The prognostic significance of CDKN2A homozygous deletion in IDH-mutant lower-grade glioma and glioblastoma: a systematic review of the contemporary literature

Abstract

Background: The most recent cIMPACT-NOW update highlighted the homozygous deletion of the Cyclin Dependent Kinase Inhibitor 2A (CDKN2A) gene as a clinically important molecular alteration in IDH-mutant glioma. Correspondingly, we systematically reviewed the contemporary literature to affirm the contemporary stance of the literature on the prognostic significance of this alteration in this setting based on the current World Health Organization (WHO) Grade classification.

Methods: A systematic search of seven electronic databases from inception to February 2020 was conducted following PRISMA guidelines. Articles were screened against pre-specified criteria to include lower-grade glioma (LGG, WHO Grade II/III) and glioblastoma (GBM, WHO Grade IV) separately. Progression free survival (PFS) and overall survival (OS) from Kaplan-Meier and multivariable analyses were outcomes of interest.

Results: Nine institutional studies describing 2193 IDH-mutant gliomas satisfied criteria for evaluation, with 1756 (80%) LGG and 437 (20%) GBM. When reported, the proportion of CDKN2A homozygous deleted gliomas ranged from 9 to 43%, with a median incidence of 22%. For LGG, Kaplan-Meier analyses demonstrated shorter PFS in the presence of CDKN2A homozygous deletion in three studies (median values, 31 versus 91 months), and shorter OS in five studies (median values, 61 versus 154 months). For GBM, Kaplan-Meier analyses demonstrated shorter PFS in the presence of CDKN2A homozygous deletion in two studies (median values, 16 versus 30 months), and shorter OS in four studies (median values, 38 versus 86 months). By multivariable analyses, CDKN2A homozygous deletion was a predictor of significantly shorter PFS and OS in both LGG and GBM across all included studies.

Conclusions: The CDKN2A homozygous deletion is an important prognostic factor for survival outcomes of IDH-mutant glioma patients across multiple histologic WHO grades with specific molecular features likely dependent on IDH-mutant status. Greater understanding of how identifying this deletion can assist in the stratification of management for these tumors to optimize clinical course is required.

Keywords: CDKN2A; Cyclin; Deletion; Glioblastoma; Glioma; Prognosis; Survival.