Abstract
Abstract TERT promoter mutation (TPM) is found in over 80% of IDH-wildtype glioblastomas (GBMs) and IDH-mutant oligodendrogliomas (ODs). As TPM-mediated reactivation of telomerase is tumor specific, TPM- tumor cells could be selectively targeted to reverse tumor cell immortalization, especially if this mutation is present throughout the tumor. Previous studies on the clonality of TPM present conflicting results and have relied on minimal tumor sampling. In this study, we use a 3D maximal tumor sampling approach to address this critical issue. We investigated TPM clonality in 253 primary and recurrent tumor samples, from 19 IDH-wildtype GBMs and 9 IDH-mutant ODs. An average of nine regions per tumor were intraoperatively biopsied in a manner that maximally represents tumor geography. The 3D location of each biopsy was then recorded and mapped back to the patient’s pre- and post-operative MRI, allowing 3D characterization of each tumor. For initial screening of TPM, PCR and Sanger sequencing were performed on all 253 samples. Deep amplicon sequencing (Amp-seq) was performed on 179 of these samples, including all those in which TPM was not detectable by Sanger. Each Amp-seq reaction included a TPM amplicon and an amplicon with IDH1 mutation for ODs or an amplicon spanning a chromosome 10 SNP to evaluate chromosome 10 loss in GBMs, which are early clonal events for these tumor types. Tumor purity, estimated by the FACETS algorithm applied to whole exome sequencing, was available for all 253 tumor samples and their patient-matched blood cell DNA. TERT expression was measured by RNA-seq (144 samples) and RNA Scope (49 samples). Correlations between TPM and clonal alterations and TPM and TERT expression were analyzed for significance. Of 253 tumor samples, tumor purity could be estimated for 210 (83.0%), and of these, 100% had TPM detected by Sanger and Amp-seq. For samples whose tumor purity could not be estimated (assigned a value of NA by FACETS), TPM was still detected in 36 of 43 (83.7%) samples. Variant allele frequencies (VAFs) of TPM showed high positive correlation with those of clonal alterations in GBMs (R = 0.85, p < 0.0001) and ODs (R = 0.86, p < 0.0001) as well as with tumor purity in both GBMs (R = 0.91, p < 0.0001) and ODs (R = 0.89, p < 0.0001). TPM VAF showed moderate positive correlation with TERT expression in GBMs (R = 0.52, p < 0.0001) and ODs (R = 0.62, p < 0.0001). TPM also showed a nonlinear relationship with TERT expression only in ODs. RNA Scope detected TERT expression in a subset of cells in both GBMs and ODs. To conclude, TPM is a tumor-wide, clonal mutation in primary and recurrent GBMs and ODs, making TPM tumor cells a possible therapeutic target. TPM VAF is moderately correlated with TERT expression, with a nonlinear relationship seen in ODs, suggesting other variables affect TERT expression. RNA Scope detected TERT expression at the single cell level in situ in GBMs and ODs and therefore could serve as a tumor cell-specific marker, although follow up studies are needed. Citation Format: Christina Leann Appin, Abigail K. Suwala, Stephanie Hilz, Radhika Mathur, Ivan V. Smirnov, Chibo Hong, Nicholas O. Stevers, Anny Shai, Albert Wang, Mitchel S. Berger, Susan M. Chang, Joanna J. Phillips, Joseph F. Costello. 3D whole tumor analysis of the TERT promoter mutation in gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3797.
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