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Pineoblastoma segregates into molecular sub-groups with distinct clinico-pathologic features: a Rare Brain Tumor Consortium registry study

Acta Neuropathologica volume 139, pages 223–241 (2020)Cite this article

Abstract

Pineoblastomas (PBs) are rare, aggressive pediatric brain tumors of the pineal gland with modest overall survival despite intensive therapy. We sought to define the clinical and molecular spectra of PB to inform new treatment approaches for this orphan cancer. Tumor, blood, and clinical data from 91 patients with PB or supratentorial primitive neuroectodermal tumor (sPNETs/CNS-PNETs), and 2 pineal parenchymal tumors of intermediate differentiation (PPTIDs) were collected from 29 centres in the Rare Brain Tumor Consortium. We used global DNA methylation profiling to define a core group of PB from 72/93 cases, which were delineated into five molecular sub-groups. Copy number, whole exome and targeted sequencing, and miRNA expression analyses were used to evaluate the clinico-pathologic significance of each sub-group. Tumors designated as group 1 and 2 almost exclusively exhibited deleterious homozygous loss-of-function alterations in miRNA biogenesis genes (DICER1, DROSHA, and DGCR8) in 62 and 100% of group 1 and 2 tumors, respectively. Recurrent alterations of the oncogenic MYC-miR-17/92-RB1 pathway were observed in the RB and MYC sub-group, respectively, characterized by RB1 loss with gain of miR-17/92, and recurrent gain or amplification of MYC. PB sub-groups exhibited distinct clinical features: group 1–3 arose in older children (median ages 5.2–14.0 years) and had intermediate to excellent survival (5-year OS of 68.0–100%), while Group RB and MYC PB patients were much younger (median age 1.3–1.4 years) with dismal survival (5-year OS 37.5% and 28.6%, respectively). We identified age < 3 years at diagnosis, metastatic disease, omission of upfront radiation, and chr 16q loss as significant negative prognostic factors across all PBs. Our findings demonstrate that PB exhibits substantial molecular heterogeneity with sub-group-associated clinical phenotypes and survival. In addition to revealing novel biology and therapeutics, molecular sub-grouping of PB can be exploited to reduce treatment intensity for patients with favorable biology tumors.

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Acknowledgements

RBTC biorepository and contributing tumor bank including NeuroBioTec Collection (Groupement Hospitalier Est, Bron, France), J. Loukides for biological specimens; C. Hanzen, I. Tennevet, O. Langlois, D. Frappaz for clinical data; M. Fèvre-Montange for histopathologic review with A. J.; A Field for targeted panel design. This project was funded by the Canadian Institutes of Health Research (Grant no. 137011) and b.r.a.i.n.child to A. H. D.A.H. is supported by the NIH/NCI (Grant 2R01CA143167). B.K.L. is a Garron Family Cancer Centre Research Fellow. AH holds a Tier 1 Canada Research Chair.

Author information

Author notes

  1. Bryan K. Li and Alexandre Vasiljevic contributed equally.

  2. Co-senior Authors: Eric Bouffet, Annie Huang and Anne Jouvet.

Authors and Affiliations

  1. Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, 555 University Ave., 10421B, Black, Toronto, ON, M5G 1X8, Canada

    Bryan K. Li, Vijay Ramaswamy, Eric Bouffet & Annie Huang

  2. Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON, Canada

    Bryan K. Li, Fupan Yao, Ben L. B. Ho, Mei Lu, Palma Solano-Paez, Vijay Ramaswamy, Cynthia Hawkins & Annie Huang

  3. Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada

    Bryan K. Li, Cynthia Hawkins & Annie Huang

  4. Faculté de Médecine, Université de Lyon, Lyon, France

    Alexandre Vasiljevic

  5. Service d’Anatomie et Cytologie Pathologiques, CHU de Lyon, Lyon, France

    Alexandre Vasiljevic & Anne Jouvet

  6. Département de Cancérologie de l’Enfant et de l’Adolescent, Institut Gustave Roussy, Villejuif, Paris, France

    Christelle Dufour

  7. Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, ON, Canada

    Fupan Yao, Vijay Ramaswamy & Annie Huang

  8. Department of Oncology, Children’s National Medical Center, Washington, DC, USA

    Eugene I. Hwang

  9. Department of Pediatrics, Preston A. Wells Jr. Center for Brain Tumor Therapy, UF Health Shands Hospital, University of Florida, Gainesville, FL, USA

    Sridharan Gururangan

  10. Children’s Cancer Centre, Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, VIC, Australia

    Jordan R. Hansford

  11. Division of Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Maryam Fouladi

  12. Department of Human Pathology, Gunma University Graduate School of Medicine, Maebashi, Japan

    Sumihito Nobusawa

  13. Department of Pathology, Normandy Center for Genomic and Personalized Medicine, Rouen University Hospital, Normandie University, UNIROUEN, Inserm U1245, F 76000, Rouen, France

    Annie Laquerriere

  14. CHU de Toulouse, Hôpital Ranguei, Toulouse, France

    Marie-Bernadette Delisle

  15. Department of Pediatric Hematology and Oncology, Children’s Healthcare of Atlanta and the Emory University School of Medicine, Atlanta, GA, USA

    Jason Fangusaro

  16. Department of Pathology, CHU St. Etienne, Saint-Étienne, France

    Fabien Forest

  17. Department of Pediatric Hematology Oncology, Schneider Children’s Medical Center of Israel, Petah Tikva, Israel

    Helen Toledano

  18. Hospital Infantil Virgen del Rocio, Seville, Spain

    Palma Solano-Paez

  19. Cancer and Blood Disorders Center, Seattle Children’s, Seattle, WA, USA

    Sarah Leary

  20. Department of Pediatrics, University of Colorado Denver, Denver, CO, USA

    Diane Birks

  21. Center for Cancer and Blood Disorders, Phoenix Children’s Hospital, Phoenix, AZ, USA

    Lindsey M. Hoffman

  22. Département de Neurochirurgie Adulte et Pédiatrique, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France

    Alexandru Szathmari

  23. Institut d’Hématologie et d’Oncologie Pédiatrique, IHOPe, Lyon, France

    Cécile Faure-Conter

  24. Department of Neurosurgery, University of Michigan, Ann Arbor, MI, USA

    Xing Fan

  25. Children’s Cancer Research Unit, The Children’s Hospital at Westmead, Westmead, NSW, Australia

    Daniel Catchpoole & Li Zhou

  26. Cancer and Blood Disorder, Children’s Hospitals and Clinics of Minnesota, Minneapolis, MN, USA

    Kris Ann P. Schultz

  27. National Cancer Centre Research Institute, Tokyo, Japan

    Koichi Ichimura

  28. Department of Pathology, CHU Nancy, Nancy, France

    Guillaume Gauchotte

  29. Departments of Pediatrics and Human Genetics, McGill University, Montreal, QC, Canada

    Nada Jabado

  30. The Institute of Cancer Research, London, UK

    Chris Jones

  31. Service d’Anatomie et de Cytologie pathologiques, CHU Nantes, Nantes, France

    Delphine Loussouarn

  32. Département de Neuropathologie, Hôpital Universitaire Pitie-Salpetriere, Paris, France

    Karima Mokhtari

  33. Département de Pathologie Cellulaire et Tissulaire, CHU d’Angers, Angers, France

    Audrey Rousseau

  34. Kids Cancer Centre, Sydney Children’s Hospital, Sydney, NSW, Australia

    David S. Ziegler

  35. Children’s Cancer Institute, Lowy Cancer Centre, University of New South Wales, Sydney, NSW, Australia

    David S. Ziegler

  36. Department of Cancer Pathology, Faculty of Medicine, Hokkaido University, Hokkaido, Japan

    Shinya Tanaka

  37. Department of Neurology, Harvard Medical School, Boston Children’s Hospital, Boston, MA, USA

    Scott L. Pomeroy

  38. Department of Oncology, Division of Neuro-Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Amar Gajjar

  39. Division of Pathology, The Hospital for Sick Children, Toronto, ON, Canada

    Cynthia Hawkins

  40. Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, UK

    Richard G. Grundy

  41. Division of Pathology, Center for Cancer and Immunology Research, Children’s National Medical Center, Washington, DC, USA

    D. Ashley Hill

  42. Pathology and Molecular Biology, SFCE, Bordeaux, France

    Anne Jouvet

Authors
  1. Bryan K. Li
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  2. Alexandre Vasiljevic
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  3. Christelle Dufour
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  15. Fabien Forest
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  18. Sarah Leary
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  19. Diane Birks
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  20. Lindsey M. Hoffman
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  23. Xing Fan
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  25. Li Zhou
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  29. Nada Jabado
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  30. Chris Jones
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  38. Vijay Ramaswamy
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  39. Cynthia Hawkins
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  40. Richard G. Grundy
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  41. D. Ashley Hill
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  42. Eric Bouffet
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  43. Annie Huang
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  44. Anne Jouvet
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Corresponding author

Correspondence to Annie Huang.

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401_2019_2111_MOESM1_ESM.pdf

Supplementary Figure 1 PBs comprise 5 molecular sub-groups. Global methylation data generated from 72 PBs using Illumina 450K or EPIC arrays were analyzed using NMF, HCL and K-means clustering methods to identify molecular sub-groups. a. Non-matrix factorization (NMF) analyses were performed on global methylation data using top 5000-15, 000 DNA methylation probes as determined by standard deviation (SD). Highest co-phonetic score was determined at rank (k) = 5 with 5000 probes; corresponding NMF heat map generated with 5000 probes is shown with PB sub-group designation. b. Silhouette plot of NMF analysis indicating best fit of individual PB sample within molecular sub-group. c. Hierarchal (HCL) and K-means cluster analyses of global methylation data using the 5000 most variable probes by standard deviation indicating 5 sub-groups of PBs. Supplementary Figure 2 SNP array copy number analyses of PB. Copy number calls were generated using ASCAT (Allele specific copy number analysis of tumor) on Illumina Omni SNP array data generated from PBs. a. ASCAT for group 2 tumor RBTC814 showing homozygous chr 14 loss. b. ASCAT plot for group RB tumor RBTC746 showing homozygous RB1 loss and gain of miR-17/92. Supplementary Figure 3 Schematic of hotspot mutations in Kelch domain of KBTBD4. a. IGV screenshot of aligned reads from whole exome sequencing of RBTC786 and -793 demonstrating in-frame insertions in KBTBD4, resulting in identical p.P311_R312 duplication mutation. Comparison is made to the same mutation reported by Lee JC, et al. 2019. b. Mapped in-frame insertions (in yellow) in our cohort, compared to those described by Lee JC, et al. in three PPTID samples, which are identical to that seen in RBTC793. All mutations result in the same p.P311_R312 duplication mutation. Supplementary Figure 4 Impact of age, metastatic status and radiation treatment on PB survival. Event-free (EFS) and overall survival (OS) analyses were determined for 46 patients treated with curative intent, using the Kaplan–Meier method and log-rank tests. a. EFS and OS of patients <3 or ≥3 years age at diagnosis. 5-yr EFS: 18.2 vs 58.2%; 5-yr OS: 24.2 vs. 77.0% for <3 yrs vs. ≥3 yrs. b. EFS and OS of patients without (M0) and with metastases (M+) at diagnosis. 5-yr EFS: 29.4 vs. 60.5%; 5-yr OS: 44.9 vs. 78.7% for M+ vs. M0. c. EFS and OS of patients treated with and without upfront radiation therapy. 5-yr EFS: 10.0 vs. 58.8%; 5-yr OS: 40.0 vs. 71.0% for not radiated vs. radiated. Supplementary Figure 5 Impact of chr 16 loss on event-free and overall survival of PB survival. Event-free (EFS) and overall survival (OS) analyses were determined for 46 patients treated with curative intent, stratified by chr 16 loss or no chr 16 q loss in tumor specimens, using the Kaplan–Meier method and log-rank tests. 5-yr EFS: 17.6 vs. 61.1%; 5-yr OS: 52.1 vs. 70.0% for chr 16q loss vs. no loss. Supplementary Table 1 Molecular analysis performed on tumors and blood samples. Supplementary Table 2 Reported Ki67/MIB-1 scores and presence of hotspot KBTBD4 mutation among PB. Supplementary Table 3 Clinical characteristics and treatment details for PB patients (PDF 4949 kb)

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Li, B.K., Vasiljevic, A., Dufour, C. et al. Pineoblastoma segregates into molecular sub-groups with distinct clinico-pathologic features: a Rare Brain Tumor Consortium registry study. Acta Neuropathol 139, 223–241 (2020). https://doi.org/10.1007/s00401-019-02111-y

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Keywords

  • Pineoblastoma
  • PNET
  • PPTID
  • miRNA
  • RB
  • MYC