Epigenetic Profiles Distinguish Malignant Pleural Mesothelioma from Lung Adenocarcinoma

Gotô, Yasuhiro; Shinjo, Keiko; Kondo, Yutaka; Shen, Lanlan; Toyota, Minoru; Suzuki, Hiromu; Gao, Wentao; An, Byonggu; Fujii, Makiko; Murakami, Hideki; Osada, Hiroyuki; Taniguchi, Tetsuo; Usami, Noriyasu; Kondo, Masashi; Hasegawa, Yoshinori; Shimokata, Kaoru; Matsuo, Keitaro; Hida, Toyoaki; Fujimoto, Nobukazu; Kishimoto, Takumi; Issa, Jean–Pierre J.; Sekido, Yoshitaka

doi:10.1158/0008-5472.can-09-1595

Cited by 115 publications

(109 citation statements)

References 45 publications

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“…Effects of 5-azaCdR, VPA and SAHA on TAA expression MPM displays multiple epigenetic abnormalities that lead to the silencing of tumour suppressor genes [25]. Such observations suggest that MPM may be a good target for epigenetic drugs that would favour the expression of new, tumourassociated genes.…”

Section: Resultsmentioning

confidence: 99%

A 5-aza-2′-deoxycytidine/valproate combination induces cytotoxic T-cell response against mesothelioma

et al. 2011

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Malignant pleural mesothelioma (MPM) is an aggressive tumour with a limited response to conventional therapy. The aim of this study was to evaluate the anticancer effect of a DNA methyltransferase inhibitor, 5-aza-29-deoxycytidine (5-azaCdR), and two histone deacetylase inhibitors, valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA).Human mesothelioma cells were treated with each epigenetic drug, either alone or in combinations. The cytotoxic effects on treated cells and the expression of specific tumour antigens were evaluated. The recognition of treated cells by a specific CD8+ T-cell clone was also measured. Additionally, the effect of combined treatments was tested in a murine model of mesothelioma.We showed that VPA and SAHA synergised with 5-azaCdR to kill MPM cells and induce tumour antigen expression in the remaining living tumour cells. As a consequence, tumour cells expressing these antigens were recognised and lysed by specific CD8+ cytotoxic T-cells. In vivo, treatment with 5-azaCdR/VPA inhibited tumour growth, and promoted lymphocyte infiltration and an immune response against tumour cells.Appropriate epigenetic drug combinations, in addition to inducing mesothelioma cell death, also affect the immunogenic status of these cells. This property could be exploited in clinical investigations to develop MPM treatments combining chemotherapeutic and immunotherapeutic approaches.

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Section: Resultsmentioning

confidence: 99%

A 5-aza-2′-deoxycytidine/valproate combination induces cytotoxic T-cell response against mesothelioma

et al. 2011

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“…Labeled MCA amplicons were then hybridized to a custom human CpG island microarray containing 15,134 probes covering 6,157 unique genes (G4497A; Agilent Technologies; ref. 18). After washing, the array was scanned using an Agilent DNA Microarray Scanner (Agilent Technologies), and the data were processed using Feature Extraction software ver.…”

Section: Methylated Cpg Island Amplification Coupled With Cpg Island mentioning

confidence: 99%

Aberrant Methylation of RASGRF1 Is Associated with an Epigenetic Field Defect and Increased Risk of Gastric Cancer

Takamaru

Yamamoto

Suzuki

et al. 2012

Cancer Prevention Research

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Aberrant DNA methylation is implicated in the epigenetic field defect seen in gastric cancer. Our aim in this study was to identify predictive biomarkers by screening for DNA methylation in noncancerous background gastric mucosa from patients with gastric cancer. Using methylated-CpG island amplification coupled with CpG island microarray (MCAM) analysis, we identified 224 genes that were methylated in the noncancerous gastric mucosa of patients with gastric cancer. Among them, RASGRF1 methylation was significantly elevated in gastric mucosa from patients with either intestinal or diffuse type gastric cancer, as compared with mucosa from healthy individuals (8.3% vs. 22.4%, P < 0.001; 8.3% vs. 19.4%, P < 0.001). RASGRF1 methylation was independent of mucosal atrophy and could be used to distinguish both serum pepsinogen test-positive [sensitivity, 70.0%; specificity, 86.7%; area under the receiver operator characteristic (ROC) curve, AUC, 0.763] and -negative patients with gastric cancer (sensitivity, 72.2%; specificity, 87.0%; AUC, 0.844) from healthy individuals. Ectopic expression of RASGRF1 suppressed colony formation and Matrigel invasion by gastric cancer cells, suggesting it may be involved in gastric tumorigenesis. Collectively, our data suggest that RASGRF1 methylation is significantly involved in an epigenetic field defect in the stomach, and that it could be a useful biomarker to identify individuals at high risk for gastric cancer. Cancer Prev Res; 5(10); 1203-12. Ó2012 AACR.

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“…To date, only a few studies have proposed a classification based on molecular data and linked to the clinical characteristics of MPM. Classifications based on methylation profiles have defined MPM subgroups characterized by different clinical outcomes (12,13). However, classifications based on transcriptomic data that make it possible to define gene expression and pathway profiles were not related to the prognosis.…”

Section: Introductionmentioning

confidence: 99%

Molecular Classification of Malignant Pleural Mesothelioma: Identification of a Poor Prognosis Subgroup Linked to the Epithelial-to-Mesenchymal Transition

Reyniès

Jaurand

Renier

et al. 2014

Clinical Cancer Research

130

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Purpose: Despite research efforts to develop more effective diagnostic and therapeutic approaches, malignant pleural mesothelioma (MPM) prognosis remains poor. The assessment of tumor response to therapy can be improved by a deeper phenotypical classification of the tumor, with emphasis on its clinicobiological heterogeneity. The identification of molecular profiles is a powerful approach to better define MPM subclasses and targeted therapies.Experimental Design: Molecular subclasses were defined by transcriptomic microarray on 38 primary MPM cultures. A three-gene predictor, identified by quantitative reverse transcription PCR, was used to classify an independent series of 108 frozen tumor samples. Gene mutations were determined in BAP1, CDKN2A, CDKN2B, NF2, and TP53. Epithelial-to-mesenchymal transition (EMT) markers were studied at the mRNA and protein levels.Results: Unsupervised hierarchical clustering on transcriptomic data defined two robust MPM subgroups (C1 and C2), closely related to prognosis and partly to histologic subtypes. All sarcomatoid/desmoplastic MPM were included in the C2 subgroup. Epithelioid MPM were found in both subgroups, with a worse survival prognosis in the C2 subgroup. This classification and its association with histologic subtypes and survival were validated in our independent series using the three-gene predictor. Similar subgroups were found after classification of other MPM series from transcriptomic public datasets. C1 subgroup exhibited more frequent BAP1 alterations. Pathway analysis revealed that EMT was differentially regulated between MPM subgroups. C2 subgroup is characterized by a mesenchymal phenotype.Conclusions: A robust classification of MPM that defines two subgroups of epithelioid MPM, characterized by different molecular profiles, gene alterations, and survival outcomes, was established. Clin Cancer Res; 20(5); 1323-34. Ó2014 AACR.

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Epigenetic Profiles Distinguish Malignant Pleural Mesothelioma from Lung Adenocarcinoma

Cited by 115 publications

References 45 publications

A 5-aza-2′-deoxycytidine/valproate combination induces cytotoxic T-cell response against mesothelioma

A 5-aza-2′-deoxycytidine/valproate combination induces cytotoxic T-cell response against mesothelioma

Aberrant Methylation of RASGRF1 Is Associated with an Epigenetic Field Defect and Increased Risk of Gastric Cancer

Molecular Classification of Malignant Pleural Mesothelioma: Identification of a Poor Prognosis Subgroup Linked to the Epithelial-to-Mesenchymal Transition

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