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

Abstract

Background: The 2016 World Health Organization (WHO) classification of central nervous system tumors stratifies isocitrate dehydrogenase (IDH)-mutant gliomas into 2 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 the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene homozygous deletion as well as WHO grading criteria (mitoses, microvascular proliferation, and necrosis). In addition, we 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 + 1p/19q codeleted (P = 0.002 for progression-free survival and P < 0.0001 for overall survival) in univariate and multivariate analysis including age, extent of surgery, adjuvant treatment, microvascular proliferation, and necrosis. In both groups, the presence of microvascular proliferation 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 2 broad categories of IDH-mutant gliomas stratified on 1p/19q codeletion and suggests that the grading of these tumors should be refined.

Keywords: CDKN2A homozygous deletion; IDH-mutant; IDH-mutant and 1p/19q codeleted; anaplastic astrocytoma; anaplastic oligodendroglioma; glioblastoma; microvascular proliferation.

Fig. 1

Kaplan–Meier survival curves of the 911 IDH-mutant gliomas. (A) Stratification on the WHO 2016 classification. (B) Stratification on both WHO 2016 classification and CDKN2A status.

Fig. 2

Kaplan–Meier survival curves of the 911 IDH-mutant gliomas stratified on 1p/19q codeletion, pathological criteria, and CDKN2A status. (A) Among IDH-mutant tumors without 1p/19q codeletion and without CDKN2A homozygous deletion (n = 354), the presence of MVP and/or necrosis was associated with shorter PFS (P = 0.04) and OS (P = 0.002), whereas among tumors with CDKN2A homozygous deletion (n = 47), the presence of MVP and/or necrosis was relevant for neither PFS (P = 0.790) nor OS (P = 0.683). (B) Among AO IDH mutant + 1p/19q codeleted without CDKN2A homozygous deletion (n = 450), the presence of MVP and/or necrosis was not relevant for PFS (P = 0.085) but was associated with shorter OS (P = 0.028), whereas among tumors with CDKN2A homozygous deletion (n = 33), the presence of MVP and/or necrosis was relevant for neither PFS (P = 0.739) nor OS (P = 0.114).