5-hydroxymethylcytosine but not MTAP methylation status can stratify malignant pleural mesothelioma based on the lineage of origin

Our plain-English summary of 5-hydroxymethylcytosine but not MTAP methylation status can stratify malignant pleural mesothelioma based on the lineage of origin, by M. Bosio, E. Salvaterra, F. Datturi, et al (Multidisciplinary Respiratory Medicine, 2018).

The study

• Authors: M. Bosio, E. Salvaterra, F. Datturi, P. Morbini, M. Zorzetto, S. Inghilleri, S. Tomaselli, P. Mangiarotti, F. Meloni, I. Cerveri, G.M. Stella
• Journal: Multidisciplinary Respiratory Medicine
• Published: 2018;13:27
• Cited by: 8 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is an aggressive tumor with poor prognosis, mainly associated with work or environmental exposure to asbestos. MPM's molecular profile is largerly unexplored and effective therapies are still lacking. MPM rarely harbours those somatic genetic lesions that usually characterize solid epithelial-derived tumors. On this basis, our study aims at investigating MPM epigenetic profile.

Methods: We here assessed through immunohistochemistry, FISH and methylation specific PCR, the expression of 5-hydroxymethylcytosine (5- hmC) - an epigenetic marker and an important regulator of embryonic development and carcinogenesis - and the methylation status of the promoter of the MTAP gene - encoding for an enzyme involved in the rescue process of methionine and adenine - in two relevant series of FF-PE MPM samples derived from MPM thoracoscopic biopsies. Tissue sampling was performed at diagnosis.

Results: Within the limitations of the study cohort, the 5-hmC immunophenotype was different among the histological MPM types analysed. In fact, 18% of the epithelial MPMs were negative, 47% weakly positive, and 35% of the cases showed an intense expression of 5-hmC. Sarcomatoid and biphasic MPMs showed intense 5-hmC expression pattern (positive and weakly positive in more than 80% of cases). Among MPM featuring epithelial lineage, none showed methylation of MTAP promoter.

Conclusions: Mesothelial sarcomatoid tumors featured a methylation profile characterized by a permanent gene silencing. Epithelial MPM methylation profile was in-between that of sarcomatoid MPM and the one of epithelial-derived tumors. MTAP promoter methylation level cannot be considered a suitable biomarker of epithelial MPM arousal.

In plain English

This Italian laboratory study examined archived tumor biopsy samples of malignant pleural mesothelioma from a hospital in Pavia. The main group was 40 patients (30 men, 10 women): 18 had epithelioid tumors, 15 sarcomatoid and 7 biphasic. Six reported proven work exposure to asbestos, and 38 (95%) reported environmental exposure. A second group of 90 epithelioid tumor samples was added for the MTAP tests. The authors stained samples for 5-hydroxymethylcytosine (5-hmC), an epigenetic marker. Of the 18 epithelioid tumors, 13 were negative and 5 showed intense staining. Sarcomatoid and biphasic tumors stained more intensely. The authors also tested the MTAP gene, which codes for an enzyme. Of 130 samples stained for the MTAP protein, two lacked it; a methylation test on 90 samples found none with a methylated MTAP promoter. The authors concluded that MTAP methylation might not be a good biomarker for mesothelioma. They said the small number of sarcomatoid and biphasic samples limits the conclusions and called the results preliminary. Several numbers in the article disagree with each other.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study of archived tumor biopsy samples using immunohistochemistry (tissue staining), fluorescence in situ hybridization (FISH) and methylation-specific PCR
• Who was studied: The main group was 40 consecutive formalin-fixed, paraffin-embedded thoracoscopic biopsy samples from malignant pleural mesothelioma patients at the IRCCS Fondazione Policlinico San Matteo, Pavia, Italy. These patients were 30 men and 10 women, with a mean age at diagnosis of 67.57 years. Their tumors were 18 epithelioid, 15 sarcomatoid and 7 biphasic. A second cohort of 90 surgical biopsy samples of epithelial MPM was used for the MTAP analyses (protein staining and promoter methylation). The article does not give study dates.
• Exposure: Of the 40 patients, 6 reported proven work exposure to asbestos fibers and 38 (95%) reported environmental exposure. No fiber types were named. Asbestos exposure was not analysed against the test results.
• Main results:
  • Of the 18 epithelioid mesotheliomas, 13 had negative 5-hmC staining and 5 had intense staining.
  • Sarcomatoid and biphasic tumors showed more intense 5-hmC staining than epithelioid tumors, in more than 50% of the cases in each group.
  • For telling mesothelioma apart from reactive mesothelial hyperplasia (a non-cancerous condition), 5-hmC staining had a sensitivity of 47% and a specificity of 76%. The authors described this sensitivity as low.
  • Among the mesotheliomas, 5-hmC staining sorted epithelioid tumors from sarcomatoid and biphasic tumors with a sensitivity of 63% and a specificity of 72%.
  • Of 130 samples stained for MTAP protein (the 40 cases plus 90 epithelioid cases), two were negative. The article prints this as 2.22%.
  • 89 FISH results were available, and 6 of these had no data. Of the results, 64 samples showed no deletion of the gene region and 19 showed homozygous deletion.
  • None of the 90 mesothelioma samples tested for methylation showed methylation of the MTAP promoter.
• The authors' conclusion: The authors concluded that MTAP promoter hypermethylation might not be a good biomarker for malignant mesothelioma.
• Limitations the authors state:
  • The small number of sarcomatoid and biphasic samples does not allow broader conclusions.
  • The authors described the MTAP results as preliminary.
  • 16 FISH results showed homozygous deletion even though MTAP protein was present. The authors found this difficult to explain and suggested experimental issues with the FISH probe as one possible reason.
  • The authors could not confirm whether the FISH analysis gave false positive results for deletion.

Topics

Medical terms in this study, explained in our Lexicon: MTAP, Pleural Mesothelioma, Prognosis, Environmental Exposure, Immunohistochemistry, Fluorescence In Situ Hybridization (FISH), Carcinogenesis, Sarcomatoid.

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