In 9p non-deleted oligodendrogliomas, p16 hyperexpression correlated with a shorter OS (p = 0.02 in OII and p = 0.0001 in OIII) whereas lack of p16 expression was correlated to a shorter EFS and OS in 9p deleted OIII (p = 0.001 and p = 0.0002 respectively).
Tumor types were characterized by specific broad and focal chromosomal events including focal loss of the INK4A/B locus in glioblastoma and loss of the RB1 gene and amplification of the PDGFRA gene in oligodendrogliomas.
Whole arm 1p19q co-deletion was present in three cases from adolescent patients and 9p loss in 3, including one low-grade oligodendroglioma with CDKN2A homozygous deletion.
After adjustment for IDH mutation, sex, and age, CDKN2A deletion was strongly associated with poorer overall survival in astrocytomas but not in oligodendrogliomas or oligoastrocytomas.
In the present study, array comparative genomic hybridization (CGH) in 15 triple-negative WHO grade II gliomas (eight diffuse astrocytomas and seven oligodendrogliomas) showed loss at 9p21 (p14(ARF) , p15(INK4b) , p16(INK4a) loci) and 13q14-13q32 (containing the RB1 locus) in three and two cases, respectively.
Because the INK4a-ARF locus is often deleted in high-grade gliomas (anaplastic oligodendroglioma and glioblastoma), we investigated the effect of the Ink4a-Arf-null background on IGFBP2-mediated progression of PDGFB-initiated oligodendroglioma.
Combined loss of 1p and 19q was found in 38 of 56 (67.9%) and exhibited distinct concomitant deletion (P = 0.000). p53 overexpression was observed in 17 cases (30.3%), GFAP expression in 18 cases (32.1%), and p16 loss in 40 cases (74%) of oligodendrogliomas.
Our data suggest that in classic oligodendrogliomas: 1) 1p/19q tumor status is a powerful predictor of patient survival, even after recurrence; 2) p16 deletions are common progression-associated alterations; and 3) 10q deletions and EGFR amplifications are sufficiently rare to suggest the possibility of alternate diagnoses.
Finally, as CDKN2A (epi)genetic alterations were found in 71% of the 1p/19q/9p-deleted oligodendrogliomas, CDKN2A may have a role in oligodendroglioma-associated microvascular proliferation.
The latter finding could be in line with the observation that CDKN2A/p16 inactivation is a step in the molecular pathway to tumor progression in oligodendrogliomas.
These data suggest that aberrant p14ARF expression due to hypermethylation is the earliest INK4a/ARF change in the evolution of oligodendrogliomas, while the presence of p14ARF and p16INK4a deletions indicates progression to anaplastic oligodendroglioma.
A mutual exclusion was found between LOH 1p/19q and EGFR amplification (p = 0.01), P16/CDKN2A deletions (p = 0.001), or LOH on 10q (p = 0.03), suggesting the existence of distinct genetic subsets in oligodendrogliomas.
CDKN2A HD did not correlate with histological grading (p = n.s.); however, it showed a correlation with survival (p = 0.03), supporting an important role of CDKN2A in the prognosis of oligodendrogliomas.
Loss of 9p or homozygous deletion of the CDKN2 gene or both are associated with anaplastic oligodendrogliomas, whereas loss of 17p or TP53 gene mutations or both are frequent in astrocytomas, but rare in oligodendrogliomas.
According to our findings CDKN2/p16 immunocytochemistry could be used as a tool to identify those oligodendrogliomas and low grade astrocytomas that are likely to progress and have poor outcome, and thus would need more aggressive therapy.