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Malignant mesothelioma (MMt) is a rare cancer that occurs in the thin layer of tissue that covers the majority of internal organs (i.e., the mesothelium). Mesothelioma most often affects the tissue that surrounds the lungs (pleura). About 90% of cases are related to exposure to asbestos fibres. The period of latency from the moment of exposure to the development of the disease is very prolonged and typically 40–50 years. Genetic analysis of MMt cells revealed changes possibly responsible for the development and progression of MMt.High-resolution oligonucleotide array comparative genomic hybridization (aCGH) and spectral karyotyping (SKY) were applied to a panel of MMt cell lines.Numerous recurrent karyotypic abnormalities have been delineated, and heterogeneity of chromosomal rearrangements were detected in MMt cell lines. A whole genome search for homozygous deletions (HDs) produced the largest set of recurrent and non-recurrent HDs for MMt; some genes located there could be new tumour suppressors for MMt. The smallest recurrent HD regions affected genes CDKN2A/CDKN2B, LINGO2, RBFOX1/A2BP1, NF2, RPL29, DUSP7, CCSER1/FAM190A, LATS2. Integrative analysis revealed that acquisition of numerical and/or structural karyotypic instability allows MMt cells to attain a complete loss of tumour suppressor genes located in 9 p21.3, which is the most frequently homozygously deleted region.Chromosomal heterogeneity detected in MMt cell lines points to the presence of structural and numerical chromosomal instability in these cells. It is reasonable to suggest that only with the acquisition of structural or numerical chromosomal instability could MMt cells attain a complete loss of tumour suppressor genes. Aneuploidy of MMt karyotypes as well as the presence of structural and numerical chromosomal heterogeneity makes MMt tumours possible candidates for treatment by anti-cancer drugs that target cells with aneuploid, karyotypically unstable phenotypes.