MODL-40. CLONAL ARCHITECTURE, TRANSCRIPTIONAL CELLULAR STATES AND IN-VITRO DRUG RESPONSE IN GLIOBLASTOMA

Abstract

Abstract Seventy-five multiregional tumors from 20 representative GBM patients (female/male ratio = 0.75, median age= 63 ys) were profiled using deep whole-exome sequencing with a nominal coverage of > 300x. The clonal complexity of each individual tumor was measured by calculating the molecular distance using the Euclidean distance of all possible paired regions based on somatic mutational profiles. Among them, fresh tumor slices of 4 patients were cultured in minimal essential media and treated with 4.2 Gy plus 200 µM temozolomide for 48 hours. Spatial Transcriptomics was performed on matched tumor slices with and without treatment. Molecular characterization of multiregional tumors revealed two patterns of evolutionary trajectory, linear and branched (linear: 8 cases, branched: 8 cases) among 16 patients. Tumors with branched evolution demonstrated considerable levels of molecular divergence, determined by high molecular distance and a low number of mutations that were shared among all regions. In-vitro drug response varied considerably between patients based on cell proliferation (minus 0.5 to 13.8 %), apoptotic rates (30.1 to 44.4 %), and cell viability (minus 7.8 to 34.1 %). Under treatment pressure an increase of mesenchymal cellular states with peculiar redistribution of transcriptional patterns and increased clonal complexity was observed. In sum, we report on an ongoing study in glioblastoma that seeks to link the clonal architecture with spatially-resolved transcriptional patterns and in-vitro drug response. Our study will provide new insights into the clinical relevance of the clonal composition of this deadly cancer.