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

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.

Homozygous deletion of CDKN2A by fluorescence in situ hybridization is prognostic in grade 4, but not grade 2 or 3, IDH-mutant astrocytomas

“…5a). Unlike the previously published studies using array-based data [7,10], FISH-based detection of CDKN2A deletion of ≥ 30% did not identify a subset of histologically low-grade tumors with highly aggressive behavior. Only a single grade 2 tumor and a single grade 3 tumor in our cohort would be upgraded under Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy -Not Official WHO (cIM-PACT-NOW) 5/6 criteria [3,12] using a ≥ 30% cutoff, and both patients were still living at the time of analysis, with survival durations of 61 and 47 months, respectively.…”

“…Additionally, some of the morphologic features used to grade IDHwt tumors do a poor job of stratifying IDHm astrocytoma survival, particularly mitotic activity [2][3][4]. To address these shortcomings, a number of groups have investigated molecular correlates of aggressive behavior in IDHm astrocytomas [5][6][7][8][9][10][11]. Based on these studies, homozygous deletion of the CDKN2A gene, which encodes the cell-cycle regulators p16INK4A and p14ARF, has emerged as a leading candidate molecular marker of high-grade behavior in these tumors [3,7,[10][11][12].…”

The Prognostic Value of MRI Subventricular Zone Involvement and Tumor Genetics in Lower Grade Gliomas

“…48 CDKN2A/B deletion has been reported in 40-70% of GBMs, 48,49 and CKDN2A deletion is associated with poorer survival in LGGs, 50 even among IDH-mutant gliomas. 51 As shown in our cohort, mutations in CDK4 and CDKN2A/B were associated with worse survival, suggesting that these mutations likewise make LGGs molecularly high grade.…”

Updating the grading criteria for adult diffuse gliomas: beyond the WHO2016CNS classification

“…They also found that the deletion did not exist in grade II astrocytoma. Although another study by Appay et al confirmed this finding [2], Yang et al identified this homozygous deletion in 12% of grade II tumors [16]. One possible reason for such a discrepancy is that while Shirahata et al [13] used pHH3 antibody, which is sensitive as mentioned above, Yang et al [16] did not; without using pHH3 antibody, they might have identified fewer mitoses, and thus regarded grade III tumors in other studies as grade II ones, resulting in a lower rate of grade III.…”

“…While one study suggested that CDKN2A homozygous deletion is a strong adverse prognostic factor in anaplastic codeleted oligodendroglioma [2], another showed that NOTCH1 mutations were associated with a shorter survival in codeleted oligodendroglioma [1], while no such association was found for CDKN2A alterations. No other studies have confirmed those results or identified biomarkers that can convincingly distinguish lower-and higher-grade oligodendrogliomas [9].…”