Epigenetic Profiles Distinguish Pleural Mesothelioma from Normal Pleura and Predict Lung Asbestos Burden and Clinical Outcome

Christensen, Brock C.; Houseman, E. Andrés; Godleski, John J.; Marsit, Carmen J.; Longacker, Jennifer L.; Roelofs, Cora; Wrensch, Margaret; Yeh, Ru Fang; Nelson, Heather H.; Wiemels, Joe; Zheng, Shichun; Wiencke, John K.; Bueno, Raphael; Sugarbaker, David J.; Kelsey, Karl T.

doi:10.1158/0008-5472.can-08-2586

Cited by 141 publications

(127 citation statements)

References 45 publications

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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

165

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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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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

165

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“…In malignant pleural mesothelioma, restricted DNA methylation profiles were predictive for the asbestos burden of the patients. 16 With respect to lung cancer, very limited data on DNA methylation in asbestos-exposed patients have been published, with CDKN2A being the best studied candidate gene but so far with discrepant results. 14,15,[17][18][19] This highlights the need to understand more comprehensively the role of DNA methylation in asbestos-related lung cancer.…”

mentioning

confidence: 99%

Asbestos‐associated genome‐wide DNA methylation changes in lung cancer

Kettunen

Hernandez-Vargas

Cros

et al. 2017

Intl Journal of Cancer

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Previous studies have revealed a robust association between exposure to asbestos and human lung cancer. Accumulating evidence has highlighted the role of epigenome deregulation in the mechanism of carcinogen-induced malignancies. We examined the impact of asbestos on DNA methylation. Our genome-wide studies (using Illumina HumanMethylation450K BeadChip) of lung cancer tissue and paired normal lung from 28 asbestos-exposed or non-exposed patients, mostly smokers, revealed distinctive DNA methylation changes. We identified a number of differentially methylated regions (DMR) and differentially variable, differentially methylated CpGs (DVMC), with individual CpGs further validated by pyrosequencing in an independent series of 91 non-small cell lung cancer and paired normal lung. We discovered and validated BEND4, ZSCAN31 and GPR135 as significantly hypermethylated in lung cancer. DMRs in genes such as RARB (FDR 1.1 3 10 219 , mean change in beta [D] 20.09), GPR135 (FDR 1.87 3 10 28 , mean D 20.09) and TPO (FDR 8.58 3 10 25 , mean D 20.11), and DVMCs in NPTN, NRG2, GLT25D2 and TRPC3 (all with p <0.05, t-test) were significantly associated with asbestos exposure status in exposed versus non-exposed lung tumors. Hypomethylation was characteristic to DVMCs in lung cancer tissue from asbestos-exposed subjects. When DVMCs related to asbestos or smoking were analyzed, 96% of the elements were unique to either of the exposures, consistent with the concept that the methylation changes in tumors may be specific for risk factors. In conclusion, we identified novel DNA methylation changes associated with lung tumors and asbestos exposure, suggesting that changes may be present in causal pathway from asbestos exposure to lung cancer.Lung cancer is the leading cause of cancer-related deaths, accounting for around every fifth global cancer death. 1 While tobacco smoking remains the principal risk factor for lung carcinogenesis, exposure to asbestos, a group of naturally occurring fibrous silicate minerals with multiple commercial applications, is the most important occupational risk factor for lung cancer. 2 Asbestos exposure causes 6 to 23% of all male lung cancers (estimates depending on the exposure and population), and >107,000 deaths annually from asbestosrelated diseases. 3,4 All forms of asbestos are carcinogenic to

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“…This indicates the therapeutic use of mTOR inhibitors sirolimus and everolimus [44]. In addition to genetic changes, epigenetic alterations are involved in the progression of MM [46] [47]. PB and vorinostat can address these abnormalities when added to therapeutic combinations [37] [38].…”

Section: Discussionmentioning

confidence: 99%

Preliminary Findings on the Use of Targeted Therapy in Combination with Sodium Phenylbutyrate in Advanced Malignant Mesothelioma: A Strategy for Improved Survival

Burzynski¹,

Janicki²,

Burzynski³

et al. 2014

JCT

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Advanced malignant mesothelioma (MM) is among the most aggressive and difficult-to-treat diseases. Industrialization and exposure to asbestos is the main causative factor for the dramatic increase in the incidence of MM, which carries a poor prognosis and a median survival of less than 12 months. Combination chemotherapy offers only palliative results; however, targeted therapy carries more promise for future successful treatment. This paper presents preliminary findings of improved overall survival (OS) using a combination of sodium phenylbutyrate (PB) with various chemotherapeutic and targeted agents in advanced MM. The data suggest using a strategy of simultaneous interruption of signal transduction involving RAS-MEK-ERK, PI3K-AKT, mTOR, Merlin, and angiogenesis pathways and interference in cell cycle and epigenetic processes. Complete response was determined in 15.4% and stable disease in 46.2% in the group of 13 evaluable patients. Median OS for MM was higher compared to other treatments (17 months compared to between 6 and 12.1 months). The longest surviving patient continues to be in complete response and in excellent condition for over 12.5 years from the treatment start. These findings are only preliminary and validation of the results using a well-designed phase I/II trial in advanced MM is proposed.

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Epigenetic Profiles Distinguish Pleural Mesothelioma from Normal Pleura and Predict Lung Asbestos Burden and Clinical Outcome

Cited by 141 publications

References 45 publications

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

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

Asbestos‐associated genome‐wide DNA methylation changes in lung cancer

Preliminary Findings on the Use of Targeted Therapy in Combination with Sodium Phenylbutyrate in Advanced Malignant Mesothelioma: A Strategy for Improved Survival

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