Genetic alterations of INK4a/ARF locus, which is a predominant event in malignant pleural mesothelioma, may result in loss of p14(ARF) and subsequent disruption of p53 pathway in cancer cells.
We used a fluorescent in situ hybridization assay for CDKN2A and MTAP on interphase nuclei in imprints of frozen tissue from 95 cases of pleural mesothelioma.
Genetic alterations in the tumour suppressor genes, P16/CDKN2A and neurofibromatosis 2 (NF2), are found both in human MPM and in asbestos-exposed Nf2-deficient mice.
Gene copy number losses predominated over gains, and the most frequent region of loss was 9p21.3 (17/26 cases), the locus of CDKN2A and CDKN2B, both known to be commonly lost in MM.
Immunohistochemical staining for p16 protein and fluorescence in situ hybridization for the P16 gene were performed using specimens from 30 Japanese patients with primary MPM.
The aim of this study was to analyze the promoter methylation status of four tumor suppressor genes, p15(INK4B), p16(INK4A), RASSF1A and NORE1A in MPM.
Dual-colour FISH for p16/CDKN2A and chromosome 9 (CEP-9) was performed on 11 benign mesothelial proliferations and 54 malignant pleural mesothelioma (MPM) cases to establish cut-off values for p16/CDKN2A deletion.
Molecular changes in MPM consist in altered expression and in activation or inactivation of critical genes in oncogenesis, especially tumor suppressor genes at the INK4 and NF2 loci.
The methylation ratios for the three genes were significantly higher in LC than in MPM (RASSF1A, P = 0.039; p16(INK4a), P = 0.005; and RARβ, P = 0.002).
MPM is a complex disease characterized by multiple genetic aberrations; some of them involve cell cycle regulatory genes. p14(ARF), p16(INK4A), Rb and p27(KIP1) seem to be involved in SV40-associated MPM whereas mdm2, p53 and p21(WAF) are related to asbestos exposure.
Methylation of p16 was observed in 7 (20.6%) of 34 informative cases. p16 FISH analysis can be a reliable test for distinguishing between sarcomatoid mesothelioma and fibrous pleuritis and a prognostic factor for MPM.
Homozygous deletion of the 9p21 locus, the site of the cyclin-dependent kinase inhibitor 2A/p16 (CDKN2A/p16) gene, frequently occurs in MPM but has never been reported in RMCs.
This paper presents a data mining and bioinformatics approach towards the evaluation of the gene expression profile of AQP1 in malignant pleural mesothelioma and of AQP1 associated markers in the context of mesothelioma disease phenotype, CDKN2A gene deletion, sex and asbestos exposure.
TERT promoter mutations were more frequent in MPM with sarcomatoid histologic subtype (P<0.01), and they were frequently associated with CDKN2A gene inactivation (P=0.03).
The most frequently inactivated tumor suppressor gene in MPM is CDKN2A/ARF, encoding for the cell cycle inhibitors p16<sup>INK4a</sup> and p14<sup>ARF</sup>, deleted in about 70% of MPM cases.
As expected, BAP1 IHC in combination with CDKN2A FISH resulted in high sensitivity (84%) and specificity (100%) for MPM, and p16 loss was an independent predictor of poor survival (hazard ratio, 2.2553; P = .0135).
In the present study, the effects of MDM2 inhibition in MPM via Nutlin-3A and standard platinum based chemotherapeutic agents were comparatively tested in three MPM cell lines (NCI-H2052, MSTO-211H, and NCI-H2452) showing different expression profiles of TP53, MDM2, and its physiological inhibitor of MDM2-P14/ARF.