BIOM-48. HOXD12 IS AN INDEPENDENTLY PROGNOSTIC AGE-ASSOCIATED INDICATOR FOR POOR SURVIVAL IN OLIGODENDROGLIOMA

Abstract

Abstract BACKGROUND Oligodendroglioma, IDH-mutant and 1p/19q-codeleted has variable outcomes that are strongly influenced by patient age. This study aimed to discover novel molecular biomarkers that may characterize an aggressive subgroup of oligodendroglioma that is associated with, but independently prognostic of patient age. METHODS Differential gene expression analysis, gene ontology analysis, and gene set enrichment analysis were conducted on TCGA RNA-seq data (N=169) to identify genes and pathways that differ significantly between older and younger patients. Genes whose expression was associated with age and survival in multivariate analyses were further studied using DNA methylation (N=171). The prognostic value of their expression and methylation profiles was then compared to known genomic biomarkers, radiographic features, and histopathologic features. RNA-seq and DNA methylation validation data were obtained from the CGGA (N=44) and a cohort published by Capper et al. (N=144), respectively. RESULTS Highly activated pathways in older oligodendrogliomas were linked to developmental transcription factors. Overexpression of HOXD12 was associated with patient age and survival in the TCGA (FDR< 0.01, FDR=1e-5) and the CGGA (p=0.03, p< 1e-3). Hypermethylation of HOXD12 was associated with age, tumor grade, and survival in the TCGA (p< 1e-5, p< 0.001, p< 1e-3) and with age and tumor grade in Capper et al. (p< 0.02, p=0.001). In the TCGA, HOXD12 hypermethylation and overexpression were independently prognostic of NOTCH1 and PIK3CA mutations, loss of 15q, and MYC activation as well as mitotic figures, Ki-67 index, microvascular proliferation, and necrosis. HOXD12 overexpression was also independently prognostic of T1-post contrast enhancement, whole tumor volume, and peritumoral edema volume. We developed a risk-stratification nomogram predicting 5- and 10-year overall survival using patient age, HOXD12 methylation, and WHO grade. CONCLUSIONS HOXD12 overexpression and hypermethylation are associated with an aggressive subtype of oligodendroglioma and may serve as superior prognostic biomarkers than previously reported genomic, radiographic, and histopathologic features.