatchey AI, Giovannini M. Membrane organization and tumorigenesis–the NF2 tumor suppressor, Merlin. Genes Dev. 2005;19:2265–77.

    Article  CAS  PubMed  Google Scholar 

  46. Sekido Y. Inactivation of Merlin in malignant mesothelioma cells and the Hippo signaling cascade dysregulation. Pathol Int. 2011;61:331–44.

    Article  CAS  PubMed  Google Scholar 

  47. Kissil JL, Johnson KC, Eckman MS, Jacks T. Merlin phosphorylation by p21-activated kinase 2 and effects of phosphorylation on merlin localization. J Biol Chem. 2002;277:10394–9.

    Article  CAS  PubMed  Google Scholar 

  48. Xiao GH, Beeser A, Chernoff J, Testa JR. p21-activated kinase links Rac/Cdc42 signaling to merlin. J Biol Chem. 2002;277:883–6.

    Article  CAS  PubMed  Google Scholar 

  49. Jin H, Sperka T, Herrlich P, Morrison H. Tumorigenic transformation by CPI-17 through inhibition of a merlin phosphatase. Nature. 2006;442:576–9.

    Article  CAS  PubMed  Google Scholar 

  50. Tang X, Jang SW, Wang X, et al. Akt phosphorylation regulates the tumour-suppressor merlin through ubiquitination and degradation. Nat Cell Biol. 2007;9:1199–207.

    Article  CAS  PubMed  Google Scholar 

  51. Morrison H, Sherman LS, Legg J, et al. The NF2 tumor suppressor gene product, merlin, mediates contact inhibition of growth through interactions with CD44. Genes Dev. 2001;15:968–80.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  52. Bai Y, Liu YJ, Wang H, Xu Y, Stamenkovic I, Yu Q. Inhibition of the hyaluronan-CD44 interaction by merlin contributes to the tumor-suppressor activity of merlin. Oncogene. 2007;26:836–50.

    Article  CAS  PubMed  Google Scholar 

  53. Lopez-Lago MA, Okada T, Murillo MM, Socci N, Giancotti FG. Loss of the tumor suppressor gene NF2, encoding merlin, constitutively activates integrin-dependent mTORC1 signaling. Mol Cell Biol. 2009;29:4235–49.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. Hamaratoglu F, Willecke M, Kango-Singh M, et al. The tumour-suppressor genes NF2/Merlin and Expanded act through Hippo signalling to regulate cell proliferation and apoptosis. Nat Cell Biol. 2006;8:27–36.

    Article  CAS  PubMed  Google Scholar 

  55. Jensen DE, Proctor M, Marquis ST, et al. BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression. Oncogene. 1998;16:1097–112.

    Article  CAS  PubMed  Google Scholar 

  56. Testa JR, Cheung M, Pei J, et al. Germline BAP1 mutations predispose to malignant mesothelioma. Nat Gene. 2011;43:1022–5.

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  59. Cheung M, Talarchek J, Schindeler K, et al. Further evidence for germline BAP1 mutations predisposing to melanoma and malignant mesothelioma. Cancer Genet. 2013;206:206–10.

    Article  CAS  PubMed  Google Scholar 

  60. Arzt L, Quehenberger F, Halbwedl I, Mairinger T, Popper HH. BAP1 Protein is a Progression Factor in Malignant Pleural Mesothelioma. Pathol Oncol Res. 2014;20(1):145–51.

    Article  CAS  PubMed  Google Scholar 

  61. Harbour JW, Onken MD, Roberson ED, et al. Frequent mutation of BAP1 in metastasizing uveal melanomas. Science. 2010;330:1410–3.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  62. Machida YJ, Machida Y, Vashisht AA, Wohlschlegel JA, Dutta A. The deubiquitinating enzyme BAP1 regulates cell growth via interaction with HCF-1. J Biol Chem. 2009;284:34179–88.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  63. Misaghi S, Ottosen S, Izrael-Tomasevic A, et al. Association of C-terminal ubiquitin hydrolase BRCA1-associated protein 1 with cell cycle regulator host cell factor 1. Mol Cell Biol. 2009;29:2181–92.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  64. Scheuermann JC, de Ayala Alonso AG, Oktaba K, et al. Histone H2A deubiquitinase activity of the Polycomb repressive complex PR-DUB. Nature. 2010;465:243–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  65. Murakami H, Mizuno T, Taniguchi T, et al. LATS2 is a tumor suppressor gene of malignant mesothelioma. Cancer Res. 2011;71:873–83.

    Article  CAS  PubMed  Google Scholar 

  66. Yokoyama T, Osada H, Murakami H, et al. YAP1 is involved in mesothelioma development and negatively regulated by Merlin through phosphorylation. Carcinogenesis. 2008;29:2139–46.

    Article  CAS  PubMed  Google Scholar 

  67. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304:1497–500.

    Article  CAS  PubMed  Google Scholar 

  68. Destro A, Ceresoli GL, Falleni M, et al. EGFR overexpression in malignant pleural mesothelioma. An immunohistochemical and molecular study with clinico-pathological correlations. Lung Cancer. 2006;51:207–15.

    Article  CAS  PubMed  Google Scholar 

  69. Mezzapelle R, Miglio U, Rena O, et al. Mutation analysis of the EGFR gene and downstream signalling pathway in histologic samples of malignant pleural mesothelioma. Brit J Cancer. 2013;108:1743–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  70. Enomoto Y, Kasai T, Takeda M, et al. Epidermal growth factor receptor mutations in malignant pleural and peritoneal mesothelioma. J Clin Pathol. 2012;65:522–7.

    Article  CAS  PubMed  Google Scholar 

  71. Betti M, Ferrante D, Padoan M, et al. XRCC1 and ERCC1 variants modify malignant mesothelioma risk: a case-control study. Mutat Res. 2011;708:11–20.

    Article  CAS  PubMed  Google Scholar 

  72. Cadby G, Mukherjee S, Musk AW, et al. A genome-wide association study for malignant mesothelioma risk. Lung Cancer. 2013;82:1–8.

    Article  PubMed  Google Scholar 

  73. Matullo G, Guarrera S, Betti M, et al. Genetic variants associated with increased risk of malignant pleural mesothelioma: a genome-wide association study. PloS one. 2013;8:e61253.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology, UC San Diego Health System, 200 W. Arbor Dr. MC8720, 92103, San Diego, CA, USA

    Grace Y. Lin M.D., Ph.D.

Authors
  1. Grace Y. Lin M.D., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Grace Y. Lin M.D., Ph.D. .

Editor information

Editors and Affiliations

  1. Department of Pathology and Laboratory Medicine, The University of Texas Medical Branch, Galveston, Texas, USA

    Timothy Craig Allen

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer Science+Business Media New York

About this chapter

Cite this chapter

Lin, G. (2015). Molecular Characteristics. In: Allen, T. (eds) Diffuse Malignant Mesothelioma. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-2374-8_6

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-2374-8_6

  • Published:

  • Publisher Name: Springer, New York, NY

  • Print ISBN: 978-1-4939-2373-1

  • Online ISBN: 978-1-4939-2374-8

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation