PL1.1 CDKN2A homozygous deletion is a strong adverse prognosis factor in diffuse malignant IDHmutant gliomas

Abstract

The 2016 WHO classification of the central nervous system tumors stratifies diffuse adult gliomas into three major groups depending on the presence or absence of two main genetic alterations: IDH mutation and 1p/19q-codeletion. However, the grading system initially based on histological criteria remains unchanged and it is now controversial whether it can be still applied to this updated molecular classification. Therefore, in a large cohort of 911 high grade IDH-mutant gliomas from the French national POLA network, we investigated the prognostic value of pathological criteria (mitoses, microvascular proliferation and necrosis) as well as CDKN2A gene homozygous deletion, with the aim to highlight a new grading approach for these tumors. We analyzed 212 anaplastic astrocytoma (AA), IDH-mutant, 216 glioblastoma (GB), IDH-mutant and 483 anaplastic oligodendroglioma (AO), IDH-mutant and 1p/19q-codeleted. In this series, the 2016 WHO integrated diagnosis was of prognostic value for progression free survival (PFS) and overall survival (OS) (p<0.0001 for both). CDKN2A homozygous deletion was associated with worse outcome among gliomas lacking 1p/19q-codeletion (p<0.0001 for PFS and p=0.004 for OS) as well as among AO, IDH-mutant and 1p/19q-codeleted (p=0.002 for PFS and p<0.0001 for OS). In both groups, the presence of microvascular proliferation and/or necrosis remained of prognostic value only in cases lacking CDKN2A homozygous deletion, whereas its prognostic value was lost in the subgroup of gliomas presenting with CDKN2A homozygous deletion. Thereby, 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 as well as the prognostic relevance of microvascular proliferation (associated or not to necrosis) among tumors lacking this alteration. We believe that these prognostic factors could be of great interest for a future grading approach of IDH-mutant gliomas.

Beyond IDH-Mutation: Emerging Molecular Diagnostic and Prognostic Features in Adult Diffuse Gliomas

“…These tumors have more frequent instances of chromothripsis [52,67], increased frequency of mutation in genes responsible for overall genomic stability [52], and increased frequency of CDK4 and CDKN2A/B alterations than their IDH-mutant lower-grade glioma counterparts, which corresponds to their worse clinical outcomes in terms of PFS and OS, but unlike within the lower-grade cohorts, we found no statistically significant prognostic effect of harboring these alterations in GBM [52]. Other groups have shown that MET amplification, PDGFRA amplification, and CDKN2A deletion are associated with poor prognosis within some IDH-mutant GBM cohorts [47,72,75,94]. Additional less-studied proposed factors include nuclear transcription factors that regulate cellular defense against oxidative damage, such as SNRX1, NRF2, and DJ2, which may have prognostic implications in IDH-mutant GBM cohorts in addition to IDH-mutant lower-grade astrocytomas [55].…”

“…Relatively frequent gains in 7p and 11p as well as losses in 14q and 15q were associated with worse outcome and tumor progression, as were alterations in the Notch pathway and PI3K-AKT pathway, NOTCH1, PIK3CA, PIK3R1, and ARID1A [36,45,93]. Like their astrocytic counterparts, homozygous loss of CDKN2A has also been associated with poor outcomes in patients with anaplastic oligodendroglioma [94]. A number of studies have also shown that the polysomy of chromosomes 1 and 19 (defined as >2 signals detected by FISH for both 1q and 19p in 1p/19q co-deleted tumors) was associated with higher histologic grade, earlier recurrence, and worse patient outcomes compared to oligodendrogliomas without polysomy, although the negative impact on overall survival was not seen in all studies [95][96][97][98].…”

“…Homozygous deletion is correlated with worse outcome in anaplastic oligodendrogliomas [94] ARID1, NOTCH1, PIK3CA, and PIK3R1…”

“…Homozygous deletion is correlated with worse clinical outcome, especially when combined with MET amplification [47,72,94] NOTE: Molecular alterations in white: Definitional; green: Overall positive effect on prognosis; red: Overall negative effect on prognosis.…”

The prognostic significance of p16 expression pattern in diffuse gliomas

“…In the previous literature, there were inconsistent findings on whether a CDKN2A homozygous deletion was associated with poor survival in IDH-mutant and 1p/19q-codeleted ODGs [4,8,28]. Similarly, our study did not show any prognostic significance of p16 protein loss in ODG.…”