The tumoral A genotype of the MGMT rs34180180 single-nucleotide polymorphism in aggressive gliomas is associated with shorter patients' survival.

Abstract

Malignant gliomas are the most common primary brain tumors. Grade III and IV gliomas harboring wild-type IDH1/2 are the most aggressive. In addition to surgery and radiotherapy, concomitant and adjuvant chemotherapy with temozolomide (TMZ) significantly improves overall survival (OS). The methylation status of the O(6)-methylguanine-DNA methyltransferase (MGMT) promoter is predictive of TMZ response and a prognostic marker of cancer outcome. However, the promoter regions the methylation of which correlates best with survival in aggressive glioma and whether the promoter methylation status predictive value could be refined or improved by other MGMT-associated molecular markers are not precisely known. In a cohort of 87 malignant gliomas treated with radiotherapy and TMZ-based chemotherapy, we retrospectively determined the MGMT promoter methylation status, genotyped single nucleotide polymorphisms (SNPs) in the promoter region and quantified MGMT mRNA expression level. Each of these variables was correlated with each other and with the patients' OS. We found that methylation of the CpG sites within MGMT exon 1 best correlated with OS and MGMT expression levels, and confirmed MGMT methylation as a stronger independent prognostic factor compared to MGMT transcription levels. Our main finding is that the presence of only the A allele at the rs34180180 SNP in the tumor was significantly associated with shorter OS, independently of the MGMT methylation status. In conclusion, in the clinic, rs34180180 SNP genotyping could improve the prognostic value of the MGMT promoter methylation assay in patients with aggressive glioma treated with TMZ.

• Authors: Anne Fogli, Emmanuel Chautard, Catherine Vaurs-Barrière, Bruno Pereira, Mélanie Müller-Barthélémy, Franck Court, Julian Biau, Afonso Almeida Pinto, Jean-Louis Kémény, Toufic Khalil, Lucie Karayan-Tapon, Pierre Verrelle, Bruno Marques Costa, Philippe Arnaud
• Journal: Carcinogenesis (Carcinogenesis) Vol. 37 Issue 2 Pg. 169-176 (Feb 2016) ISSN: 1460-2180 [Electronic] England
• PMID: 26717998 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Tumor Suppressor Proteins
• DNA Modification Methylases
• MGMT protein, human
• DNA Repair Enzymes

Topics

• Adult
• Brain Neoplasms (genetics, mortality, pathology)
• DNA Methylation (genetics)
• DNA Modification Methylases (genetics)
• DNA Repair Enzymes (genetics)
• Female
• Genotype
• Glioma (genetics, mortality, pathology)
• Humans
• Kaplan-Meier Estimate
• Male
• Polymerase Chain Reaction
• Polymorphism, Restriction Fragment Length
• Polymorphism, Single Nucleotide
• Prognosis
• Promoter Regions, Genetic (genetics)
• Proportional Hazards Models
• Retrospective Studies
• Tumor Suppressor Proteins (genetics)