Predictive and Prognostic Factors for Gliomas

Codeletion of Chromosome Arms 1p & 19q

The combined loss of one copy of chromosome arms 1p and 19q occurs in the majority of oligodendrogliomas and anaplastic oligodendrogliomas, as well as in an important number of oligoastrocytomas and anaplastic oligoastrocytomas.^[7] It is the consequence of an unbalanced whole-arm translocation between chromosomes 19 and 1 with the loss of the derivative chromosome t(1p;19q).^[8] This signature is a strong prognostic factor and also a predictive factor of response to chemotherapy as well as radiotherapy.^[9]

The codeletion of chromosome 1p and 19q is an early genetic event in oligodendroglial tumorigenesis.^[10] Its predictive impact was first reported by Cairncross et al., demonstrating that the codeletion was a strong predictor of response to the procarbazine, lomustine and vincristine (PCV) regimen and longer progression-free survival in anaplastic oligodendrogliomas.^[9] The 1p/19q codeletion has also been demonstrated to be predictive of a better outcome in patients with oligodendroglial tumors treated with radiotherapy.^[11] In both low-grade and anaplastic oligodendrogliomas, 1p/19q codeletion is predictive of longer progression-free survival and overall survival after chemotherapy, radiotherapy or both. The median survival is 12–15 years in low-grade oligodendrogliomas and more than 7 years in anaplastic oligodendrogliomas with 1p/19q codeletion, versus 5–8 years and 2–3 years, respectively, in the absence of the grade I.^[12–14] Whether 1p/19q loss is predictive for therapy efficacy or merely indicates a different natural history is still unclear and available data are contradictory: on one hand Weller et al. found no difference of outcome according to 1p/19q status in patients with grade II and III oligodendroglial tumors that did not receive radiotherapy and chemotherapy.^[15] On the other hand, Ricard et al. showed that the growth rate is significantly slower in 1p/19q codeletion versus non-codeletion grade II tumors.^[16]

The distinction between complete and partial loss of chromosome 1p is of particular importance owing to their opposite prognostic significance: partial distal deletions of chromosome 1p occur in astrocytic tumors and are associated with a poor outcome, whereas the loss of the whole chromosome 1p – associated with whole 19q deletion – is a common feature of oligodendroglial tumors and predicts favorable outcome in this tumor type.^[17–19] In this context, the choice of techniques to identify the codeletion is particularly crucial: some widely used techniques such as FISH (especially when testing the 1p36 locus alone) or microsatellite markers analysis may fail to specifically distinguish this complete 1p/19q codeletion from partial deletions.^[19] More specific and powerful methods, such as comparative genomic hybridization array or chromosome arm painting, should be preferred to distinguish both types of 1p losses and to identify the t(1q;19p).^[8,20] All previous efforts to identify the putative gene involved in the translocation – including high-density genome mapping – have failed, and the mechanism driving this translocation remains unknown.^[21]

The 1p/19q codeletion is mutually exclusive with TP53 mutation and EGFR amplification,^[22,23] frequently associated with MGMT promoter methylation, and always associated with an IDH1 or IDH2 mutation (see later). MGMT promoter hypermethylation is significantly more frequent and the percentage of methylated CpG sites was significantly higher in 1p/19q codeletion tumors compared with 1p and/or 19q intact tumors.^[24,25] The high frequency of MGMT promoter methylation in 1p/19q codeletion gliomas might partly explain their chemosensitivity. Microarray gene expression demonstrated that 1p/19q codeletion gliomas have a proneural gene-expression profile, which has been associated with a good prognosis in high-grade gliomas.^[26,27] One of the most differentially expressed of these proneural genes was INA, which encodes α-internexin (INA), a neurofilament-interacting protein. In an attempt to identify a simple and reliable marker of 1p/19q codeletion in gliomas, we evaluated the INA expression by immunohistochemistry in a series of 122 gliomas. In oligodendroglial tumors, INA expression is a surrogate marker for 1p/19q codeletion with a specificity of 86%, a sensitivity of 96%, a positive-predictive value of 76% and a negative-predictive value of 98%. In grade III gliomas, similarly to 1p/19q codeletion, positive INA expression was correlated with better progression-free survival (52.6 vs 8.7 months) and overall survival (121.1 vs 31.4 months).^[28]

Because it is a strong prognostic factor in both low-grade and anaplastic oligodendrogliomas, and is predictive of response to both chemo- and radiotherapy, 1p/19q codeletion is currently used as a selection criterion (e.g., the European Organisation for Research and Treatment of Cancer [EORTC] 26053-22054 and the North Central Cancer Treatment Group [NCCTG] N0577 trials in anaplastic gliomas) or stratification criterion (e.g., the EORTC 22033-26033 and the ECOG E3F05 trials in low-grade gliomas) in ongoing clinical trials.

Expert Rev Anticancer Ther. 2011;11(5):781-789. © 2011 Expert Reviews Ltd.

Cite this: Predictive and Prognostic Factors for Gliomas - Medscape - May 01, 2011.