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

in European journal of cancer (Oxford, England : 1990) by Marie Morfouace, Franck Bielle, Evangelia Razis, Florian Estrade, Alba Rubio, Francisco Bautista, Teresa de Rojas, Maria Vieito, Sara Meade, Marc Sanson, Andreia Capela Marques, Matthias Preusser, Helen Hatcher, Gnana Prakash Balasubramanian, Estela Pineda, Lionel D'Hondt, Johnny Duerinck, Alex Michotte, Christian Mawrin, Teresa Ribalta, Gianluca Marucci, Vassilis Golfinopoulos, Stefan M Pfister, David Tw Jones, Martin G McCabe

TLDR

  • The study investigated molecular characteristics and outcomes of AYA HGG and found that molecular profiling can guide treatment strategies and improve outcomes.

Abstract

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. 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. 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. 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.

Overview

  • The study aims to investigate molecular characteristics and outcomes of adolescent and young adult (AYA) high-grade gliomas (HGG) and to determine the impact of molecular profiling on treatment strategies.
  • The study included 50 AYAs with newly diagnosed or recurrent HGG and other high-risk central nervous system (CNS) tumors who underwent whole exome sequencing, RNA sequencing, and methylation profiling.
  • The primary objective of the study is to provide accurate, molecularly-defined diagnoses and to identify potentially actionable alterations that could guide molecularly-directed therapy.

Comparative Analysis & Findings

  • The study found that molecular and pathology review resulted in histological grade re-classification, diagnostic refinement, and revised diagnoses in a substantial proportion of cases.
  • Pathogenic constitutional alterations were present in 14% overall, largely limited to cases with IDH-wildtype glioblastoma and pediatric-type diffuse HGGs.
  • 91% of HGGs had potentially actionable alterations affecting RAS/RAF/MAPK, PI3K/AKT/mTOR, and cell cycle genes.

Implications and Future Directions

  • The study highlights the importance of accurate, molecularly-defined diagnoses for AYA HGG patients and the need for personalized molecular profiling and investigation of therapeutic opportunities.
  • The study also emphasizes the need for routine molecular profiling and investigation of therapeutic opportunities for AYA HGG patients, as current services fail to address these needs.
  • Future studies should focus on building on the results of this study to improve outcomes for AYA HGG patients and to identify potential therapeutic targets.
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