. 2020 Apr 13;37(4):569-583.e5.

doi: 10.1016/j.ccell.2020.03.011.

Integrated Molecular and Clinical Analysis of 1,000 Pediatric Low-Grade Gliomas

Scott Ryall¹, Michal Zapotocky², Kohei Fukuoka³, Liana Nobre³, Ana Guerreiro Stucklin⁴, Julie Bennett³, Robert Siddaway⁵, Christopher Li¹, Sanja Pajovic⁵, Anthony Arnoldo⁶, Paul E Kowalski⁶, Monique Johnson⁶, Javal Sheth⁷, Alvaro Lassaletta⁸, Ruth G Tatevossian⁹, Wilda Orisme⁹, Ibrahim Qaddoumi¹⁰, Lea F Surrey¹¹, Marilyn M Li¹², Angela J Waanders¹³, Stephen Gilheeney¹⁴, Marc Rosenblum¹⁵, Tejus Bale¹⁵, Derek S Tsang¹⁶, Normand Laperriere¹⁶, Abhaya Kulkarni¹⁷, George M Ibrahim¹⁷, James Drake¹⁷, Peter Dirks¹⁸, Michael D Taylor¹⁸, James T Rutka¹⁸, Suzanne Laughlin¹⁹, Manohar Shroff¹⁹, Mary Shago²⁰, Lili-Naz Hazrati²¹, Colleen D'Arcy²², Vijay Ramaswamy²³, Ute Bartels²⁴, Annie Huang²⁵, Eric Bouffet²⁴, Matthias A Karajannis¹⁴, Mariarita Santi¹¹, David W Ellison⁹, Uri Tabori²⁶, Cynthia Hawkins²⁷

Affiliations

¹ Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
² Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; Department of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada; Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.
³ Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; Department of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada.
⁴ Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; Department of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada; Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.
⁵ Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada.
⁶ Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada.
⁷ Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada.
⁸ Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; Department of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Pediatric Hematology and Oncology, Hospital Universitario Niño Jesús, Madrid, Spain.
⁹ Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
¹⁰ Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.
¹¹ Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹² Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹³ Department of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Center for Data Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Hematology, Oncology, and Stem Cell Transplant, Ann & Robert H Lurie Children's Hospital of Chicago, Chicago, IL, USA; Department of Pediatrics, Feinberg School of Medicine Northwestern University, Chicago, IL, USA.
¹⁴ Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁵ Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁶ Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
¹⁷ Department of Surgery, University of Toronto, Toronto, ON, Canada; Department of Neurosurgery, The Hospital for Sick Children, Toronto ON, Canada.
¹⁸ Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Neurosurgery, The Hospital for Sick Children, Toronto ON, Canada.
¹⁹ Department of Radiology, The Hospital for Sick Children, Toronto ON, Canada; Department of Medical Imaging, University of Toronto, Toronto, ON, Canada.
²⁰ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada.
²¹ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Pathology, The Hospital for Sick Children, Toronto, ON, Canada.
²² Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Pathology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Anatomical Pathology, The Alfred Hospital, Prahran, VIC, Australia.
²³ Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; Department of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Paediatrics, University of Toronto, Toronto, ON, Canada.
²⁴ Department of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Paediatrics, University of Toronto, Toronto, ON, Canada.
²⁵ Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada.
²⁶ Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; Department of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
²⁷ Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Pathology, The Hospital for Sick Children, Toronto, ON, Canada. Electronic address: cynthia.hawkins@sickkids.ca.

PMID: 32289278
PMCID: PMC7169997
DOI: 10.1016/j.ccell.2020.03.011

Integrated Molecular and Clinical Analysis of 1,000 Pediatric Low-Grade Gliomas

Scott Ryall et al. Cancer Cell. 2020.

. 2020 Apr 13;37(4):569-583.e5.

doi: 10.1016/j.ccell.2020.03.011.

Authors

Affiliations

¹ Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
² Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; Department of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada; Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.
³ Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; Department of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada.
⁴ Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; Department of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada; Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.
⁵ Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada.
⁶ Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada.
⁷ Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada.
⁸ Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; Department of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Pediatric Hematology and Oncology, Hospital Universitario Niño Jesús, Madrid, Spain.
⁹ Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
¹⁰ Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.
¹¹ Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹² Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹³ Department of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Center for Data Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Hematology, Oncology, and Stem Cell Transplant, Ann & Robert H Lurie Children's Hospital of Chicago, Chicago, IL, USA; Department of Pediatrics, Feinberg School of Medicine Northwestern University, Chicago, IL, USA.
¹⁴ Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁵ Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁶ Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
¹⁷ Department of Surgery, University of Toronto, Toronto, ON, Canada; Department of Neurosurgery, The Hospital for Sick Children, Toronto ON, Canada.
¹⁸ Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Neurosurgery, The Hospital for Sick Children, Toronto ON, Canada.
¹⁹ Department of Radiology, The Hospital for Sick Children, Toronto ON, Canada; Department of Medical Imaging, University of Toronto, Toronto, ON, Canada.
²⁰ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada.
²¹ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Pathology, The Hospital for Sick Children, Toronto, ON, Canada.
²² Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Pathology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Anatomical Pathology, The Alfred Hospital, Prahran, VIC, Australia.
²³ Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; Department of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Paediatrics, University of Toronto, Toronto, ON, Canada.
²⁴ Department of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Paediatrics, University of Toronto, Toronto, ON, Canada.
²⁵ Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada.
²⁶ Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; Department of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
²⁷ Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Pathology, The Hospital for Sick Children, Toronto, ON, Canada. Electronic address: cynthia.hawkins@sickkids.ca.

PMID: 32289278
PMCID: PMC7169997
DOI: 10.1016/j.ccell.2020.03.011

Abstract

Pediatric low-grade gliomas (pLGG) are frequently driven by genetic alterations in the RAS-mitogen-activated protein kinase (RAS/MAPK) pathway yet show unexplained variability in their clinical outcome. To address this, we characterized a cohort of >1,000 clinically annotated pLGG. Eighty-four percent of cases harbored a driver alteration, while those without an identified alteration also often exhibited upregulation of the RAS/MAPK pathway. pLGG could be broadly classified based on their alteration type. Rearrangement-driven tumors were diagnosed at a younger age, enriched for WHO grade I histology, infrequently progressed, and rarely resulted in death as compared with SNV-driven tumors. Further sub-classification of clinical-molecular correlates stratified pLGG into risk categories. These data highlight the biological and clinical differences between pLGG subtypes and opens avenues for future treatment refinement.

Keywords: RAS/MAPK pathway; brain tumor; low-grade glioma; molecular diagnostics; neurooncology; pediatric; risk stratification.

PubMed Disclaimer

Conflict of interest statement

Declaration of Interests The authors declare no competing interests.

Figures

**Figure 1.. pLGG Cohort Details**
(A) Anatomical location of all pLGG within the cohort (n=976). (B) The histological spectrum of all non-NF1 pLGG (n=843). PA: pilocytic astrocytoma LGG, NOS: low grade glioma, not otherwise specified, GG: ganglioglioma, DNET: dysembryoplastic neuroepithelial tumor, PXA: pleomorphic xanthoastrocytoma, GNT: glioneuronal tumor, DA: diffuse astrocytoma, AG: angiocentric glioma, ODG: oligodendroglioma, DIA/DIG: Desmoplastic infantile astrocytoma/ganglioglioma. (C) Histological distribution of samples based on tumor location of all non-NF1 pLGG (n=843). (D) Boxplot showing age at diagnosis separated by tumor location of the entire pLGG cohort (n=976). The thick line within the box represents the median, the lower and upper limits of the box represent the first and third quartiles and the whiskers the min. and max. values. Adjusted p value for all pairwise comparisons, t-test.*<0.05, **<0.01, ***<0.001, ****<0.0001, NS=not significant. (E) Progression-free survival of the pLGG cohort segregated by tumor location. Adjusted p value, log-rank test. (F) Progression-free and overall survival of the entire pLGG cohort (n=976). p value calculated via the log-rank test. See also Figure S1, Table S1.

**Figure 2.. The Molecular Landscape of pLGG**
(A) Oncoprint representation of the molecular alterations and their associated categories in 610 pLGG. Samples are arranged in columns with genes & gene categories labelled along the row. *denotes that these BRAF SNVs and fusions are not the canonical *KIAA1549-BRAF* or p.V600E. (B) Bar graph of all recurrent somatic mutations across all 477 cases diagnosed from 2000–2017 for which sufficient material for molecular testing was available, in order of frequency and colored based on the inclusion (blue) or exclusion (red) of NF1 patients. (C) Pie chart depicting the frequency of alterations per molecular category in a population-based cohort of pLGG diagnosed from 2000–2017 (n=477). (D) Pie chart depicting the frequency of alterations per molecular category in non-NF1 pLGG diagnosed from 2000–2017 (n=397). (E) Schematic representation of the rare and novel fusions identified in this study. Figures were derived using the Protein Paint feature of the St. Jude PeCan website (https://pecan.stjude.cloud/proteinpaint). See also Figures S2, S3, Table S2.

**Figure 3.. RAS/MAPK Pathway Up-regulation in Non-canonical and Molecularly Undetermined pLGG**
(A) Boxplot showing the ppERK/ERK protein levels, separated by molecular alteration. The thick line within the box represents the median, the lower and upper limits of the box represent the first and third quartiles and the whiskers the min. and max. values. Adjusted p value for all pairwise comparisons, t-test.*<0.05, **<0.01, ***<0.001, ****<0.0001, NS=not significant. (B) Pre-ranked gene set enrichment analysis (GSEA) of the RAS/MAPK pathway activation signature in molecularly undetermined pLGG. NES: normalized enrichment score; FDR: false-discovery rate. (C) Single sample gene set enrichment analysis (ssGSEA) of RAS/MAPK activation for normal brain controls and molecularly undetermined pLGG. The thick line within the box represents the median, the lower and upper limits of the box represent the first and third quartiles and the whiskers the min. and max. values. Adjusted p value for all pairwise comparisons, Mann-Whitney test.*<0.05, **<0.01, ***<0.001, ****<0.0001, NS=not significant. (D) RAS/MAPK ssGSEA scores for known RAS/MAPK mutant and molecularly undetermined pLGG compared with normal brain. The thick line within the box represents the median, the lower and upper limits of the box represent the first and third quartiles and the whiskers the min. and max. values. Adjusted p value for all pairwise comparisons, t-test.*<0.05, **<0.01, ***<0.001, ****<0.0001, NS=not significant.

**Figure 4.. Rearrangement versus SNV-driven pLGG**
(A) Pie charts depicting the molecular alteration breakdown of rearrangement (top) (n=265) and SNV (bottom)-driven (n=182) pLGG. (B) Rearrangement versus SNV-driven pLGG as compared across several clinical features. * Adjusted p < 0.05, Fisher’s exact test. GTR: gross total resection. (C) Kaplan-Meier plot of overall survival of cases separated by rearrangement- or SNV-driven status, p value calculated via the log-rank test. (D) Kaplan-Meier plot of progression-free survival of cases separated by rearrangement- or SNV-driven status, p value calculated via the log-rank test. See also Table S3.

**Figure 5.. Clinicopathologic Features of Rearrangement-driven pLGG**
Schematic representation of key clinical features and outcomes for (A) *KIAA1549-BRAF*. (B) *FGFR1-TACC1*, (C) FGFR1 TKD, (D) *FGFR2* Fusions, (E) *MYB*, and (F) *MYBL1*. PA: pilocytic astrocytoma LGG, NOS: low grade glioma, not otherwise specified, GG: ganglioglioma, DNET: dysembryoplastic neuroepithelial tumor, PXA: pleomorphic xanthoastrocytoma, GNT: glioneuronal tumor, DA: diffuse astrocytoma, AG: angiocentric glioma, ODG: oligodendroglioma, DIA/DIG: Desmoplastic infantile astrocytoma/ganglioglioma, Dx: diagnosis, GTR: gross total resection. See also Figure S4, S5, Table S4.

**Figure 6.. Clinicopathologic Features of SNV-Driven pLGG**
Schematic representation of key clinical features and outcomes for (A) BRAF p.V600E, (B) FGFR1 SNVs, (C) IDH1 p.R132H, and (D) H3.3 p.K27M. PA: pilocytic astrocytoma LGG, NOS: low grade glioma, not otherwise specified, GG: ganglioglioma, DNET: dysembryoplastic neuroepithelial tumor, PXA: pleomorphic xanthoastrocytoma, GNT: glioneuronal tumor, DA: diffuse astrocytoma, AG: angiocentric glioma, ODG: oligodendroglioma, DIA/DIG: Desmoplastic infantile astrocytoma/ganglioglioma, Dx: diagnosis, GTR: gross total resection. See also Figure S6, S7.

**Figure 7.. Risk Stratification of pLGG**
(A) Donut plot representing assigned risk portfolio of pLGG and their associated biomarkers. Risk assignment is based on the incidence of progression and/or death. In samples harboring multiple alterations, the highest potential risk group was assigned. Alterations appearing in <5 samples are not assigned a risk group. (B) Kaplan-Meier plot of overall survival of cases separated by risk, p value calculated via the log-rank test. (C) Kaplan-Meier plot of progression-free of cases separated by risk, p value calculated via the log-rank test. See also Figure S8 Table S5.

See this image and copyright information in PMC

Comment in

The "Risk" in Pediatric Low-Grade Glioma.
Fangusaro J, Bandopadhayay P. Fangusaro J, et al. Cancer Cell. 2020 Apr 13;37(4):424-425. doi: 10.1016/j.ccell.2020.03.020. Cancer Cell. 2020. PMID: 32289265
Low-grade glioma subtypes revealed.
Sidaway P. Sidaway P. Nat Rev Clin Oncol. 2020 Jun;17(6):335. doi: 10.1038/s41571-020-0380-4. Nat Rev Clin Oncol. 2020. PMID: 32355316 No abstract available.

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Integrated Molecular and Clinical Analysis of 1,000 Pediatric Low-Grade Gliomas

Affiliations

Integrated Molecular and Clinical Analysis of 1,000 Pediatric Low-Grade Gliomas

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Comment in

References

Publication types

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Grants and funding

LinkOut - more resources

Full Text Sources

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Medical

Research Materials

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