Analysis of IDH mutation, 1p/19q deletion, and PTEN loss delineates prognosis in clinical low-grade diffuse gliomas

Abstract

Background: Grades II and III gliomas have unpredictable rates of progression, making management decisions difficult. Currently, several clinical and radiological characteristics are utilized to predict progression and survival but collectively are suboptimal.

Methods: In this study, we analyzed a set of 108 nonenhancing hemispheric grade II-III gliomas. Demographic variables, including patient age, tumor diameter, extent of resection, and performance status, were combined with molecular data (IDH mutation status [mIDH], 1p/19q codeletion, PTEN deletion, and EGFR amplification). A complete dataset for all variables was compiled for 70 of the 108 patients. Both univariable and multivariable analyses were performed to determine whether the molecular data singly or in combination offer advantages over tumor type and grade for prediction of overall survival (OS) and/or progression-free rate (PFR).

Results: Patient age, clinical variables (tumor diameter, extent of resection, performance status), and pathology (tumor type and grade) were not predictive of OS or PFR. IDH mutation status alone was predictive of longer OS and PFR for the entire group of tumors; 1p/19q deletion alone was predictive of OS but not PFR. In the multivariable analysis, none of the clinical or demographic factors were predictive of OS or PFR. IDH mutation status, 1p/19q codeletion, and PTEN deletion were predictive of OS (P = .003, P = .005, P = .02, respectively). Both mIDH (P < .001) and the interaction term of 1p/19q and PTEN (P < .001) were found to be predictive of PFR.

Conclusions: We conclude that the combination of mIDH, 1p/19q codeletion, and PTEN deletion may be particularly effective in discriminating good prognosis from poor prognosis hemispheric gliomas. We propose that such a scheme merits testing on larger prospective cohorts. Should our findings be confirmed, routine clinical analysis of hemispheric gliomas for mIDH, 1p/19q codeletion, and PTEN deletion would be justified.

Fig. 1.

Pathology, immunohistochemistry, and sequence analysis. (A) Montage of hematoxylin/eosin sections (40×) of low-grade gliomas: AII, OII, OAII, AIII, OAIII, and anaplastic oligodendroglioma grade III. Inserts in the OAII and OAIII tumors show regions of astrocytoma in these mixed gliomas. (B) Immunohistochemistry for mutant R132H-mIDH1, with monoclonal mutation specific R132H-mIDH1antibody (top), and corresponding sequencing histograms (bottom) on: (B1) AII astrocytoma negative for the mutant R132H-mIDH1 by immunohistochemistry with sequence histogram demonstrating wild type CGT peak only; (B2) AII astrocytoma with cytoplasmic staining detected by the mutant specific monoclonal antibody against R132H-mIDH1. Corresponding sequence histogram shows 2 equal peaks comprising wild type peak CGT and mutant CAT in codon 132, indicative of CGT to CAT mutation in one allele and amino acid exchange from arginine to histidine and expression of the mutant R132H-mIDH1; (B3) OII oligodendroglioma with equal levels of CGT and mutant GGT in codon 132 as per sequencing data. This results in arginine to glycine exchange and expression of mutant R132G from one allele not detected by the R132H-mIDH1antibody; (B4) AIII anaplastic astrocytoma with mutant IDH2 at R172. Equal amounts of wild type AGG and mutant AAG by sequencing histogram results in arginine to glycine exchange (R172G) by one allele, which is not detected by the R132H-­mIDH1 antibody.

Fig. 2.

Survival as a function of age and tumor diameter. Patient age at time of diagnosis is not associated with either OS (A) or PFR (B). Average tumor diameter ≤4 cm is significantly associated with longer OS (C) but not associated with PFR (D).

Fig. 3.

Survival as a function of performance status and extent of resection. Neither preoperative KPS (A and B) nor extent of resection (C and D) were predictive of OS or PFR.

Fig. 4.

Survival as a function of pathology and mIDH. Tumor pathology (both type and grade) failed to predict either OS (A) or PFR (B). When mIDH is defined as the combination of tumors that are R132H-mIDH1 by immunohistochemistry in addition to those that are mIDH by sequencing, the group of mIDH tumors shows significantly longer OS (C) and PFR (D) than the group of wild-type IDH tumors.

Fig. 5.

Survival as a function of 1p/19q deletion and PTEN deletion. There was a significant difference in OS (A) and a near significant difference in PFR (B) between cases based on 1p/19q deletion. PTEN deletion alone is not predictive of OS or PFR.

Fig. 6.

Survival as a function of multivariate analysis. Cox regression analysis was applied to both OS and PFR statistics. For OS, high- and low-risk groups were constructed from IDH, PTEN, and 1p/19q data. The Kaplan–Meier curve for those groups is shown in (A). The Kaplan–Meier curve of PFR for high- and low-risk groups is shown in (B).