OpenPBTA: The Open Pediatric Brain Tumor Atlas

Joshua A Shapiro¹, Krutika S Gaonkar^{2

3

4}, Stephanie J Spielman^{1

5}, Candace L Savonen¹, Chante J Bethell¹, Run Jin^{2

3}, Komal S Rathi^{2

4}, Yuankun Zhu^{2

3}, Laura E Egolf^{6

7}, Bailey K Farrow^{2

3}, Daniel P Miller^{2

3}, Yang Yang⁸, Tejaswi Koganti^{2

3}, Nighat Noureen⁹, Mateusz P Koptyra^{2

3}, Nhat Duong⁴, Mariarita Santi^{10

11}, Jung Kim¹², Shannon Robins^{2

3}, Phillip B Storm^{2

3}, Stephen C Mack¹³, Jena V Lilly^{2

3}, Hongbo M Xie⁴, Payal Jain^{2

3}, Pichai Raman^{2

4}, Brian R Rood^{14

15}, Rishi R Lulla^{16

17}, Javad Nazarian^{14

15

18}, Adam A Kraya^{2

3}, Zalman Vaksman⁷, Allison P Heath^{2

3}, Cassie Kline⁷, Laura Scolaro⁷, Angela N Viaene^{10

11}, Xiaoyan Huang^{2

3}, Gregory P Way¹⁹, Steven M Foltz^{1

20}, Bo Zhang^{2

3}, Anna R Poetsch^{21

22}, Sabine Mueller²³, Brian M Ennis^{2

3}, Michael Prados²⁴, Sharon J Diskin^{7

25}, Siyuan Zheng⁹, Yiran Guo², Shrivats Kannan^{2

3}, Angela J Waanders^{26

27}, Ashley S Margol^{28

29}, Meen Chul Kim^{2

3}, Derek Hanson^{30

31}, Nicholas Van Kuren^{2

3}, Jessica Wong^{2

3}, Rebecca S Kaufman^{4

7}, Noel Coleman^{2

3}, Christopher Blackden^{2

3}, Kristina A Cole^{7

25

32}, Jennifer L Mason^{2

3}, Peter J Madsen^{2

3}, Carl J Koschmann^{33

34}, Douglas R Stewart¹², Eric Wafula⁴, Miguel A Brown^{2

3}, Adam C Resnick^{2

3}, Casey S Greene^{1

19

35}, Jo Lynne Rokita^{2

3

4}, Jaclyn N Taroni¹; Children’s Brain Tumor Network; Pacific Pediatric Neuro-Oncology Consortium

Affiliations

¹ Childhood Cancer Data Lab, Alex's Lemonade Stand Foundation, Bala Cynwyd, PA 19004, USA.
² Center for Data-Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
³ Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁴ Department of Bioinformatics and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁵ Rowan University, Glassboro, NJ 08028, USA.
⁶ Cell and Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
⁷ Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁸ Ben May Department for Cancer Research, University of Chicago, Chicago, IL 60637, USA.
⁹ Greehey Children's Cancer Research Institute, UT Health San Antonio, San Antonio, TX 78229, USA.
¹⁰ Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
¹¹ Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
¹² Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20850, USA.
¹³ Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
¹⁴ Children's National Research Institute, Washington, DC 20012, USA.
¹⁵ George Washington University School of Medicine and Health Sciences, Washington, DC 20052, USA.
¹⁶ Division of Hematology/Oncology, Hasbro Children's Hospital, Providence, RI 02903, USA.
¹⁷ Department of Pediatrics, The Warren Alpert School of Brown University, Providence, RI 02912, USA.
¹⁸ Department of Pediatrics, University of Zurich, Zurich, Switzerland.
¹⁹ Department of Biomedical Informatics, University of Colorado School of Medicine, Aurora, CO 80045, USA.
²⁰ Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA.
²¹ Biotechnology Center, Technical University Dresden, Dresden, Germany.
²² National Center for Tumor Diseases, Dresden, Germany.
²³ Department of Neurology, Neurosurgery and Pediatrics, University of California, San Francisco, San Francisco, CA 94115, USA.
²⁴ University of California, San Francisco, San Francisco, CA 94115, USA.
²⁵ Department of Pediatrics, University of Pennsylvania, Philadelphia, PA 19104, USA.
²⁶ Division of Hematology, Oncology, Neuro-Oncology, and Stem Cell Transplant, Ann & Robert H Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA.
²⁷ Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
²⁸ Division of Hematology and Oncology, Children's Hospital of Los Angeles, Los Angeles, CA 90027, USA.
²⁹ Department of Pediatrics, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033, USA.
³⁰ Hackensack Meridian School of Medicine, Nutley, NJ 07110, USA.
³¹ Hackensack University Medical Center, Hackensack, NJ 07601, USA.
³² Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
³³ Department of Pediatrics, University of Michigan Health, Ann Arbor, MI 48105, USA.
³⁴ Pediatric Hematology Oncology, Mott Children's Hospital, Ann Arbor, MI 48109, USA.
³⁵ Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

PMID: 37492101
PMCID: PMC10363844
DOI: 10.1016/j.xgen.2023.100340

OpenPBTA: The Open Pediatric Brain Tumor Atlas

Joshua A Shapiro et al. Cell Genom. 2023.

. 2023 May 31;3(7):100340.

doi: 10.1016/j.xgen.2023.100340. eCollection 2023 Jul 12.

Authors

Affiliations

¹ Childhood Cancer Data Lab, Alex's Lemonade Stand Foundation, Bala Cynwyd, PA 19004, USA.
² Center for Data-Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
³ Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁴ Department of Bioinformatics and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁵ Rowan University, Glassboro, NJ 08028, USA.
⁶ Cell and Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
⁷ Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁸ Ben May Department for Cancer Research, University of Chicago, Chicago, IL 60637, USA.
⁹ Greehey Children's Cancer Research Institute, UT Health San Antonio, San Antonio, TX 78229, USA.
¹⁰ Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
¹¹ Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
¹² Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20850, USA.
¹³ Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
¹⁴ Children's National Research Institute, Washington, DC 20012, USA.
¹⁵ George Washington University School of Medicine and Health Sciences, Washington, DC 20052, USA.
¹⁶ Division of Hematology/Oncology, Hasbro Children's Hospital, Providence, RI 02903, USA.
¹⁷ Department of Pediatrics, The Warren Alpert School of Brown University, Providence, RI 02912, USA.
¹⁸ Department of Pediatrics, University of Zurich, Zurich, Switzerland.
¹⁹ Department of Biomedical Informatics, University of Colorado School of Medicine, Aurora, CO 80045, USA.
²⁰ Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA.
²¹ Biotechnology Center, Technical University Dresden, Dresden, Germany.
²² National Center for Tumor Diseases, Dresden, Germany.
²³ Department of Neurology, Neurosurgery and Pediatrics, University of California, San Francisco, San Francisco, CA 94115, USA.
²⁴ University of California, San Francisco, San Francisco, CA 94115, USA.
²⁵ Department of Pediatrics, University of Pennsylvania, Philadelphia, PA 19104, USA.
²⁶ Division of Hematology, Oncology, Neuro-Oncology, and Stem Cell Transplant, Ann & Robert H Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA.
²⁷ Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
²⁸ Division of Hematology and Oncology, Children's Hospital of Los Angeles, Los Angeles, CA 90027, USA.
²⁹ Department of Pediatrics, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033, USA.
³⁰ Hackensack Meridian School of Medicine, Nutley, NJ 07110, USA.
³¹ Hackensack University Medical Center, Hackensack, NJ 07601, USA.
³² Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
³³ Department of Pediatrics, University of Michigan Health, Ann Arbor, MI 48105, USA.
³⁴ Pediatric Hematology Oncology, Mott Children's Hospital, Ann Arbor, MI 48109, USA.
³⁵ Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

PMID: 37492101
PMCID: PMC10363844
DOI: 10.1016/j.xgen.2023.100340

Abstract

Pediatric brain and spinal cancers are collectively the leading disease-related cause of death in children; thus, we urgently need curative therapeutic strategies for these tumors. To accelerate such discoveries, the Children's Brain Tumor Network (CBTN) and Pacific Pediatric Neuro-Oncology Consortium (PNOC) created a systematic process for tumor biobanking, model generation, and sequencing with immediate access to harmonized data. We leverage these data to establish OpenPBTA, an open collaborative project with over 40 scalable analysis modules that genomically characterize 1,074 pediatric brain tumors. Transcriptomic classification reveals universal TP53 dysregulation in mismatch repair-deficient hypermutant high-grade gliomas and TP53 loss as a significant marker for poor overall survival in ependymomas and H3 K28-mutant diffuse midline gliomas. Already being actively applied to other pediatric cancers and PNOC molecular tumor board decision-making, OpenPBTA is an invaluable resource to the pediatric oncology community.

Keywords: brain tumors; classification; open science; pediatric cancer; reproducibility; somatic variation; tumor atlas.

PubMed Disclaimer

Conflict of interest statement

C.S.G.’s spouse was an employee of Alex’s Lemonade Stand Foundation, which was a sponsor of this research. J.A.S., C.L.S., C.J.B., S.J.S., and J.N.T. are or were employees of Alex’s Lemonade Stand Foundation, a sponsor of this research. A.J.W. is a member of the Scientific Advisory boards for Alexion and DayOne Biopharmaceuticals.

Figures

**Figure 1**
Overview of the OpenPBTA project (A) CBTN and PNOC collected tumors from 943 patients. 22 tumor cell lines were created, and over 2,000 specimens were sequenced (n = 1035 RNA-seq, n = 940 WGS, and n = 32 WXS or targeted panel). The Kids First Data Resource Center Data harmonized the data using Amazon S3 through CAVATICA. Panel created with BioRender.com. (B) Number of biospecimens across phases of therapy, with one broad histology per panel. Each bar denotes a cancer group (abbreviations: GNG, ganglioglioma; other LGG, other low-grade glioma; PA, pilocytic astrocytoma; PXA, pleomorphic xanthoastrocytoma; SEGA, subependymal giant cell astrocytoma; DIPG, diffuse intrinsic pontine glioma; DMG, diffuse midline glioma; other HGG, other high-grade glioma; ATRT, atypical teratoid rhabdoid tumor; MB, medulloblastoma; other ET, other embryonal tumor; EPN, ependymoma; PNF, plexiform neurofibroma; DNET, dysembryoplastic neuroepithelial tumor; CRANIO, craniopharyngioma; EWS, Ewing sarcoma; CPP, choroid plexus papilloma). (C) Overview of the open analysis and manuscript contribution models. Contributors proposed analyses, implemented it in their fork, and filed a pull request (PR) with proposed changes. PRs underwent review for scientific rigor and accuracy. Container and continuous integration technologies ensured that all software dependencies were included and that code was not sensitive to underlying data changes. Finally, a contributor filed a PR documenting their methods and results to the Manubot-powered manuscript repository for review. (D) A potential path for an analytical PR. Arrows indicate revisions.

**Figure 2**
Mutational landscape of PBTA tumors Frequencies of canonical somatic gene mutations, CNVs, fusions, and TMB (top bar plot) for the top mutated genes across primary tumors within the OpenPBTA dataset. (A) LGGs (n = 226): pilocytic astrocytoma (n = 104), other LGG (n = 68), ganglioglioma (n = 35), pleomorphic xanthoastrocytoma (n = 9), and subependymal giant cell astrocytoma (n = 10). (B) Embryonal tumors (n = 129): medulloblastoma (n = 95), atypical teratoid rhabdoid tumor (n = 24), and other embryonal tumor (n = 10). (C) HGGs (n = 63): diffuse midline glioma (n = 36) and other HGG (n = 27). (D) Other CNS tumors (n = 153): ependymoma (n = 60), craniopharyngioma (n = 31), meningioma (n = 17), dysembryoplastic neuroepithelial tumor (n = 19), Ewing sarcoma (n = 7), schwannoma (n = 12), and neurofibroma plexiform (n = 7). Rare CNS tumors are displayed in Figure S3B. Histology (cancer group) and sex annotations are displayed under each plot. Only tumors with mutations in the listed genes are shown. Multiple CNVs are denoted as a complex event. n denotes the number of unique tumors (one tumor per patient).

**Figure 3**
Mutational co-occurrence and signatures highlight key oncogenic drivers (A) Non-synonymous mutations for 50 most commonly mutated genes across all histologies. “Other” denotes a histology with <10 tumors. (B) Co-occurrence and mutual exclusivity of mutated genes. The co-occurrence score is defined as $I (- \log_{10} (P))$ where $P$ is Fisher’s exact test and $I$ is 1 when mutations co-occur more often than expected or −1 when exclusivity is more common. (C) Number of SV and CNV breaks are significantly correlated (adjusted R = 0.443, p = 1.05e−38). (D) Chromothripsis frequency across cancer groups with n ≥3 tumors. (E) Sina plots of RefSig signature weights for signatures 1, 11, 18, 19, 3, 8, N6, MMR2, and other across cancer groups. Boxplot represents 5% (lower whisker), 25% (lower box), 50% (median), 75% (upper box), and 95% (upper whisker) quantiles.

**Figure 4**
*TP53* and telomerase activity (A) Receiver operating characteristic for *TP53* classifier run on stranded FPKM RNA-seq. (B) Violin and strip plots of *TP53* scores plotted by *TP53* alteration type (n_activated = 11, n_lost = 100, n_other = 866, Wilcoxon p = 0.92). (C) Violin and strip plots of *TP53* RNA expression plotted by *TP53* activation status (n_activated = 11, n_lost = 100, n_other = 866, Wilcoxon p = 0.006). (D) Boxplots of *TP53* and telomerase (EXTEND) scores across cancer groups. TMB status is highlighted in orange (hypermutant) or red (ultra-hypermutant). Boxplot represents 5% (lower whisker), 25% (lower box), 50% (median), 75% (upper box), and 95% (upper whisker) quantiles. (E) Heatmap of RefSig mutational signatures for patients with at least one hypermutant tumor or cell line. (F) Forest plot depicting prognostic effects of *TP53* and telomerase scores on overall survival (OS), controlling for extent of tumor resection, LGG group, and HGG group. (G) Forest plot depicting the effect of molecular subtype on HGG OS. Hazard ratios (HRs) with 95% confidence intervals and p values (multivariate Cox) are given in (F) and (G). Black diamonds denote significant p values, and gray diamonds denote reference groups. (H) Kaplan-Meier curve of HGGs by molecular subtype.

**Figure 5**
Transcriptomic and immune landscape of pediatric brain tumors (A) First two dimensions of transcriptome data UMAP, with points colored by broad histology. (B) Heatmap of GSVA scores for Hallmark gene sets with tumors ordered by cancer group. (C) Boxplots of quanTIseq estimates of immune cell proportions in cancer groups with n >15 tumors. Note: other HGGs and other LGGs have immune cell proportions similar to DMG and pilocytic astrocytoma, respectively, and are not shown. (D) Forest plot depicting additive effects of *CD274* expression, immune cell proportion, and extent of tumor resection on OS of medulloblastoma patients. HRs with 95% confidence intervals and p values (multivariate Cox) are listed. Black diamonds denote significant p values, and gray diamonds denote reference groups. Note: the macrophage M1 HR was 0 (coefficient = −9.90e4) with infinite upper and lower confidence intervals (CIs) and thus was not included in the figure. (E) Boxplot of *CD274* expression (log2 FPKM) for medulloblastomas grouped by subtype. Bonferroni-corrected p values from Wilcoxon tests are shown. Boxplot represents 5% (lower whisker), 25% (lower box), 50% (median), 75% (upper box), and 95% (upper whisker) quantiles. Only stranded RNA-seq data are plotted.

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OpenPBTA: The Open Pediatric Brain Tumor Atlas

Affiliations

OpenPBTA: The Open Pediatric Brain Tumor Atlas

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Grants and funding

LinkOut - more resources

Full Text Sources

Research Materials

Miscellaneous