CDKN2A homozygous deletion is a strong adverse prognosis factor in diffuse malignant IDH-mutant gliomas

Abstract

Abstract Background The 2016 WHO classification of the central nervous system tumors stratifies IDH-mutant gliomas into two major groups depending on the presence or absence of 1p/19q-codeletion. However, the grading system remains unchanged and it is now controversial whether it can be still applied to this updated molecular classification. Methods In a large cohort of 911 high grade IDH-mutant gliomas from the French national POLA network (including 428 IDH-mutant gliomas without 1p/19q-codeletion and 483 anaplastic oligodendrogliomas, IDH-mutant and 1p/19q-codeleted), we investigated the prognostic value of CDKN2A gene homozygous deletion as well as WHO grading criteria (mitoses, microvascular proliferation and necrosis). In addition, we also searched for other retinoblastoma pathway gene alterations (CDK4 amplification and RB1 homozygous deletion) in a subset of patients. CDKN2A homozygous deletion was also searched in an independent series of 40 grade II IDH-mutant gliomas. Results CDKN2A homozygous deletion was associated with dismal outcome among IDH-mutant gliomas lacking 1p/19q-codeletion (p<0.0001 for progression-free survival and p=0.004 for overall survival) as well as among anaplastic oligodendrogliomas, IDH-mutant and 1p/19q-codeleted (p=0.002 for progression-free survival and p<0.0001 for overall survival) in univariate and multivariate analysis including age, extend of surgery, adjuvant treatment, MVP and necrosis. In both groups, the presence of microvascular proliferation (MVP) and/or necrosis remained of prognostic value only in cases lacking CDKN2A homozygous deletion. CDKN2A homozygous deletion was not recorded in grade II gliomas. Conclusions Our study pointed out the utmost relevance of CDKN2A homozygous deletion as an adverse prognostic factor in the two broad categories of IDH-mutant gliomas stratified on 1p/19q-codeletion and suggest to refine the grading of these tumors.