Advertisement

Risk-adapted therapy and biological heterogeneity in pineoblastoma: integrated clinico-pathological analysis from the prospective, multi-center SJMB03 and SJYC07 trials

  • Anthony P. Y. LiuEmail author
  • Brian Gudenas
  • Tong Lin
  • Brent A. Orr
  • Paul KlimoJr.
  • Rahul Kumar
  • Eric Bouffet
  • Sridharan Gururangan
  • John R. Crawford
  • Stewart J. Kellie
  • Murali Chintagumpala
  • Michael J. Fisher
  • Daniel C. Bowers
  • Tim Hassall
  • Daniel J. Indelicato
  • Arzu Onar-Thomas
  • David W. Ellison
  • Frederick A. Boop
  • Thomas E. Merchant
  • Giles W. Robinson
  • Paul A. Northcott
  • Amar Gajjar
Original Paper
  • 35 Downloads

Abstract

Pineoblastoma is a rare embryonal tumor of childhood that is conventionally treated with high-dose craniospinal irradiation (CSI). Multi-dimensional molecular evaluation of pineoblastoma and associated intertumoral heterogeneity is lacking. Herein, we report outcomes and molecular features of children with pineoblastoma from two multi-center, risk-adapted trials (SJMB03 for patients ≥ 3 years; SJYC07 for patients < 3 years) complemented by a non-protocol institutional cohort. The clinical cohort consisted of 58 patients with histologically diagnosed pineoblastoma (SJMB03 = 30, SJYC07 = 12, non-protocol = 16, including 12 managed with SJMB03-like therapy). The SJMB03 protocol comprised risk-adapted CSI (average-risk = 23.4 Gy, high-risk = 36 Gy) with radiation boost to the primary site and adjuvant chemotherapy. The SJYC07 protocol consisted of induction chemotherapy, consolidation with focal radiation (intermediate-risk) or chemotherapy (high-risk), and metronomic maintenance therapy. The molecular cohort comprised 43 pineal parenchymal tumors profiled by DNA methylation array (n = 43), whole-exome sequencing (n = 26), and RNA-sequencing (n = 16). Respective 5-year progression-free survival rates for patients with average-risk or high-risk disease on SJMB03 or SJMB03-like therapy were 100% and 56.5 ± 10.3% (P = 0.007); respective 2-year progression-free survival rates for those with intermediate-risk or high-risk disease on SJYC07 were 14.3 ± 13.2% and 0% (P = 0.375). Of patients with average-risk disease treated with SJMB03/SJMB03-like therapy, 17/18 survived without progression. DNA-methylation analysis revealed four clinically relevant pineoblastoma subgroups: PB-A, PB-B, PB-B–like, and PB-FOXR2. Pineoblastoma subgroups differed in age at diagnosis, propensity for metastasis, cytogenetics, and clinical outcomes. Alterations in the miRNA-processing pathway genes DICER1, DROSHA, and DGCR8 were recurrent and mutually exclusive in PB-B and PB-B–like subgroups; PB-FOXR2 samples universally overexpressed the FOXR2 proto-oncogene. Our findings suggest superior outcome amongst older children with average-risk pineoblastoma treated with reduced-dose CSI. The identification of biologically and clinically distinct pineoblastoma subgroups warrants consideration of future molecularly-driven treatment protocols for this rare pediatric brain tumor entity.

Keywords

Pineoblastoma Clinical trial Molecular subgroups DICER1 MicroRNA processing FOXR2 

Notes

Acknowledgements

We thank all patients and families, physicians, and nursing, research, and administrative staff from all participating institutions. We appreciate the following core facilities at St Jude Children’s Research Hospital: the Biorepository, for providing and processing study tissues; the Diagnostic Biomarkers Shared Resource, for nucleic acid extractions; the Hartwell Center, for conducting DNA-methylation profiling and next-generation sequencing. We thank Brandon Stelter for assistance with figure preparation and artwork and Cherise Guess, PhD, ELS, for editing the manuscript.

Author contributions

Conception and design: Anthony P.Y. Liu, Arzu Onar-Thomas, David Ellison, Frederick A. Boop, Thomas E. Merchant, Giles W. Robinson, Paul A. Northcott, Amar Gajjar. Provision of study material or patients: Brent A. Orr, Paul Klimo Jr., Eric Bouffet, Sridharan Gururangan, John R. Crawford, Stewart J. Kellie, Murali Chintagumpala, Michael Fisher, Daniel C. Bowers, Tim Hassall, David Ellison, Frederick A. Boop, Thomas E. Merchant, Giles W. Robinson, Paul A. Northcott, and Amar Gajjar. Collection and assembly of data: All authors. Data analysis and interpretation: Anthony P.Y. Liu, Brian Gudenas, Tong Lin, Brent A. Orr, Arzu Onar-Thomas, Giles W. Robinson, Paul A. Northcott, and Amar Gajjar. Manuscript writing: All authors. Final approval of manuscript: All authors. Accountable for all aspects of the work: All authors.

Funding

This work was sponsored by the American Lebanese Syrian Associated Charities, the National Cancer Institute (Grant No. CA21765), and Musicians Against Childhood Cancer. P.A.N. is a Pew-Stewart Scholar for Cancer Research (Margaret and Alexander Stewart Trust) and recipient of The Sontag Foundation Distinguished Scientist Award. P.A.N. was also supported by the National Cancer Institute (Grant no. R01CA232143-01), American Association for Cancer Research (NextGen Grant for Transformative Cancer Research), The Brain Tumour Charity (Quest for Cures), the American Lebanese Syrian Associated Charities (ALSAC), and St. Jude.

Compliance with ethical standards

Conflict of interest

The author declares that they have no competing interests.

Supplementary material

401_2019_2106_MOESM1_ESM.pdf (26.7 mb)
Supplementary Fig. S1 Schematic summary of treatment approach from (a) SJMB03 and (b) SJYC07 (PDF 27350 kb)
401_2019_2106_MOESM2_ESM.pdf (26.7 mb)
Supplementary Fig. S2 Survival analysis of patients from the clinical pineoblastoma study according to study protocol and clinical characteristics. Progression-free survival (PFS) and overall-survival (OS) for (a) patients treated on SJMB03 and SJMB03-like non-protocol therapy; (b) patients on SJYC07 with or without radiation (RT), patients on SJMB03/SJMB03-like or SJYC07 therapy according to (c-d) metastatic status; (e-f) extent of resection (gross-total resection [GTR] vs. subtotal resection [STR] or biopsy [Bx]). (g) PFS and OS for patients on SJMB03/SJMB03-like therapy according to presence/absence of bulky residual disease. (h) OS by risk group for patients on SJMB03/SJMB03-like therapy and SJYC07 (PDF 27309 kb)
401_2019_2106_MOESM3_ESM.pdf (29.7 mb)
Supplementary Fig. S3 Methylation profiling reveals heterogeneity among samples from the study’s molecular cohort (n=43). Sample names are highlighted according to their respective pineoblastoma (PB) subgroups. (a) Heatmap and dendrogram from hierarchical clustering using the top 10,000 most variable probes. (b) Genome-wide chromosome copy-number alterations for each sample. PB-A, pineoblastoma group A; PB-B, pineoblastoma group B; PB-B–like, pineoblastoma group B–like; PB-FOXR2, pineoblastoma FOXR2-overexpressed (PDF 30394 kb)
401_2019_2106_MOESM4_ESM.pdf (26.8 mb)
Supplementary Fig. S4 t-stochastic neighbor embedding (t-SNE) analysis of samples from the study’s molecular cohort (n=43, open circles) with 2,801 published reference samples from 91 methylation classes by Capper et al. [14] Relevant reference classes were selected for a focused representation in Fig. 2a (PDF 27463 kb)
401_2019_2106_MOESM5_ESM.pdf (26.7 mb)
Supplementary Fig. S5 Hierarchical clustering of transcriptomic profiles (PB-B=4, PB-B–like=3, PB-FOXR2=4) using the top 200 most variably expressed genes revealed results supporting subgrouping by DNA-methylation profiling. Mut, mutated; PB-B, pineoblastoma group B; PB-B–like, pineoblastoma group B–like; PB-FOXR2, pineoblastoma FOXR2-overexpressed; WT, wild-type (PDF 27302 kb)
401_2019_2106_MOESM6_ESM.pdf (26.7 mb)
Supplementary Fig. S6 ClueGO plots showing enriched pathways in molecularly defined pineoblastoma subgroups. The top 20 terms are shown for PB-B (PDF 27339 kb)
401_2019_2106_MOESM7_ESM.pdf (28.3 mb)
Supplementary Fig. S7 Clinical, radiographic, and molecular features of two embryonal tumor with multilayered rosette (ETMR)-like samples harboring nonsense and missense DICER1 mutations (SJPB15 [histologically pineoblastoma] and SJPB16 [pineal anlage tumor]) (Fig. 2a). (a) In both cases, MRI showed a pineal region mass, and copy number plots showed the absence of chromosome 19 miRNA cluster (C19MC) amplification. (b) t-stochastic neighbor embedding (t-SNE) analysis with methylation profiles derived from 10 in-house typical ETMRs and two recently published “ETMR-like infantile cerebellar embryonal tumors” (which also lacked C19MC amplification and carried the same pattern of DICER1 mutations) showed clustering of our samples with the latter [42]. CSI, craniospinal irradiation; DOD, died of disease; Dx, diagnosis; M0, non-metastatic; PD, progressive disease; TSNE, t-stochastic neighbor embedding; WES, whole-exome sequencing (PDF 28994 kb)
401_2019_2106_MOESM8_ESM.pdf (28.8 mb)
Supplementary Fig. S8 Clinical, radiographic, and molecular features of two samples from the molecular cohort (SJPB17, clustering with WNT-activated medulloblastoma [MB-WNT], and SJPB19, clustering close to control pineal tissue; Fig. 2a) carrying a missense mutation in exon 3 of CTNNB1. In both cases, MRI showed a pineal region mass without posterior fossa involvement, and copy number plots showed the absence of monosomy 6. CTNNB1 mutations detected are highlighted in lollipop plots. CDDP, cisplatin; CPM, cyclophosphamide; CSI, craniospinal irradiation; Dx, diagnosis; IT, intrathecal; M0, non-metastatic; MB-G3, medulloblastoma group 3; MNP, MolecularNeuropathology classifier; t-SNE, t-stochastic neighbor embedding; VCR, vincristine; VP16, etoposide; WES, whole-exome sequencing (PDF 29498 kb)
401_2019_2106_MOESM9_ESM.pdf (41 kb)
Supplementary Methods: Supplementary methods and references on genome-wide DNA methylation profiling and next-generation sequencing pipelines (PDF 41 kb)
401_2019_2106_MOESM10_ESM.pdf (32 kb)
Supplementary Table S1 Clinical characteristics, treatment, outcome, and molecular features of patients with non-pineoblastoma histologies (PDF 33 kb)
401_2019_2106_MOESM11_ESM.pdf (36 kb)
Supplementary Table S2 Progression-free survival (PFS) and overall survival (OS) of study patients (PDF 37 kb)
401_2019_2106_MOESM12_ESM.xlsx (16 kb)
Supplementary Table S3 Metadata for the study cohort (XLSX 15 kb)
401_2019_2106_MOESM13_ESM.xlsx (34 kb)
Supplementary Table S4 Filtered list of variants called from whole-exome sequencing (XLSX 34 kb)
401_2019_2106_MOESM14_ESM.xlsx (91 kb)
Supplementary Table S5 Differential expression and gene set enrichment analysis in molecular pineoblastoma subgroups (XLSX 91 kb)

References

  1. 1.
    AbdelBaki M, Abu Arja M, Funk Z, Stanek J, Davidson T, Fangusaro J et al (2018) PDCT-13 Pineoblastoma in children: the head start experience. Neuro Oncol 20:vi203–vi203.  https://doi.org/10.1093/neuonc/noy148.842 CrossRefPubMedCentralGoogle Scholar
  2. 2.
    Capper D, Jones DT, Sill M, Hovestadt V, Schrimpf D, Sturm D et al (2018) DNA methylation-based classification of central nervous system tumours. Nature 555:469CrossRefGoogle Scholar
  3. 3.
    Chen H, Liu H, Qing G (2018) Targeting oncogenic Myc as a strategy for cancer treatment. Sig Transduct Target Ther 3:5.  https://doi.org/10.1038/s41392-018-0008-7 CrossRefGoogle Scholar
  4. 4.
    Chintagumpala M, Hassall T, Palmer S, Ashley D, Wallace D, Kasow K et al (2009) A pilot study of risk-adapted radiotherapy and chemotherapy in patients with supratentorial PNET. Neuro Oncol 11:33–40.  https://doi.org/10.1215/15228517-2008-079 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Cho Y-J, Tsherniak A, Tamayo P, Santagata S, Ligon A, Greulich H et al (2011) Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome. J Clin Oncol 29:1424–1430.  https://doi.org/10.1200/JCO.2010.28.5148 CrossRefPubMedGoogle Scholar
  6. 6.
    ClinicalTrials.gov (2019) Treatment of patients with newly diagnosed medulloblastoma, supratentorial primitive neuroectodermal tumor, or atypical teratoid rhabdoid tumor. https://clinicaltrials.gov/ct2/show/NCT00085202. Accessed June 10 2019
  7. 7.
    de Kock L, Sabbaghian N, Druker H, Weber E, Hamel N, Miller S et al (2014) Germ-line and somatic DICER1 mutations in pineoblastoma. Acta Neuropathol 128:583–595.  https://doi.org/10.1007/s00401-014-1318-7 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Deng X, Yang Z, Zhang X, Lin D, Xu X, Lu X et al (2018) Prognosis of pediatric patients with pineoblastoma: a SEER analysis 1990–2013. World Neurosurg 118:e871–e879CrossRefGoogle Scholar
  9. 9.
    Ellison DW, Onilude OE, Lindsey JC, Lusher ME, Weston CL, Taylor RE et al (2005) beta-Catenin status predicts a favorable outcome in childhood medulloblastoma: the United Kingdom Children’s cancer study group brain tumour committee. J Clin Oncol 23:7951–7957.  https://doi.org/10.1200/jco.2005.01.5479 CrossRefPubMedGoogle Scholar
  10. 10.
    Friedrich C, von Bueren AO, von Hoff K, Gerber NU, Ottensmeier H, Deinlein F et al (2012) Treatment of young children with CNS-primitive neuroectodermal tumors/pineoblastomas in the prospective multicenter trial HIT 2000 using different chemotherapy regimens and radiotherapy. Neuro Oncol 15:224–234.  https://doi.org/10.1093/neuonc/nos292 CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Gilheeney SW, Saad A, Chi S, Turner C, Ullrich NJ, Goumnerova L et al (2008) Outcome of pediatric pineoblastoma after surgery, radiation and chemotherapy. J Neurooncol 89:89–95.  https://doi.org/10.1007/s11060-008-9589-2 CrossRefPubMedGoogle Scholar
  12. 12.
    Gururangan S, McLaughlin C, Quinn J, Rich J, Reardon D, Halperin EC et al (2003) High-dose chemotherapy with autologous stem-cell rescue in children and adults with newly diagnosed pineoblastomas. J Clin Oncol 21:2187–2191.  https://doi.org/10.1200/jco.2003.10.096 CrossRefPubMedGoogle Scholar
  13. 13.
    Han J, Lee Y, Yeom K-H, Kim Y-K, Jin H, Kim VN (2004) The Drosha-DGCR8 complex in primary microRNA processing. Genes Dev 18:3016–3027.  https://doi.org/10.1101/gad.1262504 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Hwang EI, Kool M, Burger PC, Capper D, Chavez L, Brabetz S et al (2018) Extensive molecular and clinical heterogeneity in patients with histologically diagnosed CNS-PNET treated as a single entity: a report from the children’s oncology group randomized ACNS0332 trial. J Clin Oncol 36:3388–3395.  https://doi.org/10.1200/jco.2017.76.4720 CrossRefGoogle Scholar
  15. 15.
    Johann PD, Erkek S, Zapatka M, Kerl K, Buchhalter I, Hovestadt V et al (2016) Atypical teratoid/rhabdoid tumors are comprised of three epigenetic subgroups with distinct enhancer landscapes. Cancer Cell 29:379–393.  https://doi.org/10.1016/j.ccell.2016.02.001 CrossRefPubMedGoogle Scholar
  16. 16.
    Kivela T (1999) Trilateral retinoblastoma: a meta-analysis of hereditary retinoblastoma associated with primary ectopic intracranial retinoblastoma. J Clin Oncol 17:1829–1837.  https://doi.org/10.1200/jco.1999.17.6.1829 CrossRefPubMedGoogle Scholar
  17. 17.
    Koso H, Tsuhako A, Lyons E, Ward JM, Rust AG, Adams DJ et al (2014) Identification of FoxR2 as an oncogene in medulloblastoma. Cancer Res 74:2351–2361.  https://doi.org/10.1158/0008-5472.Can-13-1523 CrossRefPubMedGoogle Scholar
  18. 18.
    Li X, Wang W, Xi Y, Gao M, Tran M, Aziz KE et al (2016) FOXR2 interacts with MYC to promote its transcriptional activities and tumorigenesis. Cell Rep 16:487–497CrossRefGoogle Scholar
  19. 19.
    Lin S, Gregory RI (2015) MicroRNA biogenesis pathways in cancer. Nat Rev Cancer 15:321–333.  https://doi.org/10.1038/nrc3932 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Louis DN, Perry A, Reifenberger G, Von Deimling A, Figarella-Branger D, Cavenee WK et al (2016) The 2016 world health organization classification of tumors of the central nervous system: a summary. Acta Neuropathol (Berl) 131:803–820CrossRefGoogle Scholar
  21. 21.
    Mays JC, Kelly MC, Coon SL, Holtzclaw L, Rath MF, Kelley MW (2018) Single-cell RNA sequencing of the mammalian pineal gland identifies two pinealocyte subtypes and cell type-specific daily patterns of gene expression. PLoS One 13:e0205883.  https://doi.org/10.1371/journal.pone.0205883 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Mulhern RK, Palmer SL, Merchant TE, Wallace D, Kocak M, Brouwers P et al (2005) Neurocognitive consequences of risk-adapted therapy for childhood medulloblastoma. J Clin Oncol 23:5511–5519CrossRefGoogle Scholar
  23. 23.
    Mynarek M, Pizer B, Dufour C, van Vuurden D, Garami M, Massimino M et al (2017) Evaluation of age-dependent treatment strategies for children and young adults with pineoblastoma: analysis of pooled European Society for Paediatric Oncology (SIOP-E) and US Head Start data. Neuro Oncol 19:576–585.  https://doi.org/10.1093/neuonc/now234 CrossRefPubMedGoogle Scholar
  24. 24.
    Nguyen L, Crawford JR (2018) Pineoblastoma in a child with 22q11.2 deletion syndrome. BMJ Case Rep.  https://doi.org/10.1136/bcr-2018-226434 CrossRefPubMedGoogle Scholar
  25. 25.
    Northcott PA, Korshunov A, Witt H, Hielscher T, Eberhart CG, Mack S et al (2011) Medulloblastoma comprises four distinct molecular variants. J Clin Oncol 29:1408–1414.  https://doi.org/10.1200/JCO.2009.27.4324 CrossRefPubMedGoogle Scholar
  26. 26.
    Pizer BL, Weston CL, Robinson KJ, Ellison DW, Ironside J, Saran F et al (2006) Analysis of patients with supratentorial primitive neuro-ectodermal tumours entered into the SIOP/UKCCSG PNET 3 study. Eur J Cancer 42:1120–1128.  https://doi.org/10.1016/j.ejca.2006.01.039 CrossRefPubMedGoogle Scholar
  27. 27.
    Poh B, Koso H, Momota H, Komori T, Suzuki Y, Yoshida N et al (2019) Foxr2 promotes formation of CNS-embryonal tumors in a Trp53-deficient background. Neuro Oncol.  https://doi.org/10.1093/neuonc/noz067 CrossRefPubMedGoogle Scholar
  28. 28.
    Reddy AT, Janss AJ, Phillips PC, Weiss HL, Packer RJ (2000) Outcome for children with supratentorial primitive neuroectodermal tumors treated with surgery, radiation, and chemotherapy. Cancer 88:2189–2193.  https://doi.org/10.1002/(sici)1097-0142(20000501)88:9%3c2189:aid-cncr27%3e3.0.co;2-g CrossRefPubMedGoogle Scholar
  29. 29.
    Robinson GW, Rudneva VA, Buchhalter I, Billups CA, Waszak SM, Smith KS et al (2018) Risk-adapted therapy for young children with medulloblastoma (SJYC07): therapeutic and molecular outcomes from a multicentre, phase 2 trial. Lancet Oncol 19:768–784CrossRefGoogle Scholar
  30. 30.
    Sabbaghian N, Hamel N, Srivastava A, Albrecht S, Priest JR, Foulkes WD (2012) Germline DICER1 mutation and associated loss of heterozygosity in a pineoblastoma. J Med Genet 49:417–419CrossRefGoogle Scholar
  31. 31.
    Schild SE, Scheithauer BW, Schomberg PJ, Hook CC, Kelly PJ, Frick L et al (1993) Pineal parenchymal tumors: clinical, pathologic, and therapeutic aspects. Cancer 72:870–880CrossRefGoogle Scholar
  32. 32.
    Schultz KAP, Williams GM, Kamihara J, Stewart DR, Harris AK, Bauer AJ et al (2018) DICER1 and associated conditions: identification of at-risk individuals and recommended surveillance strategies. Clin Cancer Res 24:2251–2261CrossRefGoogle Scholar
  33. 33.
    Sharma T, Schwalbe EC, Williamson D, Sill M, Hovestadt V, Mynarek M (2019) Second-generation molecular subgrouping of medulloblastoma: an international meta-analysis of Group 3 and Group 4 subtypes. Acta Neuropathol.  https://doi.org/10.1007/s00401-019-02020-0 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Snuderl M, Kannan K, Pfaff E, Wang S, Stafford JM, Serrano J et al (2018) Recurrent homozygous deletion of DROSHA and microduplication of PDE4DIP in pineoblastoma. Nat Commun 9:2868.  https://doi.org/10.1038/s41467-018-05029-3 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Spence T, Sin-Chan P, Picard D, Barszczyk M, Hoss K, Lu M et al (2014) CNS-PNETs with C19MC amplification and/or LIN28 expression comprise a distinct histogenetic diagnostic and therapeutic entity. Acta Neuropathol (Berl) 128:291–303CrossRefGoogle Scholar
  36. 36.
    Stevens T, ten Bosch JVDW, De Rademaeker M, Van Den Bogaert A, van den Akker M (2017) Risk of malignancy in 22q11. 2 deletion syndrome. Clinical Case Rep 5:486CrossRefGoogle Scholar
  37. 37.
    Sturm D, Orr BA, Toprak UH, Hovestadt V, Jones DTW, Capper D et al (2016) New brain tumor entities emerge from molecular classification of CNS-PNETs. Cell 164:1060–1072.  https://doi.org/10.1016/j.cell.2016.01.015 CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Thompson MC, Fuller C, Hogg TL, Dalton J, Finkelstein D, Lau CC et al (2006) Genomics identifies medulloblastoma subgroups that are enriched for specific genetic alterations. J Clin Oncol 24:1924–1931.  https://doi.org/10.1200/jco.2005.04.4974 CrossRefPubMedGoogle Scholar
  39. 39.
    Torchia J, Golbourn B, Feng S, Ho KC, Sin-Chan P, Vasiljevic A et al (2016) Integrated (epi)-genomic analyses identify subgroup-specific therapeutic targets in CNS rhabdoid tumors. Cancer Cell 30:891–908.  https://doi.org/10.1016/j.ccell.2016.11.003 CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Trotti A, Colevas AD, Setser A, Rusch V, Jaques D, Budach V et al (2003) Coleman CN CTCAE v3. 0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol 3:176–181CrossRefGoogle Scholar
  41. 41.
    Upadhyaya SA, Robinson GW, Onar-Thomas A, Orr BA, Billups CA, Bowers DC et al (2019) Molecular grouping and outcomes of young children with newly diagnosed ependymoma treated on the multi-institutional SJYC07 trial. Neuro Oncol 21:1319–1330CrossRefGoogle Scholar
  42. 42.
    Uro-Coste E, Masliah-Planchon J, Siegfried A, Blanluet M, Lambo S, Kool M et al (2019) ETMR-like infantile cerebellar embryonal tumors in the extended morphologic spectrum of DICER1-related tumors. Acta Neuropathol 137:175–177.  https://doi.org/10.1007/s00401-018-1935-7 CrossRefPubMedGoogle Scholar
  43. 43.
    van Rijn S, Vouri M, Pfister SM, Kawauchi D, Kool M (2018) EMBR-04. what the fox say? A molecular analysis of FOXR2 in pediatric brain tumors. Neuro Oncol 20:i69–i69.  https://doi.org/10.1093/neuonc/noy059.189 CrossRefPubMedCentralGoogle Scholar
  44. 44.
    Walz AL, Ooms A, Gadd S, Gerhard DS, Smith MA, Guidry Auvil JM et al (2015) Recurrent DGCR8, DROSHA, and SIX homeodomain mutations in favorable histology Wilms tumors. Cancer Cell 27:286–297.  https://doi.org/10.1016/j.ccell.2015.01.003 CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Xu YL, Reinscheid RK, Huitron-Resendiz S, Clark SD, Wang Z, Lin SH et al (2004) Neuropeptide S: a neuropeptide promoting arousal and anxiolytic-like effects. Neuron 43:487–497.  https://doi.org/10.1016/j.neuron.2004.08.005 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Anthony P. Y. Liu
    • 1
    Email author
  • Brian Gudenas
    • 2
  • Tong Lin
    • 3
  • Brent A. Orr
    • 4
  • Paul KlimoJr.
    • 5
    • 6
    • 7
  • Rahul Kumar
    • 2
  • Eric Bouffet
    • 8
  • Sridharan Gururangan
    • 9
  • John R. Crawford
    • 10
  • Stewart J. Kellie
    • 11
  • Murali Chintagumpala
    • 12
  • Michael J. Fisher
    • 13
  • Daniel C. Bowers
    • 14
  • Tim Hassall
    • 15
  • Daniel J. Indelicato
    • 16
  • Arzu Onar-Thomas
    • 3
  • David W. Ellison
    • 4
  • Frederick A. Boop
    • 5
    • 6
    • 7
  • Thomas E. Merchant
    • 17
  • Giles W. Robinson
    • 1
  • Paul A. Northcott
    • 2
  • Amar Gajjar
    • 1
  1. 1.Department of OncologySt Jude Children’s Research HospitalMemphisUSA
  2. 2.Department of Developmental NeurobiologySt Jude Children’s Research HospitalMemphisUSA
  3. 3.Department of BiostatisticsSt Jude Children’s Research HospitalMemphisUSA
  4. 4.Department of PathologySt Jude Children’s Research HospitalMemphisUSA
  5. 5.Department of SurgerySt. Jude Children’s Research HospitalMemphisUSA
  6. 6.Department of NeurosurgeryUniversity of Tennessee Health Science CenterMemphisUSA
  7. 7.Le Bonheur Neuroscience InstituteLe Bonheur Children’s HospitalMemphisUSA
  8. 8.Division of Hematology-OncologyThe Hospital for Sick ChildrenTorontoCanada
  9. 9.Lillian S. Wells Department of NeurosurgeryUniversity of FloridaGainesvilleUSA
  10. 10.University of California San Diego and Rady Children’s HospitalSan DiegoUSA
  11. 11.Children’s Cancer CentreThe Children’s Hospital at Westmead and University of SydneySydneyAustralia
  12. 12.Department of Pediatrics, Texas Children’s Cancer CenterBaylor College of MedicineHoustonUSA
  13. 13.Division of Oncology, Department of PediatricsChildren’s Hospital of PhiladelphiaPhiladelphiaUSA
  14. 14.Division of Pediatric Hematology and OncologyUniversity of Texas Southwestern Medical CenterDallasUSA
  15. 15.Queensland Children’s HospitalBrisbaneAustralia
  16. 16.Department of Radiation OncologyUniversity of FloridaJacksonvilleUSA
  17. 17.Department of Radiation OncologySt Jude Children’s Research HospitalMemphisUSA

Personalised recommendations