Recently, loss of BRCA1-associated protein 1 (BAP1) expression and/or homozygous deletion of CDKN2A were identified in some MM, but not in reactive mesothelial proliferations.
Several key genetic alterations are associated with the development and progression of MM including mutations of the <i>CDKN2A/ARF</i>, <i>NF2</i>, and <i>BAP1</i> tumor-suppressor genes.
Additionally, the mining of an online dataset (The Cancer Genome Atlas) revealed codeletions of PTEN and TP53 and/or CDKN2A/p14ARF in ~25% of human MMs, indicating that cooperative losses of these genes contribute to the development of a significant proportion of these aggressive neoplasms and suggesting key target pathways for therapeutic intervention.
We identified BAP1, CDKN2A and NF2 alterations in the cells from MM pleural effusions at a higher frequency than what is typically seen in MM tumours from surgical series.
The odds of carrying a mutation in BAP1 (OR, 1,658; 95% CI, 199 to 76,224; P < .001), BRCA2 (OR, 5; 95% CI, 1.0 to 14.7; P = .03), CDKN2A (OR, 53; 95% CI, 6 to 249; P < .001), TMEM127 (OR, 88; 95% CI, 1.7 to 1,105; P = .01), VHL (OR, 51; 95% CI, 1.1 to 453; P = .02), and WT1 (OR, 20; 95% CI, 0.5 to 135; P = .049) were significantly higher in MM cases than in a noncancer control population.
Expression of MM-associated markers, as well as the status of CDKN2A, NF2, the 'gatekeeper' in MM development, and their products demonstrated that primary cell lines are more representative of the tumor close to its native state and show a degree of molecular diversity, thus capturing the disease heterogeneity in a patient cohort.
Driver gene mutations in BRAF, EGFR, ERBB2, HRAS, KRAS, MET, NRAS, PIK3CA, STK11, and ephrin receptor genes (EPHA1-8, 10 and EPHB1-4, 6) were studied for both LAC and MM, and in BAP1, CUL1, CDKN2A, and NF2 for MM.
Here, we have reviewed the involvement of erionite, SV40, as well as, the role of several genes (p16(INK4a), p14(ARF), NF2, LATS2, SAV, CTNNB1 and among others), the pathways (RAS, PI3K, Wnt, BCL and Hippo), and their respective roles in the development of MM.
The cyclin-dependent kinase inhibitor 2A/alternative reading frame (CDKN2A/ARF), neurofibromatosis type 2 (NF2) and BRCA1-associated protein-1 (BAP1) genes are the most frequently mutated tumor suppressor genes detected in MM cells; the alterations of the latter two are relatively characteristic of MM.
The majority of malignant mesothelioma possesses the wild-type p53 gene with a homologous deletion of the INK4A/ARF locus containing the p14(ARF) and the p16(INK4A) genes.
Mice doubly deficient for Ink4a and Arf, due to deletion of Cdkn2a/Arf exon 2, showed accelerated asbestos-induced MM formation relative to mice deficient for Ink4a or Arf alone, and MMs exhibited biallelic loss of both tumor suppressor genes.
Mice doubly deficient for Ink4a and Arf, due to deletion of Cdkn2a/Arf exon 2, showed accelerated asbestos-induced MM formation relative to mice deficient for Ink4a or Arf alone, and MMs exhibited biallelic loss of both tumor suppressor genes.
Individual gene methylation was higher in the MM than the RM cases for most of the genes; however, this was not statistically significant (RARbeta2: 58% vs. 33%, P > 0.05; GPC3: 36% vs. 27%, P > 0.05; CDKN2A: 4% vs. 0%; TERT: 4% vs. 0%), while CCND2 methylation was not detected in any case.
In this work, the tumor suppressor gene p16 was efficiently transferred into FR cells isolated from a patient with malignant mesothelioma using cationic liposomes prepared from trimethyl aminoethane carbamoyl cholesterol (TMAEC-Chol) and triethyl aminopropane carbamoyl cholesterol (TEAPC-Chol).