Comprehensive genetic alteration profiling in primary and recurrent glioblastoma

Abstract

Introduction: Glioblastoma (GBM) is heterogeneous and underlying genomic profiles influence evolution, resistance, and therapeutic responses. While extensive knowledge regarding genomic profiling of primary GBM exists, there remains a lack of understanding of genomic differences in recurrent GBM. Methods: We used the FoundationOne® comprehensive genomic profiling assay (CGP) to analyze ten matched primary and recurrent GBM. Genomic alterations (GA) were compared to the cancer database Catalogue of Somatic Mutations in Cancer (COSMIC). Results: All matched tumor pairs demonstrated differences in GA between the primary and recurrence including one resected without any intervening therapy. This suggests that time and/or therapeutic intervention contribute to GA. Although mutations were common to both the primary and recurrence, the percent reads varied substantially suggesting clonal expansions and contractions. For example, EGFR mutations were significantly expanded in three patients, and CNAs were increased in two patients at recurrence. Four genes that were commonly altered in both primary and recurrent GBM were more prevalent in our cohort than reported in COSMIC: CDKN2A (86% vs. 53%) and CDKN2B (86% vs. 54%) deletions, EGFR activating mutation (52% vs. 10%) or amplification (81% vs. 45%), and TERT mutation (95% vs. 51%). Lastly, PI3K pathway activating mutations were also commonly seen in our cohort (67%). Conclusions: CGP revealed that GA identified in GBM changed over time and with treatment. Mutations in TERT, CDKN2A/CDKN2B, EGFR, and PI3K pathway were commonly observed in both primary and recurrent GBM revealing their prognostic and therapeutic potential. This may have important implications for individualized therapies and needs further evaluation.