Molecular classification of low-grade diffuse gliomas

Abstract

The current World Health Organization classification recognizes three histological types of grade II low-grade diffuse glioma (diffuse astrocytoma, oligoastrocytoma, and oligodendroglioma). However, the diagnostic criteria, in particular for oligoastrocytoma, are highly subjective. The aim of our study was to establish genetic profiles for diffuse gliomas and to estimate their predictive impact. In this study, we screened 360 World Health Organization grade II gliomas for mutations in the IDH1, IDH2, and TP53 genes and for 1p/19q loss and correlated these with clinical outcome. Most tumors (86%) were characterized genetically by TP53 mutation plus IDH1/2 mutation (32%), 1p/19q loss plus IDH1/2 mutation (37%), or IDH1/2 mutation only (17%). TP53 mutations only or 1p/19q loss only was rare (2 and 3%, respectively). The median survival of patients with TP53 mutation ± IDH1/2 mutation was significantly shorter than that of patients with 1p/19q loss ± IDH1/2 mutation (51.8 months vs. 58.7 months, respectively; P = 0.0037). Multivariate analysis with adjustment for age and treatment confirmed these results (P = 0.0087) and also revealed that TP53 mutation is a significant prognostic marker for shorter survival (P = 0.0005) and 1p/19q loss for longer survival (P = 0.0002), while IDH1/2 mutations are not prognostic (P = 0.8737). The molecular classification on the basis of IDH1/2 mutation, TP53 mutation, and 1p/19q loss has power similar to histological classification and avoids the ambiguity inherent to the diagnosis of oligoastrocytoma.

Figure 1

Age distribution of patients with and without IDH1/2 mutations in low-grade diffuse gliomas. Note that low-grade diffuse gliomas without IDH1/2 mutations develop in younger patients (mean, 42.1 versus 35.8 years; P = 0.0017).

Figure 2

Upper panel: The survival of patients with diffuse astrocytoma is significantly shorter than that of patients with oligodendroglioma (left). This difference was also clearly observed when tumors were classified genetically (right). Lower panel: Patients with diffuse astrocytoma and those with low-grade diffuse glioma carrying TP53 mutation + IDH1/2 mutation have very similar survival (left). Patients with oligodendroglioma and those with low-grade diffuse glioma carrying 1p/19q loss + IDH1/2 mutation have very similar survival (right).