Article
Genomic characterisation of IDH-Wildtype Glioblastoma in different age groups
Genomische Charakterisierung der IDH-Wildtyp Glioblastome in verschiedenen Altersgruppen
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Published: | May 25, 2022 |
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Objective: IDH-wildtype Glioblastomas (IDH-wt GBM) are molecularly heterogeneous tumors with poor prognosis and a high incidence in the elderly population. However, IDH-wt GBM may occur in young patients and are associated with a relatively better prognosis. Here, we sought to explore whether IDH-wt GBM have an age-specific molecular signature that correlates with patients' outcome.
Methods: We performed a comprehensive molecular characterization of 55 IDH-wt GBM, using Whole Exome Sequencing (WES) in addition to Sanger Sequencing for the TERT-promoter region. Moreover, progression- and overall survival (PFS, OS) data, clinical- and tumor features were collected.
Results: The patients’ median age at diagnosis (AAD) was 58 yrs. (range: 22.9-70.8 yrs.). We divided our study cohort into three subgroups based on quartiles of AAD for further analysis: Group A: 22.9-40.4 yrs. (Q1), Group B: 44.5-71.0 yrs. (Q2-3) and Group C: 72.7-79.8 yrs. (Q4). The median OS for all patients was 15.9 Mo. with a PFS of 9.5 Mo. The median tumor volume at initial presentation was 43.8 cm3 and correlated with AAD: 63.6 cm3 (Group A) vs. 41.2 cm3 (Group C).
We identified a median of 32 mutations per tumor. Exome and Sanger sequencing detected frequent alterations on TERT-promoter (76.4%) and EGFR (90.9% gain, 50.1% amplification, 29.1% mutation). Chromosome 7 gain (92.7%) and Chromosome 10 deletion (85.5%) occurred significantly less in younger patients (Group A vs. Groups B+C; p=0.037, p=0.013). However, other individual alterations did not correlate with AAD. Via clustering of various alterations (e.g. TP53, PDGFRA, ATRX), we found an association between a proneural GBM signature with younger AAD (p=0.036). AAD itself had an independent impact on OS: 21.5 Mo. (Group A) vs. 10.1 Mo. (Group C). Moreover, we described TET1-deletions on Chr. 10 in 90.1% of cases, which was not previously described in IDH-wt GBM. Bi-allelic TET1-deletions (32.7%) with concurrent EGFR-amplification had a significant impact on patient’s outcome (OS 12.2 Mo. vs. 17.6 Mo.; p=0.013).
Conclusion: Even though GBM signatures showed subtle association with AAD, our data suggests that there is no age-specific molecular pattern for IDH-wt GBM. The heterogeneity of IDH-wt GBM persists throughout the entire spectrum of AAD, leaving the cause of better prognosis at younger age unclear on a molecular explanatory approach. Finally, TET1-deletion may represent a relevant alteration in IDH-wt GBM.