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Regulation of KEAP1 expression by promoter methylation in malignant gliomas and association with patient's outcome.

ABSTRACT: In light with the view that KEAP1 loss of function may impact tumour behavior and modify response to chemotherapeutical agents, we sought to determine whether KEAP1 gene is epigenetically regulated in malignant gliomas. We developed a Quantitative Methylation Specific PCR (QMSP) assay to analyze 86 malignant gliomas and 20 normal brain tissues. The discriminatory power of the assay was assessed by Receiving Operating Characteristics (ROC) curve analysis. The AUC value of the curve was 0.823 (95%CI: 0.764-0.883) with an optimal cut off value of 0.133 yielding a 74% sensitivity (95%CI: 63%-82%) and an 85% specificity (95%CI: 64%-95%). Bisulfite sequencing analysis confirmed QMSP results and demonstrated a direct correlation between percentage of methylated CpGs and methylation levels (Spearman's Rho 0.929, P=0.003). Remarkably, a strong inverse correlation was observed between methylation levels and KEAP1 mRNA transcript in tumour tissue (Spearman's Rho -0.656 P=0.0001) and in a cell line before and after treatment with 5-azacytidine (P=0.003). RECPAM multivariate statistical analysis studying the interaction between MGMT and KEAP1 methylation in subjects treated with radiotherapy and temozolomide (n=70), identified three prognostic classes of glioma patients at different risk to progress. While simultaneous methylation of MGMT and KEAP1 promoters was associated with the lowest risk to progress, patients showing only MGMT methylation were the subgroup at the higher risk (HR 5.54, 95% CI 1.35-22.74). Our results further suggest that KEAP1 expression is epigenetically regulated. In addition we demonstrated that KEAP1 is frequently methylated in malignant gliomas and a predictor of patient's outcome.

SUBMITTER: Muscarella LA

PROVIDER: S-EPMC3092680 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Regulation of KEAP1 expression by promoter methylation in malignant gliomas and association with patient's outcome.

Muscarella Lucia Anna LA Barbano Raffaela R D'Angelo Vincenzo V Copetti Massimiliano M Coco Michelina M Balsamo Teresa T la Torre Annamaria A Notarangelo Angelo A Troiano Michele M Parisi Salvatore S Icolaro Nadia N Catapano Domenico D Valori Vanna Maria VM Pellegrini Fabio F Merla Giuseppe G Carella Massimo M Fazio Vito Michele VM Parrella Paola P

Epigenetics 20110301 3

In light with the view that KEAP1 loss of function may impact tumour behavior and modify response to chemotherapeutical agents, we sought to determine whether KEAP1 gene is epigenetically regulated in malignant gliomas. We developed a Quantitative Methylation Specific PCR (QMSP) assay to analyze 86 malignant gliomas and 20 normal brain tissues. The discriminatory power of the assay was assessed by Receiving Operating Characteristics (ROC) curve analysis. The AUC value of the curve was 0.823 (95% ...[more]

PMID: 21173573

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Project description:Purpose:KIT/PDGFRA wild-type (WT) gastrointestinal stromal tumors (GISTs) represent a heterogeneous subgroup of GISTs that lack KIT or PDGFRA mutations and possess distinct genetic alterations and primary resistance to imatinib. Succinate dehydrogenase (SDH)-deficient GISTs comprise the largest subpopulation of WT GISTs that are characterized by loss-of-function of SDH. O6-methylguanine-DNA methyltransferase (MGMT) is a specific DNA repair enzyme that has been identified as a predictor of positive treatment response to alkylating agents in a variety of cancers. The aim of this study was to evaluate the expression of MGMT and the prevalence of MGMT promoter methylation in GISTs and to determine the association between MGMT promoter methylation and clinicopathological characteristics and clinical outcomes. Patients and Methods:A heterogeneous cohort of 137 primary GISTs that confirmed by immunohistochemistry and KIT/PDGFRA mutation analysis were retrospectively selected and analyzed for MGMT expression and MGMT promoter methylation using immunohistochemical staining and methylation-specific PCR (MSP). A concordance analysis between MGMT promoter methylation and clinicopathological characteristics and prognosis was also performed. Results:A total of 44.5% (65/137) of GIST patients displayed loss of MGMT protein expression, and 10.9% (15/137) of these patients exhibited MGMT promoter methylation. However, no significant correlation was observed between the loss of MGMT protein expression and MGMT promoter methylation. WT GISTs possessing an epithelioid or mixed phenotype, particularly those that were SDH-deficient, displayed a markedly higher prevalence of MGMT promoter methylation compared to that in KIT/PDGFRA mutated GISTs. Moreover, MGMT promoter methylation was identified as a potential independent prognostic factor for OS and DFS in patients with GIST. Conclusion:MGMT promoter methylation is particularly frequent in SDH-deficient GISTs and in WT GISTs possessing an epithelioid/mixed phenotype, and knowledge of this methylation status may offer a novel potential therapeutic option for WT GISTs.

Dataset Information

Regulation of KEAP1 expression by promoter methylation in malignant gliomas and association with patient's outcome.

Publications

Regulation of KEAP1 expression by promoter methylation in malignant gliomas and association with patient's outcome.

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