Molecular Genetics of Malignant Mesothelioma

Abstract

Malignant mesothelioma (MM) is an aggressive tumour arising primarily from the pleural or peritoneal cavities. MM develops by asbestos exposure after a long latency, which is highly refractory to conventional therapeutic modalities. Molecular genetic analysis has revealed several key genetic alterations which are responsible for the development and progression of MM. The frequently mutated tumour suppressor genes detected in MM cells are CDKN2A/ ARF, NF2, BAP1, and LATS2. In contrast, frequent activating mutation of any oncogenes has not been clearly identified yet, which is one of the reasons that current molecular target therapy is not very effective for MM patients. Recent studies have also indicated characteristic epigenetic alterations in MM, which include distinct deoxyribonucleic acid (DNA) methylation patterns and the involvement of noncoding ribonucleic acid (RNA). Aberrant histone modification caused by BAP1 inactivation may also lead to the disturbance of global expression profiling. With further comprehensive genome analyses, new genetic and epigenetic alterations in MM cells are expected to be revealed more precisely, and the new knowledge based on them would be applied for developing a new diagnostic tool and new target therapies against MMs.

Key Concepts:

  • Malignant mesothelioma cells harbour multiple key genetic mutations, which mainly inactivate tumour suppressor genes.

  • Asbestos fibre induces chromosome and DNA damages in normal mesothelial cells with several possible mechanisms, but it is not clear why it takes so long from asbestos exposure to mesothelioma development.

  • People differ in their susceptibility to development of mesothelioma after similar levels of asbestos exposure, possibly due to the differences in genetic polymorphisms or expression levels of genes involved in the DNA repair system and epigenetics modification.

  • Mesothelioma has long been considered a representative type of tumour primarily caused by environmental factors, especially asbestos, but familial cases of mesothelioma with a specific gene mutation have challenged this idea.

  • Neurofibromatosis type 2 (NF2) gene inactivation is found in a nearly half of mesothelioma cases and the inactivation of one of its downstream signal transduction cascades, Hippo signalling, plays a significant role in dysregulation of cell proliferation.

  • Epigenetic alterations such as aberrant histone modification by BAP1 gene inactivation play significant roles in mesothelioma development.

  • The overall picture of the genetic abnormality landscape of mesothelioma cells lags behind other common human malignancies.

  • If an oncogene‚Äźtype gene with frequent activating mutation in mesothelioma cells were discovered, molecular target strategies aiming at controlling the activated molecule could be aggressively pursued to develop new therapeutic tools against mesothelioma.

Keywords: malignant mesothelioma; genome; oncogene; tumour suppressor gene; CDKN2A; NF2; BAP1; epigenetics

Figure 1.

Possible mechanisms of asbestos‐induced carcinogenesis. Reproduced from Toyokuni with permission of Nagoya University School of Medicine/Graduate School of Medicine. Reproduced from “Mechanisms of asbestos‐induced carcinogenesis” by Toyokuni S (Nagoya J. Med. Sci. 71, p1‐10, 2009) with permission of Nagoya University School of Medicine/Graduate School of Medicine, with permission from Nagoya University School of Medicine.

Figure 2.

Schematic representation of Merlin (Mer)‐Hippo signalling cascade. Signals from extracellular environment, transduced via cell–cell contact (cadherin), cell‐matrix contact (CD44), or growth factors (RTKs), affect the tumour‐suppressive activity of Merlin. Activated (underphosphorylated) Merlin regulates the Hpo (Hippo) cascade, suppressing the activity of YAP transcriptional coactivator. Merlin also regulates mTOR signalling pathway in MM cells. SMAD2/3 activated by TGF‐β makes a complex with YAP and TEAD to transcribe CTGF. CTGF, connective tissue growth factor; LATS2, large tumour suppressor homologue 2; Mer, Merlin; MST, mammalian sterile 20‐like kinase; mTORC1, mammalian target of rapamycin; RTK, receptor tyrosine kinase; SAV1, Salvador homolog 1; TEAD, TEA domain family member; TGF, transforming growth factor; YAP, Yes‐associated protein.

Figure 3.

BAP1 tumour suppressor. (a) Schematic representation of BAP1. BAP1 is a 729 amino acid protein that functions as a nuclear‐localised deubiquitinating enzyme (DUB). BAP1 binds to multiple proteins including the transcriptional regulator host cell factor ‐1 (HCF‐1), and additional sex combs like 1/2 (ASXL1/2) and BRCA1. Human BAP1 is composed of a ubiquitin carboxyl hydrolase (UCH) domain (1‐240 a.a.), an HCF‐1‐binding motif (HBM) (NHNY, 363‐366 a.a.), a region that mediates association with BRCA1 (596‐721 a.a.), a helical motif that shares conservation with UCH family proteins (ULD for UCH37‐like domain, 634‐694), and a nuclear localisation signal (NLS, 717‐722 a.a.). (b) Two major BAP1 deubiquitination targets, HCF‐1 and histone 2A, are involved in chromatin modification and transcriptional regulation. HDAC, histone deacetylase; HMT, histone methyl transferase; PRC, Polycomb complex; Ub, ubiquitin.

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Sekido, Yoshitaka(Jul 2012) Molecular Genetics of Malignant Mesothelioma. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0022448]