Molecular analysis of adolescent and young adult high grade gliomas in the SPECTA-AYA study: Poorly characterised tumours with frequent germline alterations

Background

Adolescent and young adult (AYA) high grade gliomas (HGG) have the worst survival of AYA malignancies yet are poorly represented in large-scale molecular datasets.

Methods

50 AYAs aged 12–29 with newly diagnosed or recurrent HGG and other high risk central nervous system (CNS) tumours were prospectively recruited to the EORTC SPECTA platform study and underwent whole exome sequencing, RNA sequencing and methylation profiling, with central pathological review. Actionable mutations were reported and patients followed up for therapies and outcome.

Results

From 46 locally diagnosed HGGs and 4 other recurrent CNS tumours, molecular and pathology review resulted in histological grade re-classification (n = 10), diagnostic refinement (n = 9) and revised diagnoses (n = 12) in a substantial proportion. Pathogenic constitutional alterations were present in 14 % overall and were largely limited to cases with IDH-wildtype glioblastoma and paediatric-type diffuse HGGs. 91 % of HGGs had potentially actionable alterations affecting RAS/RAF/MAPK (60 %), PI3K/AKT/mTOR (27 %) and cell cycle genes (11 %). High tumour mutational burden (> 10 somatic non-synonymous mutations per Mb of genome targeted) was present in 12 % at diagnosis and 18 % at recurrence, all in histological grade 4 tumours. Ten patients’ treatment was modified on the basis of molecular profile, of whom 5 remained on treatment at last follow-up.

Conclusion

AYA HGGs comprise a diverse group of entities; accurate, molecularly-defined diagnosis is critical to direct primary treatment, determine risk of genetic predisposition and guide molecularly-directed therapy. Current services fail to routinely address diagnosis, personalised molecular profiling or investigation of therapeutic opportunities for this high risk, poor prognosis group of rare cancer patients.