IDH mutant lower grade (WHO Grades II/III) astrocytomas can be stratified for risk by CDKN2A, CDK4 and PDGFRA copy number alterations

Abstract

In the 2016, WHO classification of tumors of the central nervous system, isocitrate dehydrogenase (IDH) mutation is a main classifier for lower grade astrocytomas and IDH-mutated astrocytomas is now regarded as a single group with longer survival. However, the molecular and clinical heterogeneity among IDH mutant lower grade (WHO Grades II/III) astrocytomas have only rarely been investigated. In this study, we recruited 160 IDH mutant lower grade (WHO Grades II/III) astrocytomas, and examined PDGFRA amplification, CDKN2A deletion and CDK4 amplification by FISH analysis, TERT promoter mutation by Sanger sequencing and ATRX loss and p53 expression by immunohistochemistry. We identified PDGFRA amplification, CDKN2A homozygous deletion and CDK4 amplification in 18.8%, 15.0% and 18.1% of our cohort respectively, and these alterations occurred in a mutually exclusive fashion. PDGFRA amplification was associated with shorter PFS (P = 0.0003) and OS (P < 0.0001). In tumors without PDGFRA amplification, CDKN2A homozygous deletion or CDK4 amplification was associated with a shorter OS (P = 0.035). Tumors were divided into three risk groups based on the presence of molecular alterations: high risk (PDGFRA amplification), intermediate risk (CDKN2A deletion or CDK4 amplification) and low risk (neither CDKN2A deletion and CDK4 amplification nor PDGFRA amplification). These three risk groups were significantly different in overall survival with mean survivals of 40.5, 62.9 and 71.5 months. The high-risk group also demonstrated a shorter PFS compared to intermediate- (P = 0.036) and low-risk (P < 0.0001) groups. One limitation of this study is the relatively short follow-up period, a common confounding factor for studies on low-grade tumors. Our data illustrate that IDH mutant lower grade astrocytomas is not a homogeneous group and should be molecularly stratified for risk.

Keywords: CDK4 amplification; CDKN2A deletion; IDH mutant astrocytomas; PDGFRA amplification.

Figure 1

Kaplan–Meier survival curves of TERTp mutation, ATRX loss and p53 accumulation. TERTp mutation had no clinical impact on (A) PFS and (B) OS. ATRX loss was not associated with (C) PFS and (D) OS. P53 accumulation was not associated with (E) PFS and (F) OS. The hash marks represent censored patients.

Figure 2

Kaplan–Meier survival curves of PDGFRA amplification, CDKN2A deletion and CDK4 amplification. Alteration in PDGFRA (a member in the RTK‐PI3K‐mTOR pathway) was associated with shorter (A) PFS (P < 0.0001) and (B) OS (P < 0.0001). Alteration in CDKN2A or CDK4 (members in the RB pathway) showed a trend toward a poorer (C) PFS (P = 0.077) and was associated with a shorter (D) OS (P = 0.035).

Figure 3

Summary of clinical data and molecular characteristics of low‐, intermediate‐ and high‐risk groups. IDH mutant lower grade (WHO Grades II/III) astrocytomas were divided into three groups according to PDGFRA, CDKN2A and CDK4 alterations. The high‐risk group was assigned to tumors carrying PDGFRA amplification (n = 30). The intermediate‐risk group was assigned to tumors showing CDKN2A homozygous deletion or CDK4 amplification (n = 53). The low‐risk group was assigned to tumors showing no change in PDGFRA, CDKN2A and CDK4 (n = 78).

Figure 4

Risk stratification of IDH mutant lower grade astrocytomas based on molecular markers. Kaplan–Meier survival curves of molecular‐based risk group for (A) PFS and (B) OS. Green, orange and red lines represent survival curves for low‐, intermediate‐ and high‐risk groups respectively. Patients with PDGFRA amplification representing a change in the RTK‐PI3K‐mTOR pathway were assigned to high‐risk group. Patients with CDKN2A deletion or CDK4 amplification representing a change in the RB pathway were grouped into intermediate‐risk group. Patients without PDGFRA, CDKN2A and CDK4 aberrations were grouped into low‐risk group. These three risk groups had distinct PFS (P < 0.001) and OS (P < 0.001).