GE-03 * GENOMIC CHARACTERIZATION OF SURVIVAL OUTLIERS IN GLIOBLASTOMA MULTIFORME

Abstract

Despite the general poor prognosis for patients with GBM, a proportion survives well beyond the median survival of 12-14 months following diagnosis. To elucidate molecular features associated with disproportionately protracted survival, we conducted deep genomic comparative analysis of a cohort of patients receiving standard therapy (surgery plus concurrent radiation and temozolomide) wherein outliers were identified: patients who responded (long-term survivor, LTS) versus those who failed rapidly (short-term survivor, STS). The datasets enabled interrogation for signatures indicative of tumor vulnerability. Whole genomic, epigenetic and transcriptomic analyses of 18 patients, including 8 LTS with an average 30 months overall survival (OS) and 10 STS with an average of 7 months OS were performed to capture single nucleotide variants (SNVs), indels, translocations, intra-chromosomal rearrangements, copy number variants, along with DNA methylation and mRNA expression. LTS and STS cases showed equal proportion of 7p11.2 (EGFR) amplification and 9p21.3 (CDKN2A) deletion. However, LTS GBM showed frequent chromosomal gains in 4q12 (PDGFRA and KIT) and 12q14.1 (CDK4) and deletion in 19q13.33 (BAX, BCAT2 and CD33), whereas, STS GBM showed frequent deletion in 9p11.2 (FOXD4L2 and AQP7P3) and 22q11.21 (HIC2). In addition, LTS GBM showed a 2-fold increased chromosomal instability as compared to STS GBM. By gene expression analysis, supervised clustering using the CIN70 chromosomal instability signature showed a decreased expression of these markers in LTS GBM, corroborating the genomic analysis. Finally, integrating DNA methylation data with gene expression revealed in STS GBM hypermethylation and downregulation of EPHA3, MEG, and PPP1R9A, linked to defective cell migration and adhesion. In contrast, LTS GBM showed hypomethylation and an increased gene expression of KIT. We posit that genomic instability predicts vulnerability of GBM to standard therapy and coupled with genetic and epigenetic signatures may identify patients where front-line entry into alternative, targeted regimens would be a preferred, more-efficacious management.