Abstract 3427: Gatekeeper inactivation drives glioma progression into secondary glioblastoma

Abstract <Glioblastoma (GBM) is the most common and lethal form of brain cancer in humans. Median survival is 15 months with best available treatment. Most GBMs arise de novo (primary GBM), but 5 - 10% progress from lower grade gliomas (secondary GBM). As progression of low grade glioma into secondary GBM significantly impacts prognosis, a better understanding of this process is paramount for treatment and monitoring of affected patients. In this study, we applied whole genome and transcriptome sequencing to primary glioma and relapsed secondary GBM tissue from seven patients with progression. All primary gliomas carried IDH1 mutations, and in all cases the mutation was inherited by the secondary GBM. ATRX alterations in all five astrocytomas and TERT promoter mutations in both 1p19q-codeleted oligoastrocytomas were also inherited in progressed tumors. In five patients, progression was associated with increased genomic instability, whereas mutation load was significantly increased in two other patients. One of them exhibited a hypermutation signature caused by a mutation in the proofreading domain of DNA polymerase epsilon, while the second had lost both copies of the DNA mismatch protein MSH2. In addition, both 1p19q-codeleted tumors had acquired focal inactivating deletions of the protein tyrosine phosphatase PTPRD at progression, suggesting a novel driver mechanism for GBM progression. The most common progression-related genomic alterations were CDKN2A deletions, TP53 mutations, RB1 deletions, PTEN deletions, and deletions of genes crucial to the double strand break repair pathway. Taken together, progression into secondary GBM was significantly related to deletions in tumor suppressor genes as well as TP53 mutations. Disruption of these gatekeepers appears to be a significant mechanism for glioma progression.> Citation Format: Kirsi Johanna Granberg, Matti Annala, Serafiina Jaatinen, Joonas Haapasalo, Olli Yli-Harja, Hannu Haapasalo, Wei Zhang, Matti Nykter. Gatekeeper inactivation drives glioma progression into secondary glioblastoma [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 3427.