MOLECULAR-BASED GRADING IN IDH-MUTANT LOWER GRADE GLIOMAS

Abstract

BACKGROUND: As diffuse grade II-III gliomas are further characterized using genome-wide studies, additional markers could be used clinically to stratify patients into distinct risk groups A rational grading system for lower grade gliomas might account for IDH status, since this marker defines 2 biologic groups of diffuse gliomas. Methylation profiling using the Illumina 450k array provides a source of possible biomarkers for patient outcome. This study examined factors associated with prognosis in IDHmut tumors from the TCGA LGG study. METHODS: Illumina 450k data and associated clinical were available on 164 cases in the TCGA LGG study. Average beta-values in clinically favorable versus unfavorable outcome patients for progression-free and overall survival (using cutoffs of 2 years and 5 years, respectively) were calculated from the highly variable CpG sites among the 164 samples. Approximately 800 CpG sites showed a fold change of >1.5 or 0.2 for both). A score from the 38 markers was calculated and high methylation score-cases showed improved outcome compared to low methylation score-cases for both PFS (7.1 years vs. 3.1 years) and OS (9.0 years vs. 4.5 years, both p < 0.01, log rank). In multivariate analysis, methylation score remained significantly associated with outcome (p < 0.01) after adjustment for patient age and 1p/19q status. Interestingly, the prognostic methylation score derived from IDHmut cases was not prognostic when applied to IDHwt cases. CONCLUSIONS: WHO histologic grade (II vs. III) may not be optimal for IDHmut diffuse gliomas, indicating a need for alternative modalities to stratify patients into clinically distinct risk groups. Genome-wide studies, including Illumina 450k data offer a promising source of markers. As more cases and data are analyzed, additional markers will be identified from TCGA data and this study provides proof-of-principle that set of markers from can be identified that stratifies distinct risk groups of patients with IDHmut tumors. Future stratification of diffuse gliomas into clinical risk groups should account for distinct biologic subtypes based on early genetic lesions such as IDH status. SECONDARY CATEGORY: n/a.