A population-based analysis of the molecular landscape of glioma in adolescents and young adults reveals insights into gliomagenesis

Julie Bennett^#^{1

2

3}, Adrian B Levine^#^{4

5

6}, Liana Nobre⁷, Logine Negm⁴, Jiil Chung⁴, Karen Fang⁴, Monique Johnson⁵, Martin Komosa⁴, Stacey Krumholtz⁴, Nuno Miguel Nunes⁴, Mansuba Rana⁵, Scott Ryall^{4

5}, Javal Sheth^{4

5}, Robert Siddaway^{4

5}, Tejus A Bale⁸, Eric Bouffet^{9

4}, Michael D Cusimano^{10

11

12}, Sunit Das^{4

10}, Jay Detsky¹³, Peter Dirks^{4

11}, Matthias A Karajannis¹⁴, Paul Kongkham¹², Alexandra Giantini-Larsen¹⁵, Bryan Kincheon Li^{14

16}, Mary Jane Lim-Fat¹⁷, Andrew L Lin¹⁸, Warren P Mason¹⁹, Alexandra Miller^{14

18}, James R Perry¹⁷, Arjun Sahgal¹³, Sameer Farouk Sait¹⁴, Derek S Tsang²⁰, Gelareh Zadeh¹², Normand Laperriere²⁰, Lananh Nguyen^{6

21}, Andrew Gao^{6

22}, Julia Keith^{6

23}, David G Munoz^{6

21}, Uri Tabori^{9

4}, Cynthia Hawkins^{4

5

6}

Affiliations

¹ Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada. Julie.bennett@sickkids.ca.
² Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. Julie.bennett@sickkids.ca.
³ Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. Julie.bennett@sickkids.ca.
⁴ Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁵ Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁶ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
⁷ Division of Hematology/Oncology (iHOPE), Department of Pediatrics, Stollery Children's Hospital, University of Alberta, Edmonton, Alberta, Canada.
⁸ Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁹ Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.
¹⁰ Division of Neurosurgery, Unity Health, Toronto, Ontario, Canada.
¹¹ Division of Neurosurgery, The Hospital for Sick Children, Toronto, Ontario, Canada.
¹² Department of Neurosurgery, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada.
¹³ Department of Radiation Oncology, Sunnybrook Health Science Centre, Toronto, Ontario, Canada.
¹⁴ Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁵ Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁶ Division of Pediatric Hematology/Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁷ Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
¹⁸ Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁹ Department of Medicine, Princess Margaret Cancer Centre, University Health Network and University of Toronto, Toronto, Ontario, Canada.
²⁰ Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
²¹ Department of Laboratory Medicine, Unity Health, Toronto, Ontario, Canada.
²² Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada.
²³ Laboratory Medicine and Molecular Diagnostics, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.

^# Contributed equally.

PMID: 40335748
DOI: 10.1038/s43018-025-00962-x

A population-based analysis of the molecular landscape of glioma in adolescents and young adults reveals insights into gliomagenesis

Julie Bennett et al. Nat Cancer. 2025 Jun.

. 2025 Jun;6(6):1102-1119.

doi: 10.1038/s43018-025-00962-x. Epub 2025 May 7.

Authors

Affiliations

¹ Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada. Julie.bennett@sickkids.ca.
² Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. Julie.bennett@sickkids.ca.
³ Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. Julie.bennett@sickkids.ca.
⁴ Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁵ Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁶ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
⁷ Division of Hematology/Oncology (iHOPE), Department of Pediatrics, Stollery Children's Hospital, University of Alberta, Edmonton, Alberta, Canada.
⁸ Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁹ Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.
¹⁰ Division of Neurosurgery, Unity Health, Toronto, Ontario, Canada.
¹¹ Division of Neurosurgery, The Hospital for Sick Children, Toronto, Ontario, Canada.
¹² Department of Neurosurgery, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada.
¹³ Department of Radiation Oncology, Sunnybrook Health Science Centre, Toronto, Ontario, Canada.
¹⁴ Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁵ Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁶ Division of Pediatric Hematology/Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁷ Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
¹⁸ Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁹ Department of Medicine, Princess Margaret Cancer Centre, University Health Network and University of Toronto, Toronto, Ontario, Canada.
²⁰ Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
²¹ Department of Laboratory Medicine, Unity Health, Toronto, Ontario, Canada.
²² Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada.
²³ Laboratory Medicine and Molecular Diagnostics, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.

^# Contributed equally.

PMID: 40335748
DOI: 10.1038/s43018-025-00962-x

Abstract

Gliomas are a major cause of cancer-related deaths in adolescents and young adults (AYAs; ages 15-39 years). Different molecular alterations drive gliomas in children and adults, leading to distinct biology and clinical consequences, but the implications of pediatric- versus adult-type alterations in AYAs are unknown. Our population-based analysis of 1,456 clinically and molecularly characterized gliomas in patients aged 0-39 years addresses this gap. Pediatric-type alterations were found in 31% of AYA gliomas and conferred superior outcomes compared to adult-type alterations. AYA low-grade gliomas with specific RAS-MAPK alterations exhibited senescence, tended to arise in different locations and were associated with superior outcomes compared to gliomas in children, suggesting different cellular origins. Hemispheric IDH-mutant, BRAF p.V600E and FGFR-altered gliomas were associated with the risk of malignant transformation, having worse outcomes with increased age. These insights into gliomagenesis may provide a rationale for earlier intervention for certain tumors to disrupt the typical behavior, leading to improved outcomes.

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Conflict of interest statement

Competing interests: The authors declare no competing interests.

References

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1. Ostrom, Q. T. et al. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2016–2020. Neuro Oncol. 25, iv1–iv99 (2023). - PubMed - PMC - DOI

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A population-based analysis of the molecular landscape of glioma in adolescents and young adults reveals insights into gliomagenesis

Affiliations

A population-based analysis of the molecular landscape of glioma in adolescents and young adults reveals insights into gliomagenesis

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

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