Abstract 289: Probing the non-enhancing component of glioblastoma: Targeting what is left behind

Abstract

Abstract While genomic profiling and therapeutic selection support individualized GBM treatment, such therapeutic decision-making is usually made with reference to tumor obtained from the enhancing core region. GBM is known to be heterogeneous and exhibits a high resistance to standard therapies. To address whether non-enhancing tumor (representing the majority of tumor left behind after surgery) shows distinct genomic characteristics and therapeutic targets compared to the enhancing tumor core, we performed genome-wide exome-sequencing and RNA-sequencing for 12 patients with matched enhancing region and at least one non-enhancing region. Non-enhancing biopsies show a surprisingly high level of tumor content, with a median of 28% tumor cells and 6 of the 22 samples having greater than 50% tumor cells. Cognate non-enhancing and enhancing specimens demonstrated overall concordance in therapeutically actionable alterations (single nucleotide variants) and copy number alterations. However, non-enhancing regions were not genetically identical and did reveal additional and distinct variants compared to enhancing cores. For example, the non-enhancing region of patient 1 showed two nonsense NF1 mutations (R1534X; R2517X) while the enhancing region showed an NF1 frameshift mutation (F1247fs). Clonality analysis by LumosVar also indicated that 7 out of 12 patients harbored dissimilar cellular prevalence patterns between enhancing and non-enhancing regions. In addition, comparison of alternative polyadenylation between enhancing and non-enhancing regions uncovered distinct 3' UTR usage: e.g. SGMS2 and TOB1 tended to have longer 3' UTR in enhancing regions whereas longer 3' UTR of SYNPO and NOS1AP were prevalent in non-enhancing regions. We posit that the enhancing component of glioblastoma probably underrepresents the genomic alterations in patients' tumors. Given non-enhancing tumor is left behind after surgical debulking, genomic profiling of this region would potentially reveal more accurate tumor vulnerabilities and lead to more effective therapy. Supported by a grant from the Ben & Catherine Ivy Foundation. Citation Format: Sen Peng, Rebecca Halperin, Harshil Dhruv, Sara Byron, Christophe Legendre, Joanna Phillips, Michael Prados, Michael Berens, Nhan Tran. Probing the non-enhancing component of glioblastoma: Targeting what is left behind [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 289.