PATH-42. IDH-MUTANT LOWER-GRADE ASTROCYTOMAS CAN BE STRATIFIED FOR RISK BY CDKN2A, CDK4 AND PDGFRA COPY NUMBER ALTERATIONS

Abstract In the 2016 WHO classification of tumors of the CNS, isocitrate dehydrogenase (IDH) mutation is a main classifier for lower-grade astrocytomas and IDH mutated astrocytomas is now regarded as a single group with good prognosis. However, the molecular and clinical heterogeneity among IDH-mutant lower-grade astrocytomas have only rarely been investigated. In this study, we recruited 161 IDH-mutant lower-grade 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 deletion, and CDK4 amplification in 18.6%, 14.9%, and 18.0% of our cohort respectively, and these alterations occurred in a mutually exclusive fashion. PDGFRA amplification was associated with shorter PFS (p< 0.0001) and OS (p< 0.0001). In tumors without PDGFRA amplification, CDKN2A deletion was associated with a shorter PFS (p=0.0332). Tumors were then 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, CDK4 amplification nor PDGFRA amplification). These three risk groups were significantly different in overall survival with mean survivals of 40.2, 62.9, and 71.8 months. The high-risk group also demonstrated a shorter PFS compared to intermediate- (p=0.036) and low-risk (p< 0.0001) groups. Our data illustrate that IDH-mutant lower-grade astrocytomas is not a homogeneous group and should be molecularly stratified for risk.