Studies have identified several molecular abnormalities with clinical or biological relevance to AOD (e.g. t(1;19)(q10;p10), IDH1, IDH2, CIC and FUBP1 mutations).To better characterize the clinical and biological behavior of this tumor type, the creation of a national multicentric network, named "Prise en charge des OLigodendrogliomes Anaplasiques (POLA)," has been supported by the Institut National du Cancer (InCA).
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.
Univariate analysis was followed by multivariate analysis according to a Cox model. p14(ARF), p16(INK4A) and PTEN expressions, and 10p 10q23, 10q26 and 13q LOH for the entire cohort, hTERT expression for high-grade tumours, EGFR for glioblastomas, 10q26 LOH for grade III tumours and anaplastic oligodendrogliomas were found to be correlated with overall survival on univariate analysis and age and grade on multivariate analysis only.
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.
These findings demonstrate that oligodendroglial neoplasms usually have loss of 1p and 19q whereas astrocytomas of the progressive type frequently contain mutations of the TP53 gene, and that 9p loss and CDKN2A deletions are associated with progression from well-differentiated to anaplastic oligodendrogliomas.
Within the 1p/19q-codeleted AO, the contrast enhancement was associated with larger tumor volumes (P = .001), chromosome 9p loss and CDKN2A loss (P = .006), genomic instability (P = .03), and angiogenesis-related gene expression (P < .001), particularly for vascular endothelial growth factor A and angiopoietin 2.
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 this study, we screened 28 oligodendrogliomas (WHO grade II) and 20 anaplastic oligodendrogliomas (WHO grade III) for alterations in the RB1/CDK4/p16INK4a/p15INK4b and TP53/p14ARF/MDM2 pathways.
The inverse relationship between CDKN2A gene deletions and losses of chromosomes 1p and 19q further implies that these differential clinical behaviors reflect two independent genetic subtypes of anaplastic oligodendroglioma.
CDKN2/p16 expression was frequently decreased in grade II and anaplastic oligodendrogliomas (17/42) where lack of CDKN2/p16 protein predicted poor survival (p = 0.0045).
Subsequent progression of oligodendroglial tumors appears to be triggered by additional molecular features underlying the transition to anaplastic oligodendroglioma and glioblastoma multiforme (GBM) such as deletions of 9p and 10q, and alterations of CDKN2A (p16), which is located at 9p21.
In this study, we screened 28 oligodendrogliomas (WHO grade II) and 20 anaplastic oligodendrogliomas (WHO grade III) for alterations in the RB1/CDK4/p16INK4a/p15INK4b and TP53/p14ARF/MDM2 pathways.
We present the case of a 28-year-old man with an IDH1 and TP53 mutant high grade glioma with abnormalities in chromosomes 1 and 19 suggestive of anaplastic oligodendroglioma that rapidly progressed to widespread metastatic disease.
In addition, in patients with both IDH1 mutation and MGMT methylation, p53 overexpression was a significant poor prognostic factor both in LOs and AOs.
Therefore, we have analyzed molecular genetic alterations involving chromosomes 1p, 10q, and 19q and the TP53 (on chromosome 17p) and CDKN2A (on chromosome 9p) genes, in addition to clinicopathologic features in 39 patients with anaplastic oligodendrogliomas for whom chemotherapeutic response and survival could be assessed.
These findings demonstrate that oligodendroglial neoplasms usually have loss of 1p and 19q whereas astrocytomas of the progressive type frequently contain mutations of the TP53 gene, and that 9p loss and CDKN2A deletions are associated with progression from well-differentiated to anaplastic oligodendrogliomas.
The expression of p53 protein was more frequently observed in patients without a 1p or 19q deletion in anaplastic oligodendrogliomas (P = 0.032, 0.025).
We find evidence of regional mutational heterogeneity in multiple tumors, including mutations in TP53 and RB1 in an anaplastic oligodendroglioma and amplifications in PDGFRA and KIT in two glioblastomas (GBMs).
EGFR gene amplification was found in only one case of anaplastic oligodendroglioma, which additionally showed a deletion/rearrangement at the 5' end of the gene.
To help determine the molecular mechanism behind this prognostic effect, we have conducted genome-wide methylation profiling and determined the MGMT promoter methylation status, 1p19q LOH, IDH1 mutation status, and expression profile on a series of oligodendroglial tumors [anaplastic oligodendrogliomas (AOD) and anaplastic oligoastrocytomas (AOA)] within EORTC study 26951.
YKL-40 expression was higher in GBMs than AOs (P < 0.0001) and among GBMs, YKL-40 expression was lower in tumors with either EGFR amplification (P = 0.005) or elevated EGFR expression (P = 0.001).
Novel MSH6 mutations in treatment-naïve glioblastoma and anaplastic oligodendroglioma contribute to temozolomide resistance independently of MGMT promoter methylation.
The most frequently amplified genes were epidermal growth factor receptor (EGFR) and cyclin-dependent kinase 4/sarcoma amplified sequence (CDK4/SAS) in 17% and 8% of anaplastic oligodendrogliomas, respectively.