BI-06 * ATRX LOSS IN CHINESE ADULT DIFFUSE ASTROCYTOMAS CORRELATES WITH IDH1 AND TP53 MUTATION AND PREDICTS BETTER OUTCOME IN TP53 MUTATED PATIENTS

Abstract

The mutation or loss of the ATRX gene was documented in World Health Organization grade 2 to 4 astrocytic tumors and might indicate better prognosis in anaplastic astrocytomas. Astrocytomas with mutation/loss of ATRX also frequently had mutations in IDH1 and TP53. However, the relationships among ATRX alterations, TP53 and IDH1 mutations, as well as MGMT hypermethylation in Chinese adult astrocytomas, as well as their prognosis value are not yet well understood. In this study, we explored potential links between ATRX, MGMT, IDH1 and TP53 in 160 adult astrocytic tumors from Chinese patients. We also investigated the prognosis value of ATRX status, with or without TP53, IDH1 and MGMT alterations. Our results showed that loss of ATRX expression was detected in 18.1% of tumors by immunohistochemistry (IHC), and showed a distinct age dependence. The alterations occurred far less frequently in primary glioblastoma than in grade 2, 3 astrocytomas and grade 4 secondary glioblastoma (p = 0.0002). Nuclei accumulation of TP53 protein was identified in 32.9% (24/73) cases by IHC. Methylation specific polymerase chain reaction analysis showed that 59.8% of the astrocytomas (55/92) harbored hypermethylated MGMT. Direct sequencing and/or IHC analysis of IDH1 demonstrated that 27.7% of astrocytomas (44/159) carried the IDH1R132H mutation. In addition, ATRX loss was observed much more frequently in astrocytic tumors with mutations of IDH1 and TP53 than in tumors expressing wild-type IDH1 (p < 0.0001) and TP53 (p = 0.0007), respectively. Survival analysis revealed TP53 mutated patients carrying ATRX loss had a significantly longer progression-free survival (PFS) and overall survival (OS) than those with wild-type ATRX. In conclusions our data show that loss of ATRX expression is closely linked with IDH1 and TP53 mutation. Furthermore, ATRX loss predicts better clinical outcome in astrocytic tumors carrying mutated TP53. These results lead to a more detailed molecular classification of astrocytomas and improved prediction of patient outcome.