Methylation of MGMT in malignant pleural mesothelioma occurs in a subset of patients and is associated with the T allele of the rs16906252 MGMT promoter SNP

Our plain-English summary of Methylation of MGMT in malignant pleural mesothelioma occurs in a subset of patients and is associated with the T allele of the rs16906252 MGMT promoter SNP, by L.S. Kristensen, H.M. Nielsen, H. Hager, et al (Lung Cancer, 2011).

The study

• Authors: L.S. Kristensen, H.M. Nielsen, H. Hager, L.L. Hansen
• Journal: Lung Cancer
• Published: 2011;71(2):130-6
• Cited by: 33 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Silencing of the DNA repair gene O⁶-methylguanine DNA methyltransferase (MGMT) by promoter methylation is an early event in several human cancers. MGMT removes alkyl adducts from the O⁶ position of guanine thereby preventing G>A mutations in the genome. For this reason, MGMT promoter methylation predicts a favorable outcome for glioblastoma patients treated with alkylating agents. In this study, we investigated whether MGMT becomes silenced by promoter methylation in malignant pleural mesothelioma (MPM), an aggressive cancer of the pleura associated with a poor prognosis. Ninety-five samples from patients diagnosed with MPM were studied. These samples were genotyped for the MGMT rs16906252 promoter SNP using high-resolution melting, and methylation status was analyzed using SMART-MSP and confirmed by Sanger sequencing. The SMART-MSP assay was designed to provide information on the allelic methylation status in samples heterozygous for rs16906252. MGMT immunohistochemistry was performed on samples showing no methylation, monoallelic methylation, and biallelic methylation. Thirteen of the 95 MPM samples (13.7%) were methylation positive and a strong association with the T allele of the rs16906252 SNP (P<0.001) was observed. Detection of the protein was found to be dependent not only on the allelic methylation status but also on the methylation level, and complete silencing was observed in only one sample, showing biallelic methylation and a methylation level close to 100%. In conclusion, methylation of the MGMT promoter occurs in a subset of MPM patients and is associated with the T allele of the MGMT rs16906252 SNP. However, complete silencing of MGMT in MPM is a rare event.

Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

In plain English

This Danish laboratory study asked whether the DNA repair gene MGMT is switched off by a chemical tag called promoter methylation in malignant pleural mesothelioma. The authors tested archived tumor biopsies from 95 patients at Aarhus University Hospital (61 epithelial, 12 biphasic and 22 sarcomatous). They also recorded which version, C or T, of a common single-letter DNA variant in the gene (rs16906252) each sample carried. The article did not report the patients' asbestos exposure. Methylation was found in 13 of 95 samples (13.7%), mostly at low levels. It was found in 6 of 80 samples with two C copies, and in 7 of 15 samples carrying at least one T. This association had a p-value below 0.001. The MGMT protein was absent in only one sample, which had both gene copies methylated at a level of 93.3%. All other samples tested still showed the protein. The authors concluded that MGMT methylation occurs in a subset of these patients and is associated with the T allele, but that complete silencing of MGMT in this cancer is rare.

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 (molecular) study of archived tumor samples: genotyping, methylation testing and immunohistochemistry
• Who was studied: Archived surgical biopsy blocks from 95 patients diagnosed with malignant pleural mesothelioma, from the Institute of Pathology, Aarhus University Hospital, Denmark: 61 epithelial, 12 biphasic and 22 sarcomatous types. Dates are not given.
• Exposure: Asbestos exposure was not studied or reported. The factor examined was each patient's genotype at the MGMT rs16906252 promoter SNP (C or T allele).
• Main results:
  • Of the 95 samples, 80 had two copies of the C allele, 14 were heterozygous (C/T) and 1 had two copies of the T allele.
  • 13 of 95 mesothelioma samples (13.7%) were positive for MGMT methylation.
  • Methylation was positive in 6 of 80 C/C samples (7.5%), 6 of 14 C/T samples (42.9%), 1 of 1 T/T sample, and 7 of 15 samples carrying a T allele (46.7%).
  • People carrying the T allele were more likely to have detectable MGMT methylation (p less than 0.001).
  • Methylation was found predominately at low levels.
  • No correlation was found between mesothelioma subtype and methylation status (data not shown).
  • Sample 13 had both alleles methylated at a level of 93.3% and was negative for MGMT protein on immunohistochemistry.
  • Sample 28 had only the T allele methylated, at a level of 35.4%, and was positive for MGMT protein.
  • All unmethylated samples tested, and all samples methylated at low levels, stained positive for MGMT protein.
• The authors' conclusion: The authors concluded that MGMT promoter methylation occurs in a subset of malignant pleural mesothelioma patients and is associated with the T allele of the rs16906252 SNP, but that complete silencing of MGMT in this cancer is a rare event.
• Limitations the authors state:
  • The authors stated that they cannot exclude that the rs16906252 SNP is closely linked to another DNA variant that is actually responsible for the T allele's greater tendency to become methylated.
  • At very low methylation levels the test sometimes failed to detect the C allele (allelic drop-out) in some replicates; the authors confirmed allelic status by repeating the analysis and by sequencing.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Pleura, Prognosis, Immunohistochemistry.

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• Aberrant methylation of the CDKN2a/p16INK4a gene promoter region in preinvasive bronchial lesions: a prospective study in high-risk patients without invasive cancer — A. Lamy, R. Sesboüé, et al. (2002)
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