Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • DNA Methylation
  • Oligonucleotide Array Sequence Analysis
  • Polymerase Chain Reaction
  • MME
  • Gene Expression Profiling
  • FISH
  • Occupational Exposure
  • Minerals
  • Smoking
  • Cancer Gene Expression Regulation
  • Immunohistochemistry
  • Genetic Predisposition
  • Peritoneal Neoplasms
  • Mesothelioma
  • Promoter Regions
  • Pleural Neoplasms
  • CDKN2A
  • WT1
  • Lung Cancer
  • Asbestos
  • Base Sequence
  • Chromosome Aberrations
  • DNA Sequence Analysis
  • LATS2
  • BAP1
  • Sex Factors
  • Single-Stranded Conformational Polymorphism
  • Tumor Suppressor Gene
  • Trisomy
  • Staining and Labeling
  • Cancer RNA
  • p53 Protein
  • Gene Deletion
  • Radiation Tolerance
  • Cancer DNA
  • Point Mutation
  • Gene Expression
  • Testis
  • Transfection
  • Apoptosis
  • Messenger RNA
  • Cell Proliferation
  • PTEN
  • Mutation
  • NF2
Tag cloud generated 08 August, 2015 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (11)

How to use this data tableClicking on the Gene or Topic will take you to a separate more detailed page. Sort this list by clicking on a column heading e.g. 'Gene' or 'Topic'.

CDKN2A 9p21 ARF, MLM, P14, P16, P19, CMM2, INK4, MTS1, TP16, CDK4I, CDKN2, INK4A, MTS-1, P14ARF, P19ARF, P16INK4, P16INK4A, P16-INK4A -CDKN2A Deletion in Mesothelioma
WT1 11p13 GUD, AWT1, WAGR, WT33, NPHS4, WIT-2, EWS-WT1 Prognostic
-WT1 expression in Mesothelioma
NF2 22q12.2 ACN, SCH, BANF -NF2 Mutations in Mesothelioma
TP53 17p13.1 P53, BCC7, LFS1, TRP53 -TP53 Transfer to Mesothelioma Cells (Gene Therapy)
-TP53 mutation in Mesothelioma
BAP1 3p21.1 UCHL2, hucep-6, HUCEP-13 -BAP1 and Mesothelioma
-BAP1 Germline Mutations in Mesothelioma
PTEN 10q23.3 BZS, DEC, CWS1, GLM2, MHAM, TEP1, MMAC1, PTEN1, 10q23del -PTEN expression in Mesothelioma
MSLN 16p13.3 MPF, SMRP -MSLN and Mesothelioma
MME 3q25.2 NEP, SFE, CD10, CALLA -MME and Mesothelioma
LATS2 13q12.11 KPM -LATS2 inactivation in Mesothelioma
THBS1 15q15 TSP, THBS, TSP1, TSP-1, THBS-1 -THBS1 Expression in Mesothelioma
DTX2P1-UPK3B 7q11.23 PMSR6, PMS2L11, PMS2P11 -DTX2P1-UPK3B and Mesothelioma

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Recurrent Chromosome Abnormalities

Selected list of common recurrent structural abnormalities

This is a highly selective list aiming to capture structural abnormalies which are frequesnt and/or significant in relation to diagnosis, prognosis, and/or characterising specific cancers. For a much more extensive list see the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer.

14q Deletions in Mesothelioma (14q11-q12 and 14q23-q24)

CGH studies indicate that loss of material from chromosome 14q is one of the most frequent aberrations in mesothelioma. A Finnish LOH study of primary tumour samples (Bjorkqvist, 1999) found 10/18 (56%) had 14q loss, with the most commonly involved regions being 14q11.1-q12 and 14q23-q24. Similarly, in an American series (De Rienzo, 2000) 13/30 (43%) of tumours had LOH(14q) and 3 distinct regions were identified as 14q11.2-13.2, 14q22.3-24.3, and 14q32.12.

Björkqvist AM, Wolf M, Nordling S, et al.
Deletions at 14q in malignant mesothelioma detected by microsatellite marker analysis.
Br J Cancer. 1999; 81(7):1111-5 [PubMed] Free Access to Full Article Related Publications
Previous molecular cytogenetic studies by comparative genomic hybridization (CGH) on primary tumours of human malignant mesothelioma have revealed that loss of genetic material at chromosome 14q is one of the most frequently occurring aberrations. Here we further verify the frequency and pattern of deletions at 14q in mesothelioma. A high-resolution deletion mapping analysis of 23 microsatellite markers was performed on 18 primary mesothelioma tumours. Eight of these had previously been analysed by CGH. Loss of heterozygosity or allelic imbalance with at least one marker was detected in ten of 18 tumours (56%). Partial deletions of varying lengths were more common than loss of all informative markers, which occurred in only one tumour. The highest number of tumours with deletions at a specific marker was detected at 14q11.1-q12 with markers D14S283 (five tumours), D14S972 (seven tumours) and D14S64 (five tumours) and at 14q23-q24 with markers D14S258 (five tumours), D14S77 (five tumours) and D14S284 (six tumours). We conclude from these data that genomic deletions at 14q are more common than previously reported in mesothelioma. Furthermore, confirmation of previous CGH results was obtained in all tumours but one. This tumour showed deletions by allelotyping, but did not show any DNA copy number change at 14q by CGH. Although the number of tumours allelotyped was small and the deletion pattern was complex, 14q11.1-q12 and 14q23-q24 were found to be the most involved regions in deletions. These regions provide a good basis for further molecular analyses and may highlight chromosomal locations of tumour suppressor genes that could be important in the tumorigenesis of malignant mesothelioma.

De Rienzo A, Jhanwar SC, Testa JR
Loss of heterozygosity analysis of 13q and 14q in human malignant mesothelioma.
Genes Chromosomes Cancer. 2000; 28(3):337-41 [PubMed] Related Publications
Cytogenetic investigations of malignant mesothelioma (MM) have revealed frequent losses in chromosomes 13 and 14, suggesting that inactivation of tumor suppressor genes (TSGs) residing in these chromosomes may contribute to mesothelial cell tumorigenesis. To define the shortest region of overlap (SRO) of deletions from these chromosomes, we performed loss of heterozygosity (LOH) analyses on 30 MMs using 25 microsatellite markers in 13q and 21 markers in 14q. Twenty of the 30 MMs (67%) showed allelic loss of at least one marker in 13q. The SRO of deletions was delineated as an approximately 7 centiMorgan region, flanked by markers D13S1253 and D13S291, located at 13q13.3-14.2. Thirteen of the 30 MMs (43%) displayed allelic losses from 14q, with at least three distinct regions of LOH located at segments q11.2-13.2, q22.3-24.3, and q32. 12. These data highlight a single region of chromosomal loss in 13q in many MMs, implicating the involvement of a TSG that is critical to the pathogenesis of this malignancy. In contrast, the lower incidence and diffuse pattern of allelic losses in 14q suggest that several TSGs in this chromosome arm may contribute to tumorigenic progression in a subset of MMs. Genes Chromosomes Cancer 28:337-341, 2000.

Latest Publications

Sneddon S, Leon JS, Dick IM, et al.
Absence of germline mutations in BAP1 in sporadic cases of malignant mesothelioma.
Gene. 2015; 563(1):103-5 [PubMed] Related Publications
Malignant mesothelioma (MM) is a uniformly fatal tumour caused predominantly by exposure to asbestos. It is not known why some exposed individuals get mesothelioma and others do not. There is some epidemiological evidence of host susceptibility. BAP1 gene somatic mutations and allelic loss are common in mesothelioma and recently a BAP1 cancer syndrome was described in which affected individuals and families had an increased risk of cancer of multiple types, including MM. To determine if BAP1 mutations could underlie any of the sporadic mesothelioma cases in our cohort of patients, we performed targeted deep sequencing of the BAP1 exome on the IonTorrent Proton sequencer in 115 unrelated MM cases. No exonic germline BAP1 mutations of known functional significance were observed, further supporting the notion that sporadic germline BAP1 mutations are not relevant to the genetic susceptibility of MM.

Walter RF, Mairinger FD, Ting S, et al.
MDM2 is an important prognostic and predictive factor for platin-pemetrexed therapy in malignant pleural mesotheliomas and deregulation of P14/ARF (encoded by CDKN2A) seems to contribute to an MDM2-driven inactivation of P53.
Br J Cancer. 2015; 112(5):883-90 [PubMed] Article available free on PMC after 03/03/2016 Related Publications
BACKGROUND: Malignant pleural mesothelioma (MPM) is a highly aggressive tumour that is first-line treated with a combination of cisplatin and pemetrexed. Until now, predictive and prognostic biomarkers are lacking, making it a non-tailored therapy regimen with unknown outcome. P53 is frequently inactivated in MPM, but mutations are extremely rare. MDM2 and P14/ARF are upstream regulators of P53 that may contribute to P53 inactivation.
METHODS: A total of 72 MPM patients were investigated. MDM2 immunoexpression was assessed in 65 patients. MDM2 and P14/ARF mRNA expression was analysed in 48 patients of the overall collective. The expression results were correlated to overall survival (OS) and progression-free survival (PFS).
RESULTS: OS and PFS correlated highly significantly with MDM2 mRNA and protein expression, showing a dismal prognosis for patients with elevated MDM2 expression (for OS: Score (logrank) test: P⩽0.002, and for PFS: Score (logrank) test; P<0.007). MDM2 was identified as robust prognostic and predictive biomarker for MPM on the mRNA and protein level. P14/ARF mRNA expression reached no statistical significance, but Kaplan-Meier curves distinguished patients with low P14/ARF expression and hence shorter survival from patients with higher expression and prolonged survival.
CONCLUSIONS: MDM2 is a prognostic and predictive marker for a platin-pemetrexed therapy of patients with MPMs. Downregulation of P14/ARF expression seems to contribute to MDM2-overexpression-mediated P53 inactivation in MPM patients.

Guo G, Chmielecki J, Goparaju C, et al.
Whole-exome sequencing reveals frequent genetic alterations in BAP1, NF2, CDKN2A, and CUL1 in malignant pleural mesothelioma.
Cancer Res. 2015; 75(2):264-9 [PubMed] Related Publications
Malignant pleural mesothelioma (MPM) is an aggressive neoplasm associated with asbestos exposure. Although previous studies based on candidate gene approaches have identified important common somatic mutations in MPM, these studies have focused on small sets of genes and have provided a limited view of the genetic alterations underlying this disease. Here, we performed whole-exome sequencing on DNA from 22 MPMs and matched blood samples, and identified 517 somatic mutations across 490 mutated genes. Integrative analysis of mutations and somatic copy-number alterations revealed frequent genetic alterations in BAP1, NF2, CDKN2A, and CUL1. Our study presents the first unbiased view of the genomic basis of MPM.

Panagopoulos I, Gorunova L, Davidson B, Heim S
Novel TNS3-MAP3K3 and ZFPM2-ELF5 fusion genes identified by RNA sequencing in multicystic mesothelioma with t(7;17)(p12;q23) and t(8;11)(q23;p13).
Cancer Lett. 2015; 357(2):502-9 [PubMed] Related Publications
Multicystic mesothelioma is a rare disease of unknown etiology and pathogenesis. Nothing has been known about the cytogenetic and molecular genetic features of these tumors. Here we present the first cytogenetically analyzed multicystic mesothelioma with the karyotype 46,XX,t(7;17)(p13;q23),t(8;11)(q23;p13). RNA-sequencing showed that the t(7;17)(p13;q23) generated a chimeric TNS3-MAP3K3 gene, which codes for a chimeric protein kinase, as well as the reciprocal MAP3K3-TNS3 in which the region of TNS3 coding for the SH2_Tensin_like region and the tensin phosphotyrosine-binding domain is under the control of the MAP3K3 promoter. The other translocation, t(8;11)(q23;p13), generated a chimeric ZFPM2-ELF5 gene which codes for a chimeric transcription factor in which the first 40 amino acids of ELF5 are replaced by the first 100 amino acids of ZFPM2. RT-PCR together with Sanger sequencing verified the presence of the above-mentioned fusion transcripts. The finding of acquired clonal chromosome abnormalities in cells cultured from the lesion and the presence of the TNS3-MAP3K3 chimeric protein kinase and the ZFPM2-ELF5 chimeric transcription factor confirm the neoplastic nature of multicystic mesothelioma.

Baumann F, Flores E, Napolitano A, et al.
Mesothelioma patients with germline BAP1 mutations have 7-fold improved long-term survival.
Carcinogenesis. 2015; 36(1):76-81 [PubMed] Article available free on PMC after 01/01/2016 Related Publications
BRCA1-associated protein-1 (BAP1) mutations cause a new cancer syndrome, with a high rate of malignant mesothelioma (MM). Here, we tested the hypothesis that MM associated with germline BAP1 mutations has a better prognosis compared with sporadic MM. We compared survival among germline BAP1 mutation MM patients with that of all MM (N = 10 556) recorded in the United States Surveillance, Epidemiology, and End Results (SEER) data from 1973 to 2010. We identified 23 MM patients--11 alive--with germline BAP1 mutations and available data on survival. Ten patients had peritoneal MM, ten pleural MM and three MM in both locations. Thirteen patients had one or more malignancies in addition to MM. Actuarial median survival for the MM patients with germline BAP1 mutations was 5 years, as compared with <1 year for the median survival in the United States SEER MM group. Five-year survival was 47%, 95% confidence interval (24-67%), as compared with 6.7% (6.2-7.3%) in the control SEER group. Analysis of the pooled cohort of germline BAP1 mutation MM showed that patients with peritoneal MM (median survival of 10 years, P = 0.0571), or with a second malignancy in addition to MM (median survival of 10 years, P = 0.0716), survived for a longer time compared with patients who only had pleural MM, or MM patients without a second malignancy, respectively. In conclusion, we found that MM patients with germline BAP1 mutations have an overall 7-fold increased long-term survival, independently of sex and age. Appropriate genetic counseling and clinical management should be considered for MM patients who are also BAP1 mutation carriers.

Ramírez-Salazar EG, Salinas-Silva LC, Vázquez-Manríquez ME, et al.
Analysis of microRNA expression signatures in malignant pleural mesothelioma, pleural inflammation, and atypical mesothelial hyperplasia reveals common predictive tumorigenesis-related targets.
Exp Mol Pathol. 2014; 97(3):375-85 [PubMed] Related Publications
Pleural chronic inflammation (PP) and mesothelial hyperplasia (HP) may be critical to the development of malignant pleural mesothelioma (MPM). Nonetheless, studies searching for mechanistic links involving microRNA (miRNA) regulation among these interrelated processes have not been reported. Using PCR-Array, we identified the miRNAs expressed in pleural tissues diagnosed with MPM (n=5), PP (n=4) and HP (n=5), as well as in non-cancerous/non-inflammatory tissue as the normal control (n=5). We performed bioinformatics and network analysis of differentially expressed miRNAs to identify tumorigenesis-related miRNAs and their biological networks. The targets of four down-regulated miRNAs in MPM (mir-181a-5p, miR-101-3p, miR-145-5p and miR-212-3p), one in PP (mir-101-3p) and one in HP (mir-494) were significantly enriched in "pathways in cancer". Interactome networks revealed that >50% of down-regulated miRNAs in MPM targeted the signaling-activation molecule MAPK1, the transcription factor ETS1 and the mesenchymal transition-associated molecule FZDA, which have been associated with oncogenic function. Comparative analysis revealed that FZD4 was an overlapping gene target of down-regulated miRNAs that were associated with "pathways in cancer" in MPM, PP and HP. Moreover, MAPK1, ETS1 and Cox-2, a pro-inflammatory enzyme associated with over-expression in cancers, were among the 25 overlapping target genes in MPM and PP. This network analysis revealed a potential combinatory effect of deregulated miRNAs in MPM pathogenesis and indicated potential molecular links between pleural inflammation and hyperplasia with tumorigenesis mechanisms in pleura.

Betti M, Casalone E, Ferrante D, et al.
Inference on germline BAP1 mutations and asbestos exposure from the analysis of familial and sporadic mesothelioma in a high-risk area.
Genes Chromosomes Cancer. 2015; 54(1):51-62 [PubMed] Related Publications
Inherited loss-of-function mutations in the BAP1 oncosuppressor gene are responsible for an inherited syndrome with predisposition to malignant mesothelioma (MM), uveal and keratinocytic melanoma, and other malignancies. Germline mutations that were inherited in an autosomal dominant fashion were identified in nine families with multiplex MM cases and 25 families with multiple melanoma, renal cell carcinoma, and other tumors. Germline mutations were also identified in sporadic MM cases, suggesting that germline mutations in BAP1 occur frequently. In this article, we report the analysis of BAP1 in five multiplex MM families and in 103 sporadic cases of MM. One family carried a new truncating germline mutation. Using immunohistochemistry, we show that BAP1 is not expressed in tumor tissue, which is in accordance with Knudson's two hits hypothesis. Interestingly, whereas the three individuals who were possibly exposed to asbestos developed MM, the individual who was not exposed developed a different tumor type, that is, mucoepidermoid carcinoma. This finding suggests that the type of carcinogen exposure may be important for the cancer type that is developed by mutation carriers. On the contrary, the other families or the 103 sporadic patients did not show germline mutations in BAP1. Our data show that BAP1 mutations are very rare in patients with sporadic MM, and we report a new BAP1 mutation, extend the cancer types associated with these mutations, and suggest the existence of other yet unknown genes in the pathogenesis of familial MM.

Kanteti R, Dhanasingh I, Kawada I, et al.
MET and PI3K/mTOR as a potential combinatorial therapeutic target in malignant pleural mesothelioma.
PLoS One. 2014; 9(9):e105919 [PubMed] Article available free on PMC after 01/01/2016 Related Publications
Malignant pleural mesothelioma (MPM) is an aggressive disease with a poor prognosis. Studies have shown that both MET and its key downstream intracellular signaling partners, PI3K and mTOR, are overexpressed in MPM. Here we determined the combinatorial therapeutic efficacy of a new generation small molecule inhibitor of MET, ARQ 197, and dual PI3K/mTOR inhibitors NVP-BEZ235 and GDC-0980 in mesothelioma cell and mouse xenograft models. Cell viability results show that mesothelioma cell lines were sensitive to ARQ 197, NVP-BEZ235 and GDC-0980 inhibitors. The combined use of ARQ 197 with either NVP-BEZ235 or GDC-0980, was synergistic (CI<1). Significant delay in wound healing was observed with ARQ 197 (p<0.001) with no added advantage of combining it with either NVP-BEZ235 or GDC-0980. ARQ 197 alone mainly induced apoptosis (20±2.36%) that was preceded by suppression of MAPK activity, while all the three suppressed cell cycle progression. Both GDC-0980 and NVP-BEZ235 strongly inhibited activities of PI3K and mTOR as evidenced from the phosphorylation status of AKT and S6 kinase. The above observation was further substantiated by the finding that a majority of the MPM archival samples tested revealed highly active AKT. While the single use of ARQ 197 and GDC-0980 inhibited significantly the growth of MPM xenografts (p<0.05, p<0.001 respectively) in mice, the combination of the above two drugs was highly synergistic (p<0.001). Our results suggest that the combined use of ARQ 197/NVP-BEZ235 and ARQ 197/GDC-0980 is far more effective than the use of the drugs singly in suppressing MPM tumor growth and motility and therefore merit further translational studies.

Takeda M, Kasai T, Enomoto Y, et al.
Comparison of genomic abnormality in malignant mesothelioma by the site of origin.
J Clin Pathol. 2014; 67(12):1038-43 [PubMed] Related Publications
AIMS: Malignant mesothelioma (MM) results from the accumulation of a number of acquired genetic events at the onset. In MM, the most frequent changes are losses in 9p21, 1p36, 22q12 and 14q32, and gains in 5p, 7p and 8q24 by comparative genomic hybridisation analysis. We have examined various genomic losses and gains in MM and benign mesothelial proliferation by fluorescence in situ hybridisation (FISH) analysis. 9p21 deletion was reported to be less frequent in peritoneal than in pleural MMs. This study analysed various genomic losses and gains in MM by the site of origin using FISH analysis.
MATERIALS AND METHODS: We performed FISH analysis using paraffin-embedded tissues from 54 cases (40 pleural and 14 peritoneal) of MMs and compared the frequency of genomic abnormality by the site of origin.
RESULTS: 9p21 deletion was shown in 34 of 40 cases (85%) of pleural MMs, and was less frequent in five of 14 cases (36%) of peritoneal MMs (p<0.001) by FISH analysis. By contrast, 5p15 and 7p12 amplification was more significantly frequent in peritoneal than in pleural MMs. No difference between the two sites of MM in other genes was found.
CONCLUSIONS: 9p21 homozygous deletion assessed by FISH has been reported to be useful for differentiating MM from reactive mesothelial proliferation, but it should be noted that 9p21 deletion was less frequent in peritoneal MM. Our study suggests that the pathway of the genetic abnormality might vary between pleural and peritoneal MM.

Assis LV, Isoldi MC
Overview of the biochemical and genetic processes in malignant mesothelioma.
J Bras Pneumol. 2014 Jul-Aug; 40(4):429-42 [PubMed] Article available free on PMC after 01/01/2016 Related Publications
Malignant mesothelioma (MM) is a highly aggressive form of cancer, has a long latency period, and is resistant to chemotherapy. It is extremely fatal, with a mean survival of less than one year. The development of MM is strongly correlated with exposure to asbestos and with other factors, such as erionite and simian virus 40 [corrected]. Although various countries have banned the use of asbestos, MM has proven to be difficult to control and there appears to be a trend toward an increase in its incidence in the years to come. In Brazil, MM has not been widely studied from a genetic or biochemical standpoint. In addition, there have been few epidemiological studies of the disease, and the profile of its incidence has yet to be well established in the Brazilian population. The objective of this study was to review the literature regarding the processes of malignant transformation, as well as the respective mechanisms of tumorigenesis, in MM.

Shukuya T, Serizawa M, Watanabe M, et al.
Identification of actionable mutations in malignant pleural mesothelioma.
Lung Cancer. 2014; 86(1):35-40 [PubMed] Related Publications
BACKGROUND: Genetic alterations in malignant pleural mesothelioma (MPM) patients are not well-understood.
PATIENTS AND METHODS: Surgical specimens and tumor biopsies from 42 patients with MPM were collected from 2003 to 2012. The samples were analyzed for mutations in EGFR, KRAS, BRAF, PIK3CA, NRAS, MEK1, AKT1, PTEN, and HER2 and amplifications in EGFR, MET, PIK3CA, FGFR1, and FGFR2. In addition, 21 patients' samples were analyzed using amplicon-based massively parallel sequencing for actionable mutations in 48 cancer-related genes.
RESULTS: Genetic alterations were detected in 4 patients (one KRAS mutation and 3 PIK3CA amplifications). Patients harboring genetic alterations showed significantly poorer survival than patients with no genetic alterations. Moreover, significance was maintained if the patients only harbored PIK3CA amplification. A total 16 genetic mutations were identified in the 9 patients' samples (4 TP53 mutations, 3 APC mutations, 3 PIK3CA mutations, and 2 VHL mutations, etc.) by deep sequencing.
CONCLUSIONS: Genetic alterations that are potential targets for molecular targeted therapy were detected in MPM. Amplicon-based massively parallel sequencing was shown to have the advantage of more comprehensive genetic analysis. Further investigation in a larger cohort is necessary to uncover more targetable genetic alterations in MPM and to validate their clinical significance.

Comar M, Zanotta N, Bonotti A, et al.
Increased levels of C-C chemokine RANTES in asbestos exposed workers and in malignant mesothelioma patients from an hyperendemic area.
PLoS One. 2014; 9(8):e104848 [PubMed] Article available free on PMC after 01/01/2016 Related Publications
BACKGROUND: Asbestos-induced mesothelial inflammatory processes are thought to be the basic mechanisms underlying Malignant Mesothelioma (MM) development. Detection of MM often occurs at late stage due to the long and unpredictable latent period and the low incidence in asbestos exposed individuals. The aim of this study was to investigate early immunological biomarkers to characterize the prognostic profile of a possible asbestos-induced disease, in subjects from a MM hyperendemic area.
METHODS: The Luminex Multiplex Panel Technology was used for the simultaneous measurement of serum levels of a large panel of 47 analytes, including cytokines and growth factors, from workers previously exposed to asbestos (Asb-workers), asbestos-induced MM patients and healthy subjects. In addition, to explore the influence on serum cytokines profile exerted by SV40 infection, a cofactor in MM development, a quantitative real time PCR was performed for sequences detection in the N-terminal and intronic regions of the SV40 Tag gene. Statistical analysis was done by means of the Mann-Whitney test and the Kruskall-Wallis test for variance analysis.
RESULTS: A variety of 25 cytokines linked to pulmonary inflammation and tumor development were found significantly associated with Asb-workers and MM patients compared with healthy controls. A specific pattern of cytokines were found highly expressed in Asb-workers: IFN-alpha (p<0.05), EOTAXIN (p<0.01), RANTES (p<0.001), and in MM patients: IL-12(p40), IL-3, IL-1 alpha, MCP-3, beta-NGF, TNF-beta, RANTES (p<0.001). Notably, the chemokine RANTES measured the highest serum level showing an increased gradient of concentration from healthy subjects to Asb-workers and MM patients (p<0.001), independently of SV40 infection.
CONCLUSION: This study shows that, in subjects from an hyperendemic area for MM, the C-C chemokine RANTES is associated with the exposure to asbestos fibres. If validated in larger samples, this factor could have the potential to be a critical biomarker for MM prognosis as recently reported for breast tumor.

Plönes T, Beckers F, Engel-Riedel W, et al.
Absence of amplification of the FGFR1-gene in human malignant mesothelioma of the pleura: a pilot study.
BMC Res Notes. 2014; 7:549 [PubMed] Article available free on PMC after 01/01/2016 Related Publications
BACKGROUND: Mesothelioma (MPM) is a rare malignant disease with a worse outcome. Fibroblast growth factor 1 (FGFR1) may be an interesting target for selective tyrosine kinases inhibitors (TKI) in MPM. The aim of this study was to evaluate the amplification of the FGFR1 gene in patients suffering from MPM.
FINDINGS: We identified nineteen male patients treated in our department between August 2008 and July 2010 matching the inclusion criteria. Mean age was 68 years. Histopathological examination confirmed thirteen patients with epitheloid subtype, five with biphasic and one patient with sarcomatoid. Fluorescence in situ hybridization analysis revealed no polysomy nor an amplification of the FGFR gene copy number in any case.
CONCLUSION: Regarding that also EGFR amplifications in MPM are absolute rarities, our findings may be a hint that TKI's will not satisfy the hope for a new era in the treatment of MPM.

Dabir S, Kluge A, Kresak A, et al.
Low PIAS3 expression in malignant mesothelioma is associated with increased STAT3 activation and poor patient survival.
Clin Cancer Res. 2014; 20(19):5124-32 [PubMed] Related Publications
PURPOSE: Deregulation of STAT3 activation is a hallmark of many cancer cells, and the underlying mechanisms are subject to intense investigation. We examined the extent of PIAS3 expression in mesothelioma cells and human tumor samples and determined the functional effects of PIAS3 expression on STAT3 signaling.
EXPERIMENTAL DESIGN: We evaluated the expression of PIAS3 in mesothelioma tumors from patients and correlated the expression levels with the course of the disease. We also measured the effects of enhanced PIAS3 activity on STAT3 signaling, cellular growth, and viability in cultured mesothelioma cells.
RESULTS: Gene expression databases revealed that mesotheliomas have the lowest levels of PIAS3 transcripts among solid tumors. PIAS3 expression in human mesothelioma tumors is significantly correlated with overall survival intervals (P = 0.058). The high expression of PIAS3 is predictive of a favorable prognosis and decreases the probability of death within one year after diagnosis by 44%. PIAS3 expression is functionally linked to STAT3 activation in mesothelioma cell lines. STAT3 downregulation with siRNA or enhanced expression of PIAS3 both inhibited mesothelioma cell growth and induced apoptosis. Mesothelioma cells are sensitive to curcumin and respond by the induction of PIAS3. Corroborative evidence has been obtained from STAT3 inhibition experiments. Exposure of the cells to a peptide derived from the PIAS3 protein that interferes with STAT3 function resulted in apoptosis induction and the inhibition of cell growth.
CONCLUSION: These results suggest that PIAS3 protein expression impacts survival in patients with mesothelioma and that PIAS3 activation could become a therapeutic strategy. Clin Cancer Res; 20(19); 5124-32. ©2014 AACR.

Giroux Leprieur E, Hirata T, Mo M, et al.
The homeobox gene EMX2 is a prognostic and predictive marker in malignant pleural mesothelioma.
Lung Cancer. 2014; 85(3):465-71 [PubMed] Related Publications
OBJECTIVES: Malignant pleural mesothelioma (MPM) is a highly aggressive neoplasm with a poor prognosis and limited treatment options. EMX2 is a homeobox transcription factor that may regulate key developmental pathways known to promote tumorigenesis. In this study, we evaluated the prognostic and predictive significance of EMX2 expression in MPM.
MATERIALS AND METHODS: Fifty surgically resected MPM specimens were studied. Quantitative real-time RT-PCR was used to analyze EMX2 mRNA expression. Association of EMX2 levels with clinical outcomes was evaluated with using the Kaplan-Meier method and a multivariate Cox proportional hazards regression model.
RESULTS: EMX2 expression was significantly associated with IMIG stage (p<0.001) and smoking history (p=0.006). Cox hazard regression modeling identified low-EMX2 expression as a negative prognostic factor in progression-free survival by both univariate (p=0.002) and multivariate analysis (p=0.002). Kaplan-Meier analysis revealed significant differences in progression-free survival between low- and high-EMX expressing groups in all patients (p=0.001), and also when grouped by early (I/II) stage disease (p<0.001), patients undergoing pleurectomy (p<0.001) and patients with an epitheliod subtype (p<0.004). Furthermore, EMX2 expression predicted response to neoadjuvant chemotherapy. High-EMX2 expression was associated with decreased progression-free survival after neoadjuvant therapy, suggesting that induction therapy should be avoided in these patients.
CONCLUSIONS: EMX2 expression is downregulated in advanced cases of malignant pleural mesothelioma and may serve as an important prognostic and predictive molecular biomarker of progression-free survival.

Marek LA, Hinz TK, von Mässenhausen A, et al.
Nonamplified FGFR1 is a growth driver in malignant pleural mesothelioma.
Mol Cancer Res. 2014; 12(10):1460-9 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
UNLABELLED: Malignant pleural mesothelioma (MPM) is associated with asbestos exposure and is a cancer that has not been significantly affected by small molecule-based targeted therapeutics. Previously, we demonstrated the existence of functional subsets of lung cancer and head and neck squamous cell carcinoma (HNSCC) cell lines in which fibroblast growth factor receptor (FGFR) autocrine signaling functions as a nonmutated growth pathway. In a panel of pleural mesothelioma cell lines, FGFR1 and FGF2 were coexpressed in three of seven cell lines and were significantly associated with sensitivity to the FGFR-active tyrosine kinase inhibitor (TKI), ponatinib, both in vitro and in vivo using orthotopically propagated xenografts. Furthermore, RNAi-mediated silencing confirmed the requirement for FGFR1 in specific mesothelioma cells and sensitivity to the FGF ligand trap, FP-1039, validated the requirement for autocrine FGFs. None of the FGFR1-dependent mesothelioma cells exhibited increased FGFR1 gene copy number, based on a FISH assay, indicating that increased FGFR1 transcript and protein expression were not mediated by gene amplification. Elevated FGFR1 mRNA was detected in a subset of primary MPM clinical specimens and like MPM cells; none harbored increased FGFR1 gene copy number. These results indicate that autocrine signaling through FGFR1 represents a targetable therapeutic pathway in MPM and that biomarkers distinct from increased FGFR1 gene copy number such as FGFR1 mRNA would be required to identify patients with MPM bearing tumors driven by FGFR1 activity.
IMPLICATIONS: FGFR1 is a viable therapeutic target in a subset of MPMs, but FGFR TKI-responsive tumors will need to be selected by a biomarker distinct from increased FGFR1 gene copy number, possibly FGFR1 mRNA or protein levels.

Blackshear PE, Pandiri AR, Nagai H, et al.
Gene expression of mesothelioma in vinylidene chloride-exposed F344/N rats reveal immune dysfunction, tissue damage, and inflammation pathways.
Toxicol Pathol. 2015; 43(2):171-85 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
A majority (∼80%) of human malignant mesotheliomas are asbestos-related. However, non-asbestos risk factors (radiation, chemicals, and genetic factors) account for up to 30% of cases. A recent 2-year National Toxicology Program carcinogenicity bioassay showed that male F344/N rats exposed to the industrial toxicant vinylidene chloride (VDC) resulted in a marked increase in malignant mesothelioma. Global gene expression profiles of these tumors were compared to spontaneous mesotheliomas and the F344/N rat mesothelial cell line (Fred-PE) in order to characterize the molecular features and chemical-specific profiles of mesothelioma in VDC-exposed rats. As expected, mesotheliomas from control and VDC-exposed rats shared pathways associated with tumorigenesis, including cellular and tissue development, organismal injury, embryonic development, inflammatory response, cell cycle regulation, and cellular growth and proliferation, while mesotheliomas from VDC-exposed rats alone showed overrepresentation of pathways associated with pro-inflammatory pathways and immune dysfunction such as the nuclear factor kappa-light-chain-enhancer of activated B cells signaling pathway, interleukin (IL)-8 and IL-12 signaling, interleukin responses, Fc receptor signaling, and natural killer and dendritic cells signaling, as well as overrepresentation of DNA damage and repair. These data suggest that a chronic, pro-inflammatory environment associated with VDC exposure may exacerbate disturbances in oncogene, growth factor, and cell cycle regulation, resulting in an increased incidence of mesothelioma.

Goričar K, Kovač V, Dolžan V
Polymorphisms in translesion polymerase genes influence treatment outcome in malignant mesothelioma.
Pharmacogenomics. 2014; 15(7):941-50 [PubMed] Related Publications
AIM: We evaluated the influence of genetic variability in translesion polymerases REV1 and REV3L on the outcome of cisplatin treatment in malignant mesothelioma patients.
MATERIALS & METHODS: In total, 139 malignant mesothelioma patients were genotyped for seven tag SNPs in REV1 and REV3L. Logistic regression and Cox regression were used to assess the influence of SNPs on treatment outcome.
RESULTS: Polymorphic REV1 rs3087403 allele and REV1 TGT haplotype were associated with increased risk for leukopenia (p = 0.013 and p = 0.047, respectively) and neutropenia (p = 0.048 and p = 0.024, respectively). REV3L rs465646, rs462779 and REV3L CCGG haplotype were significantly associated with longer overall survival (p = 0.007, p = 0.022 and p = 0.013, respectively).
CONCLUSION: Our results suggest for the first time that REV1 and REV3L SNPs might serve as potential predictive markers of outcome of cisplatin-based chemotherapy. Original submitted 7 October 2013; Revision submitted 15 January 2014.

Xu J, Kadariya Y, Cheung M, et al.
Germline mutation of Bap1 accelerates development of asbestos-induced malignant mesothelioma.
Cancer Res. 2014; 74(16):4388-97 [PubMed] Article available free on PMC after 15/08/2015 Related Publications
Malignant mesotheliomas are highly aggressive tumors usually caused by exposure to asbestos. Germline-inactivating mutations of BAP1 predispose to mesothelioma and certain other cancers. However, why mesothelioma is the predominate malignancy in some BAP1 families and not others, and whether exposure to asbestos is required for development of mesothelioma in BAP1 mutation carriers are not known. To address these questions experimentally, we generated a Bap1(+/-) knockout mouse model to assess its susceptibility to mesothelioma upon chronic exposure to asbestos. Bap1(+/-) mice exhibited a significantly higher incidence of asbestos-induced mesothelioma than wild-type (WT) littermates (73% vs. 32%, respectively). Furthermore, mesotheliomas arose at an accelerated rate in Bap1(+/-) mice than in WT animals (median survival, 43 weeks vs. 55 weeks after initial exposure, respectively) and showed increased invasiveness and proliferation. No spontaneous mesotheliomas were seen in unexposed Bap1(+/-) mice followed for up to 87 weeks of age. Mesothelioma cells from Bap1(+/-) mice showed biallelic inactivation of Bap1, consistent with its proposed role as a recessive cancer susceptibility gene. Unlike in WT mice, mesotheliomas from Bap1(+/-) mice did not require homozygous loss of Cdkn2a. However, normal mesothelial cells and mesothelioma cells from Bap1(+/-) mice showed downregulation of Rb through a p16(Ink4a)-independent mechanism, suggesting that predisposition of Bap1(+/-) mice to mesothelioma may be facilitated, in part, by cooperation between Bap1 and Rb. Drawing parallels to human disease, these unbiased genetic findings indicate that BAP1 mutation carriers are predisposed to the tumorigenic effects of asbestos and suggest that high penetrance of mesothelioma requires such environmental exposure.

Riquelme E, Suraokar MB, Rodriguez J, et al.
Frequent coamplification and cooperation between C-MYC and PVT1 oncogenes promote malignant pleural mesothelioma.
J Thorac Oncol. 2014; 9(7):998-1007 [PubMed] Article available free on PMC after 15/08/2015 Related Publications
INTRODUCTION: Malignant pleural mesothelioma (MPM) is a deadly disease with poor prognosis and few treatment options. We characterized and elucidated the roles of C-MYC and PVT1 involved in the pathogenesis of MPM.
METHODS: We used small interfering RNA (siRNA)-mediated knockdown in MPM cell lines to determine the effect of C-MYC and PVT1 abrogation on MPM cells undergoing apoptosis, proliferation, and cisplatin sensitivity. We also characterized the expression of microRNAs spanning the PVT1 region in MPM cell lines. Copy number analysis was measured by quantitative polymerase chain reaction and fluorescence in situ hybridization.
RESULTS: Copy number analysis revealed copy number gains (CNGs) in chromosomal region 8q24 in six of 12 MPM cell lines. MicroRNA analysis showed high miR-1204 expression in MSTO-211H cell lines with four copies or more of PVT1. Knockdown by siRNA showed increased PARP-C levels in MSTO-211H transfected with siPVT1 but not in cells transfected with siC-MYC. C-MYC and PVT1 knockdown reduced cell proliferation and increased sensitivity to cisplatin. Analysis of the expression of apoptosis-related genes in the MSTO-211H cell line suggested that C-MYC maintains a balance between proapoptotic and antiapoptotic gene expression, whereas PVT1 and, to a lesser extent, miR-1204 up-regulate proapoptotic genes and down-regulate antiapoptotic genes. Fluorescence in situ hybridization analysis of MPM tumor specimens showed a high frequency of both CNGs (11 of 75) and trisomy (three copies; 11 of 75) for the C-MYC locus.
CONCLUSION: Our results suggest that C-MYC and PVT1 CNG promotes a malignant phenotype of MPM, with C-MYC CNG stimulating cell proliferation and PVT1 both stimulating proliferation and inhibiting apoptosis.

Yoshikawa Y, Sato A, Tsujimura T, et al.
Biallelic germline and somatic mutations in malignant mesothelioma: multiple mutations in transcription regulators including mSWI/SNF genes.
Int J Cancer. 2015; 136(3):560-71 [PubMed] Related Publications
We detected low levels of acetylation for histone H3 tail lysines in malignant mesothelioma (MM) cell lines resistant to histone deacetylase inhibitors. To identify the possible genetic causes related to the low histone acetylation levels, whole-exome sequencing was conducted with MM cell lines established from eight patients. A mono-allelic variant of BRD1 was common to two MM cell lines with very low acetylation levels. We identified 318 homozygous protein-damaging variants/mutations (18-78 variants/mutations per patient); annotation analysis showed enrichment of the molecules associated with mammalian SWI/SNF (mSWI/SNF) chromatin remodeling complexes and co-activators that facilitate initiation of transcription. In seven of the patients, we detected a combination of variants in histone modifiers or transcription factors/co-factors, in addition to variants in mSWI/SNF. Direct sequencing showed that homozygous mutations in SMARCA4, PBRM1 and ARID2 were somatic. In one patient, homozygous germline variants were observed for SMARCC1 and SETD2 in chr3p22.1-3p14.2. These exhibited extended germline homozygosity and were in regions containing somatic mutations, leading to a loss of BAP1 and PBRM1 expression in MM cell line. Most protein-damaging variants were heterozygous in normal tissues. Heterozygous germline variants were often converted into hemizygous variants by mono-allelic deletion, and were rarely homozygous because of acquired uniparental disomy. Our findings imply that MM might develop through the somatic inactivation of mSWI/SNF complex subunits and/or histone modifiers, including BAP1, in subjects that have rare germline variants of these transcription regulators and/or transcription factors/co-factors, and in regions prone to mono-allelic deletion during oncogenesis.

Renganathan A, Kresoja-Rakic J, Echeverry N, et al.
GAS5 long non-coding RNA in malignant pleural mesothelioma.
Mol Cancer. 2014; 13:119 [PubMed] Article available free on PMC after 15/08/2015 Related Publications
BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive cancer with short overall survival. Long non-coding RNAs (lncRNA) are a class of RNAs more than 200 nucleotides long that do not code for protein and are part of the 90% of the human genome that is transcribed. Earlier experimental studies in mice showed GAS5 (growth arrest specific transcript 5) gene deletion in asbestos driven mesothelioma. GAS5 encodes for a lncRNA whose function is not well known, but it has been shown to act as glucocorticoid receptor decoy and microRNA "sponge". Our aim was to investigate the possible role of the GAS5 in the growth of MPM.
METHODS: Primary MPM cultures grown in serum-free condition in 3% oxygen or MPM cell lines grown in serum-containing medium were used to investigate the modulation of GAS5 by growth arrest after inhibition of Hedgehog or PI3K/mTOR signalling. Cell cycle length was determined by EdU incorporation assay in doxycycline inducible short hairpinGAS5 clones generated from ZL55SPT cells. Gene expression was quantified by quantitative PCR. To investigate the GAS5 promoter, a 0.77 kb sequence was inserted into a pGL3 reporter vector and luciferase activity was determined after transfection into MPM cells. Localization of GAS5 lncRNA was identified by in situ hybridization. To characterize cells expressing GAS5, expression of podoplanin and Ki-67 was assessed by immunohistochemistry.
RESULTS: GAS5 expression was lower in MPM cell lines compared to normal mesothelial cells. GAS5 was upregulated upon growth arrest induced by inhibition of Hedgehog and PI3K/mTOR signalling in in vitro MPM models. The increase in GAS5 lncRNA was accompanied by increased promoter activity. Silencing of GAS5 increased the expression of glucocorticoid responsive genes glucocorticoid inducible leucine-zipper and serum/glucocorticoid-regulated kinase-1 and shortened the length of the cell cycle. Drug induced growth arrest was associated with GAS5 accumulation in the nuclei. GAS5 was abundant in tumoral quiescent cells and it was correlated to podoplanin expression.
CONCLUSIONS: The observations that GAS5 levels modify cell proliferation in vitro, and that GAS5 expression in MPM tissue is associated with cell quiescence and podoplanin expression support a role of GAS5 in MPM biology.

Cortes-Dericks L, Froment L, Boesch R, et al.
Cisplatin-resistant cells in malignant pleural mesothelioma cell lines show ALDH(high)CD44(+) phenotype and sphere-forming capacity.
BMC Cancer. 2014; 14:304 [PubMed] Article available free on PMC after 15/08/2015 Related Publications
BACKGROUND: Conventional chemotherapy in malignant pleural mesothelioma (MPM) has minimal impact on patient survival due to the supposed chemoresistance of cancer stem cells (CSCs). We sought to identify a sub-population of chemoresistant cells by using putative CSC markers, aldehyde dehydrogenase (ALDH) and CD44 in three MPM cell lines; H28, H2052 and Meso4.
METHODS: The Aldefluor assay was used to measure ALDH activity and sort ALDH(high) and ALDH(low) cells. Drug-resistance was evaluated by cell viability, anchorage-independent sphere formation, flow-cytometry and qRT-PCR analyses.
RESULTS: The ALDH(high) - and ALDH(low) -sorted fractions were able to demonstrate phenotypic heterogeneity and generate spheres, the latter being less efficient, and both showed an association with CD44. Cis- diamminedichloroplatinum (II) (cisplatin) treatment failed to reduce ALDH activity and conferred only a short-term inhibition of sphere generation in both ALDH(high) and ALDH(low) fractions of the three MPM cell lines. Induction of drug sensitivity by an ALDH inhibitor, diethylaminobenzaldehyde (DEAB) resulted in significant reductions in cell viability but not a complete elimination of the sphere-forming cells, suggestive of the presence of a drug-resistant subpopulation. At the transcript level, the cisplatin + DEAB-resistant cells showed upregulated mRNA expression levels for ALDH1A2, ALDH1A3 isozymes and CD44 indicating the involvement of these markers in conferring chemoresistance in both ALDH(high) and ALDH(low) fractions of the three MPM cell lines.
CONCLUSIONS: Our study shows that ALDH(high) CD44(+) cells are implicated in conveying tolerance to cisplatin in the three MPM cell lines. The combined use of CD44 and ALDH widens the window for identification and targeting of a drug-resistant population which may improve the current treatment modalities in mesothelioma.

Varesano S, Leo C, Boccardo S, et al.
Status of Anaplastic Lymphoma Kinase (ALK) in malignant mesothelioma.
Anticancer Res. 2014; 34(5):2589-92 [PubMed] Related Publications
BACKGROUND: Malignant mesothelioma (MM) is a particularly aggressive type of primary tumor, associated with exposure to asbestos, and characterized by high mortality. To date, there is no curative therapy for MM. The receptor anaplastic lymphoma kinase (ALK) was found to be mutated in many cases of cancer and used as a target in biological therapies. We investigated whether this pharmacological treatment could also be applicable to MM.
MATERIALS AND METHODS: The state of ALK was analyzed by immunohistochemistry and fluorescent in situ hybridization in 63 MM tissue specimens.
RESULTS: None of the 63 MM samples showed overexpression or translocation of ALK.
CONCLUSION: Our preliminary data exclude the utility of analysis of the ALK gene in MM and suggest that ALK inhibitor therapy is not applicable to MM.

Tsao AS, Harun N, Fujimoto J, et al.
Elevated PDGFRB gene copy number gain is prognostic for improved survival outcomes in resected malignant pleural mesothelioma.
Ann Diagn Pathol. 2014; 18(3):140-5 [PubMed] Article available free on PMC after 15/08/2015 Related Publications
PDGF/PDGFR pathway has been implicated in malignant pleural mesothelioma (MPM) carcinogenesis, and evidence suggests autocrine mechanisms of proliferation. We sought to evaluate the incidence of PDGFRB gene copy number gain (CNG) by fluorescence in situ hybridization and PDGFR pathway protein expression by immunohistochemistry (IHC) and correlate it to patient clinical outcome. Eighty-eight archived tumor blocks from resected MPM with full clinical information were used to perform IHC biomarkers (PDGFRα, PDGFRβ, p-PDGFRβ) and fluorescence in situ hybridization analysis of PDGFRB gene CNG. Spearman rank correlation, Wilcoxon rank-sum test, Kruskal-Wallis test, BLiP plots, and Kaplan-Meier method were used to analyze the biomarkers and correlation to clinical outcome. Several correlations between the IHC biomarkers were seen; however, none correlated to clinically relevant patient demographics or histology. In the CNG analysis, PDGFRB gene CNG in >10% of tumor cells had lower cytoplasmic p-PDGFRβ (P=.029), while PDGFRB gene CNG in >40% of tumor cells had a higher cytoplasmic PDGFRβ (P=.04). PDGFRB gene CNG status did not associate with patient demographics or tumor characteristics. PDGFR pathway IHC biomarkers did not associate with survival outcomes. However, patients with PDGFRB CNG >40% of tumor cells had improved relapse-free survival (HR 0.25 [95% CI 0.09-0.72], P=.0096) and improved overall survival (HR 0.32 [95% CI 0.11-0.89], P=.029). PDGFRB CNG >40% of MPM tumor cells is a potential prognostic biomarker for surgery and may identify a unique population of mesothelioma patients. Future validation of this biomarker in prospective trials is needed. From a retrospective review of archived tissue specimens from patients with resected malignant pleural mesothelioma tumors, we show that patients with PDGFRB CNG >40% of tumor cells had improved relapse-free survival (HR 0.25 [95% CI 0.09-0.72], P=.0096) and improved overall survival (HR 0.32 [95% CI 0.11-0.89], P=.029). PDGFRB CNG >40% of MPM tumor cells is a potential prognostic biomarker for surgery and may identify a unique population of mesothelioma patients.

Suraokar MB, Nunez MI, Diao L, et al.
Expression profiling stratifies mesothelioma tumors and signifies deregulation of spindle checkpoint pathway and microtubule network with therapeutic implications.
Ann Oncol. 2014; 25(6):1184-92 [PubMed] Article available free on PMC after 15/08/2015 Related Publications
BACKGROUND: Malignant pleural mesothelioma (MPM) is a lethal neoplasm exhibiting resistance to most treatment regimens and requires effective therapeutic options. Though an effective strategy in many cancer, targeted therapy is relatively unexplored in MPM because the therapeutically important oncogenic pathways and networks in MPM are largely unknown.
MATERIALS AND METHODS: We carried out gene expression microarray profiling of 53 surgically resected MPMs tumors along with paired normal tissue. We also carried out whole transcriptomic sequence (RNA-seq) analysis on eight tumor specimens. Taqman-based quantitative Reverse-transcription polymerase chain reaction (qRT-PCR), western analysis and immunohistochemistry (IHC) analysis of mitotic arrest deficient-like 1 (MAD2L1) was carried out on tissue specimens. Cell viability assays of MPM cell lines were carried out to assess sensitivity to specific small molecule inhibitors.
RESULTS: Bioinformatics analysis of the microarray data followed by pathway analysis revealed that the mitotic spindle assembly checkpoint (MSAC) pathway was most significantly altered in MPM tumors with upregulation of 18 component genes, including MAD2L1 gene. We validated the microarray data for MAD2L1 expression using quantitative qRT-PCR and western blot analysis on tissue lysates. Additionally, we analyzed expression of the MAD2L1 protein by IHC using an independent tissue microarray set of 80 MPM tissue samples. Robust clustering of gene expression data revealed three novel subgroups of tumors, with unique expression profiles, and showed differential expression of MSAC pathway genes. Network analysis of the microarray data showed the cytoskeleton/spindle microtubules network was the second-most significantly affected network. We also demonstrate that a nontaxane small molecule inhibitor, epothilone B, targeting the microtubules have great efficacy in decreasing viability of 14 MPM cell lines.
CONCLUSIONS: Overall, our findings show that MPM tumors have significant deregulation of the MSAC pathway and the microtubule network, it can be classified into three novel molecular subgroups of potential therapeutic importance and epothilone B is a promising therapeutic agent for MPM.

Otterstrom C, Soltermann A, Opitz I, et al.
CD74: a new prognostic factor for patients with malignant pleural mesothelioma.
Br J Cancer. 2014; 110(8):2040-6 [PubMed] Article available free on PMC after 15/08/2015 Related Publications
BACKGROUND: The pro-inflammatory cytokine migration inhibitory factor (MIF) and its receptor CD74 have been proposed as possible therapeutic targets in several cancers. We studied the expression of MIF and CD74 together with calretinin in specimens of malignant pleural mesothelioma (MPM), correlating their expression levels with clinico-pathologic parameters, in particular overall survival (OS).
METHODS: Migration inhibitory factor, CD74, and calretinin immunoreactivity were investigated in a tissue microarray of 352 patients diagnosed with MPM. Protein expression intensities were semiquantitatively scored in the tumour cells and in the peritumoral stroma. Markers were matched with OS, age, gender, and histological subtype.
RESULTS: Clinical data from 135 patients were available. Tumour cell expressions of MIF and CD74 were observed in 95% and 98% of MPM specimens, respectively, with a homogenous distribution between the different histotypes. CD74 (P<0.001) but not MIF overexpression (P=0.231) emerged as an independent prognostic factor for prolonged OS. High expression of tumour cell calretinin correlated with the epithelioid histotype and was also predictive of longer OS (P<0.001). When compared with previously characterised putative epithelial-to-mesenchymal transition markers, CD74 correlated positively with tumoral PTEN and podoplanin expressions, but was inversely related with periostin expression.
CONCLUSIONS: High expression of CD74 is an independent prognostic factor for prolonged OS in mesothelioma patients.

Truini A, Coco S, Alama A, et al.
Role of microRNAs in malignant mesothelioma.
Cell Mol Life Sci. 2014; 71(15):2865-78 [PubMed] Related Publications
Malignant mesothelioma (MM) is an aggressive tumor, mainly derived from the pleura, which is predominantly associated with exposure to asbestos fibers. The prognosis of MM patients is particularly severe, with a median survival of approximately 9-12 months and latency between exposure and diagnosis ranging from 20-50 years (median 30 years). Emerging evidence has demonstrated that tumor aggressiveness is associated with genome and gene expression abnormalities; therefore, several studies have recently focused on the role of microRNAs (miRNAs) in MM tumorigenesis. miRNAs are small non-protein coding single-stranded RNAs (17-22 nucleotides) involved in numerous cellular processes that negatively regulate gene expression by modulating the expression of downstream target genes. miRNAs are often deregulated in cancer; in particular, the differential miRNA expression profiles of MM cells compared to unaffected mesothelial cells have suggested potential roles of miRNAs as either oncogenes or tumor suppressor genes in MM oncogenesis. In this review, the mechanism of MM carcinogenesis was evaluated through the analysis of the published miRNA expression data. The roles of miRNAs as diagnostic biomarkers and prognostic factors for potential therapeutic strategies will be presented and discussed.

Hwang H, Tse C, Rodriguez S, et al.
p16 FISH deletion in surface epithelial mesothelial proliferations is predictive of underlying invasive mesothelioma.
Am J Surg Pathol. 2014; 38(5):681-8 [PubMed] Related Publications
An atypical mesothelial proliferation along the pleural or peritoneal surface without evidence of invasive tumor poses a diagnostic challenge. Homozygous deletion of p16 (CDKN2A) by fluorescence in situ hybridization (FISH) has been shown to be a good marker of malignancy in mesothelial proliferations, but correlations of p16 status between atypical surface proliferations and underlying mesothelioma have not been described. We used p16 FISH to investigate 11 pleural and 7 peritoneal mesotheliomas that had both an invasive component and a separate surface mesothelial proliferation. In 5/11 pleural samples and 1/7 peritoneal samples, the invasive mesotheliomas showed homozygous deletion of p16 (all cases in excess of 90% of cells deleted); the surface proliferation in all 6 cases with deletion in the invasive tumor was also p16 deleted. Conversely, the 12 tumors that did not show p16 deletion in the invasive compartment also did not have deletion in the surface component. We conclude that (1) surface mesothelial proliferations near invasive mesotheliomas show the same pattern of p16 by FISH as the underlying tumor and may represent in situ disease or growth of the underlying mesothelioma along the serosal surface; (2) p16 deletion in mesothelial surface proliferations is strongly associated with p16 deletion in underlying mesotheliomas, and biopsies consisting of pure surface mesothelial proliferations that are p16 deleted allow a diagnosis of mesothelioma without an additional biopsy if there is clinical (thoracosopic/laparoscopic) or radiologic evidence of diffuse pleural or peritoneal tumor; (3) however, the absence of p16 deletion in surface proliferations does not rule out underlying invasive mesothelioma.

de Assis LV, Locatelli J, Isoldi MC
The role of key genes and pathways involved in the tumorigenesis of Malignant Mesothelioma.
Biochim Biophys Acta. 2014; 1845(2):232-47 [PubMed] Related Publications
Malignant Mesothelioma (MM) is a very aggressive cancer with low survival rates and often diagnosed at an advanced stage. Several players have been implicated in the development of this cancer, such as asbestos, erionite and the simian virus 40 (SV40). 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.

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