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


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.


Pineoblastoma Clinical trial Molecular subgroups DICER1 MicroRNA processing FOXR2 



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.


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)


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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

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