54P - ATRX-deficient IDH-wildtype adult high-grade gliomas display novel, clinically relevant genetic patterns by comprehensive genomic profiling

Background

Glioblastomas are the most common IDH-wildtype adult high-grade gliomas, frequently harboring mutations in the promoter region of the TERT gene (pTERT) and utilizing the subsequent telomerase overexpression for telomere length maintenance. However, some rare cases show loss of ATRX and use alternative lengthening of telomeres. We aimed to perform the first complex genetic analysis specifically concentrating on the latter subgroup, since the molecular properties including potential clinically relevant features are poorly characterized.

Methods

Comprehensive genomic profiling (CGP) of 12 ATRX-deficient and 13 ATRX-intact IDH-wildtype adult high-grade gliomas was performed using the Illumina TruSight Oncology 500 targeted next-generation sequencing panel.

Results

ATRX and pTERT mutations were revealed to be mutually exclusive by CGP. DNMT3A alterations were confined to ATRX-deficient, while PTEN mutations to ATRX-intact cases. EGFR amplification was relatively rare, while alterations of the RAS-MAPK pathway, including NF1 mutations and BRAF alterations, were more characteristic in the ATRX-deficient group. Several pathogenic or likely pathogenic variants of genes related to homologous recombination repair were detected in both groups, but with different patterns of affected genes. Two ATRX-deficient tumors with high tumor mutational burden and mismatch repair deficiency were found. One of these showed a peculiar association of oligodendroglioma-like morphology, novel fusions involving the NTRK2 and LRRFIP2 genes, POLE mutations as well as therapy-induced MLH1 and PMS2 loss. The other showed loss of MSH2 and MSH6 without genetic alterations in the encoding genes suggesting an epigenetic background.

Conclusions

Apparent, statistically significant differences in the genetic characteristics of ATRX-deficient and ATRX-intact IDH-wildtype adult high-grade gliomas were revealed by our study. These observations suggest that tumors from the former group are particularly intriguing targets of potential future therapeutic interventions including immunotherapies combined with MAPK pathway inhibition and DNA-repair inhibitors.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

EU Horizon 2020 Research and Innovation Program; Ministry of Innovation and Technology of Hungary; ÚNKP-22-3-II New National Excellence Program of the Ministry for Culture and Innovation from the National Research, Development and Innovation Fund.

Disclosure

All authors have declared no conflicts of interest.