Diagnostic and prognostic value of alpha internexin expression in a series of 409 gliomas

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Abstract

The neuronal intermediate filament alpha internexin (INA) is expressed in most gliomas with 1p19q codeletion and could represent a valuable prognostic marker in clinical routine. INA expression was analysed on 409 gliomas and correlated with histology, progression free survival (PFS), overall survival (OS), genomic profile assessed by CGH-array, IDH1/IDH2 mutation and p53 expression. INA was expressed in 59% of grade II oligodendrogliomas (n = 73), 45% of grade III oligodendrogliomas (n = 133), 15% of grade II oligoastrocytomas (n = 61), 12% of grade III oligoastrocytomas (n = 41), 23% of glioblastomas with oligodendroglial component (n = 31), 0% of grade I astrocytomas (n = 3), 0% of grade II astrocytomas (n = 14), 6% of grade III astrocytomas (n = 17) and 0% of glioblastomas (n = 36). INA expression was detected in 85% of gliomas with complete 1p19q codeletion (‘true 1p19q signature’) (n = 85) versus 15% of gliomas without 1p19q codeletion (n = 245), including 14% of gliomas with variable/partial 1p19q deletion (‘false 1p19q signature’) (n = 72) (p < 0.0001). INA was expressed by 43% of gliomas with IDH1 mutation (n = 197) versus 12% of gliomas without IDH1 mutation (n = 156) (p < 0.0001). In oligodendroglial gliomas (n = 240), INA expression specificity for 1p19q codeletion was 80%, sensitivity 85%, positive predictive value 70%, and negative predictive value was 91%. Combining INA and p53 expressions improved INA predictive accuracy for 1p19q codeletion. In grade III gliomas, INA expression was associated with longer PFS (42.1 versus 10.2 months, p = 0.0007) and longer OS (124.6 versus 20.6 months, p = 0.0001). In conclusion, INA expression is a fast, cheap and reliable prognostic marker, and represents a surrogate marker for 1p19q complete codeletion.

Introduction

Current histological classification of gliomas is still based on subjective criteria – both for phenotype determination and grading. It lacks reproducibility and precision in terms of prognosis, particularly for grade II/III gliomas. Genetic subtyping of a given histological phenotype and robust biomarkers has improved the prognostic assessment: the chromosome arms 1p/19q codeletion characterises a subtype of oligodendroglial tumours with better prognosis and higher chemosensitivity.1, 2 More recently, IDH1 (more rarely IDH2) mutations have been found in nearly 40% of gliomas and strongly predict better outcomes.3, 4, 5, 6, 7 Using gene expression arrays we have shown that 1p19q codeleted gliomas (mostly oligodendrogliomas) express preferentially neural genes. We found that alpha internexin (INA) was one of the most differentially expressed genes between 1p19q codeleted and EGFR amplified gliomas.8 INA is a proneural gene located on 10q24.33, encoding a neurofilament interacting protein. A retrospective study on 112 gliomas has shown that INA expression was tightly related to 1p19q codeletion and was also predictive of good outcome in anaplastic oligodendrogliomas (OIII) and anaplastic oligoastrocytomas (OAIII).9 The aim of the present study was to assess the diagnostic and prognostic value of INA expression in a series of 409 adult gliomas.

Section snippets

Materials and methods

INA immunohistochemistry was performed on histological sections of formalin-fixed paraffin-embedded tumor samples in a series of 409 adult patients with gliomas, which included the previously published 112 cases.9 The clinical annotations were retrieved from the database of the Pitié-Salpêtrière neurooncology department. Patients provided written informed consent for this study.

INA immunohistochemistry was carried out on 3 μm thick paraffin embedded sections of formalin-fixed tumor samples using

Results

The histology, INA expression, 1p19q codeletion status, IDH1 mutation status and p53 expression of the 409 gliomas are reported in Table 1. INA expression was detected in 59% of grade II oligodendrogliomas (OII), 45% of grade III oligodendrogliomas (OIII), 15% of grade II oligoastrocytomas (OAII), 12% of grade III oligoastrocytomas (OAIII), 23% of glioblastomas with an oligodendroglial component (GBMO), 0% of grade I astrocytomas (AI), 0% of grade II astrocytomas (AII), 6% of grade III

Discussion

The 1p19q codeletion, the MGMT promoter methylation and the IDH1 mutation are currently the most important prognostic biomarkers in adult gliomas. However, their assessment requires molecular biology techniques that in contrast to immunohistochemistry are not available worldwide and not always feasible. The present study of 409 gliomas confirms our preliminary results showing that INA expression is tightly related to oligodendroglial histology and to 1p19q codeletion.9 The 1p19q codeletion is

Conflict of interest statement

None declared.

Acknowledgement

Study supported by a grant of the Cancéropôle Ile-de-France.

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