Molecular genetics of oligodendrogliomas: a model for improved clinical management in the field of neurooncology

Abstract

<jats:p>Over the last several years, oligodendroglial tumors have become a model for the positive role of molecular genetics in improved treatment of patients with brain tumors. Oligodendrogliomas, in contrast to astrocytic gliomas, frequently respond to chemotherapy and have a better overall prognosis. Combined loss of chromosomes 1p and 19q has proven to be a powerful predictor of chemotherapeutic response and survival in oligodendrogliomas. In contrast, other genetic alterations, such as <jats:italic>TP53</jats:italic> and <jats:italic>PTEN</jats:italic> mutations, <jats:italic>EGFR</jats:italic> amplification, and homozygous deletion of <jats:italic>CDKN2A</jats:italic> have been correlated with worse outcome in these tumors. Furthermore, 1p/19q loss has been shown to correlate with unequivocal oligodendroglial tumor histology, location and growth pattern of tumors within the brain, and magnetic resonance imaging characteristics. Although much is also known about the molecular pathological characteristics of astrocytic gliomas, the significance of this information to clinical management in patients with these tumors has not been as striking as has been the case for oligodendrogliomas; possible reasons for this are discussed. In this paper the author will summarize these advances, thus attempting to highlight the molecular genetic study of oligodendrogliomas as a model for improved clinical management in the field of neurooncology.</jats:p>

Molecular pathology in adult gliomas: diagnostic, prognostic, and predictive markers

“…Although the responsible oncogenic genes on 1p and 19q remain unidentified, many correlations have been made regarding 1p/19q loss. For example, 1p/19q deleted tumours frequently show classic histology 13–15. and often have IDH1 and IDH2 mutations 16.…”

“…1p/19q codeleted AO III preferentially display a proneural gene expression profile,17 This profile, which is partly characterized by expression of neuronal genes, is overrepresented among low grade gliomas and may predict for therapeutic response in glioblastoma 18. On the other hand, 1p and 19q loss correlates inversely with TP53 mutations, 10q deletions and amplification of EGFR 13. Tumour location is also associated with 1p/ 19q co-deletions: low grade oligodendroglioma and AO III in the frontal, parietal and occipital lobes are more likely to show loss than tumours involving the temporal lobe, insula and diencephalon 19,20,21…”

Evolvement of Molecular Biomarkers in Targeted Therapy of Malignant Gliomas

“…Furthermore, there are common alterations that are found with 1p/19q co-deletion, such as isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations (Yan et al, 2009). LOH of 1p/19q also has been shown to be mutually exclusive of TP53 mutations, 10q deletion, and amplification of epidermal growth factor receptor (EGFR) (Nutt, 2005). Surprisingly, the location of the tumor site also appears to be associated with 1p/19q co-deletions (Jansen et al, 2010).…”

“…Furthermore, it is believed that the predictive power of MGMT is only for chemotherapy, although this remains a controversial topic as discussed before (Riemenschneider et al, 2010). Moreover, MGMT promoter methylation has been shown to be closely linked to pseudoprogression (Nutt, 2005;Riemenschneider et al, 2010). Although MGMT can be useful as a marker of survival, the current standard of care for GBM does not require knowing MGMT status; however, it may help distinguish between pseudoprogression and true progression (Nutt, 2005;Riemenschneider et al, 2010) as well as possibly determining if a MGMT-specific inhibitor should be combined with the current standard treatment modality.…”

“…Interestingly, LOH at these loci confers a favorable response to chemotherapy, radiation, and survival (Nutt, 2005;Gladson et al, 2010). Exactly how the unidentified genes on chromosomes 1p and 19q contribute to a more favorable therapeutic response remains to be determined.…”