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Clinical and molecular heterogeneity of pineal parenchymal tumors: a consensus study

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Abstract

Recent genomic studies have shed light on the biology and inter-tumoral heterogeneity underlying pineal parenchymal tumors, in particular pineoblastomas (PBs) and pineal parenchymal tumors of intermediate differentiation (PPTIDs). Previous reports, however, had modest sample sizes and lacked the power to integrate molecular and clinical findings. The different proposed molecular group structures also highlighted a need to reach consensus on a robust and relevant classification system. We performed a meta-analysis on 221 patients with molecularly characterized PBs and PPTIDs. DNA methylation profiles were analyzed through complementary bioinformatic approaches and molecular subgrouping was harmonized. Demographic, clinical, and genomic features of patients and samples from these pineal tumor groups were annotated. Four clinically and biologically relevant consensus PB groups were defined: PB-miRNA1 (n = 96), PB-miRNA2 (n = 23), PB-MYC/FOXR2 (n = 34), and PB-RB1 (n = 25). A final molecularly distinct group, designated PPTID (n = 43), comprised histological PPTID and PBs. Genomic and transcriptomic profiling allowed the characterization of oncogenic drivers for individual tumor groups, specifically, alterations in the microRNA processing pathway in PB-miRNA1/2, MYC amplification and FOXR2 overexpression in PB-MYC/FOXR2, RB1 alteration in PB-RB1, and KBTBD4 insertion in PPTID. Age at diagnosis, sex predilection, and metastatic status varied significantly among tumor groups. While patients with PB-miRNA2 and PPTID had superior outcome, survival was intermediate for patients with PB-miRNA1, and dismal for those with PB-MYC/FOXR2 or PB-RB1. Reduced-dose CSI was adequate for patients with average-risk, PB-miRNA1/2 disease. We systematically interrogated the clinical and molecular heterogeneity within pineal parenchymal tumors and proposed a consensus nomenclature for disease groups, laying the groundwork for future studies as well as routine use in tumor diagnostic classification and clinical trial stratification.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors would like to thank the clinical and research staff of participating sites for contributing to the care and study of all involved patients, collaborators of the Rare Brain Tumor Consortium (Rarebraintumorconsortium.ca), German Cancer Research Center, and St. Jude Children’s Research Hsopital. We are grateful to Dr. Carmine Mottolese, Department of Pediatric Neurosurgery, Hôpital Femme Mère Enfant, Hospices Civils de Lyon for his neurosurgical expertise. We would like to acknowledge the MSK Kids Pediatric Translational Medicine Program (PTMP), the Director of the PTMP, Dr. Neerav Shukla, and the Scarlett Fund for their support with the data generation and curation. Funding was provided by American Lebanese Syrian Associated Charities, National Cancer Institute Cancer Center Grant (P30 CA021765) to St. Jude Children’s Research Hospital, National Cancer Institute Cancer Center Grant (P30 CA008748) to Memorial Sloan Kettering Cancer Center, the German Childhood Cancer Foundation (DKS 2015.01; “Molecular Neuropathology 2.0—Increasing diagnostic accuracy in pediatric neurooncology”) (D.T.W.J.), the GPOH HIT-MED trial group (S.R.), the Friedberg Charitable Foundation (M.S.), the Making Headway Foundation to NYU (M.S.), b.r.a.i.n.child (B.K.L.), Garron Family Center Research Fellowship (B.K.L.), Canada Research Chair Award (A.H.), Canadian Cancer Society Research Institute Grant (A.H.), Canadian Institute of Health Research Grant (A.H.), and SickKids Foundation Pitblado Grant (A.H.).

Funding

The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

Author information

Authors and Affiliations

  1. Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Anthony P. Y. Liu, Giles W. Robinson & Amar Gajjar

  2. Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Anthony P. Y. Liu, Brian Gudenas & Paul A. Northcott

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

    Bryan K. Li, Eric Bouffet & Annie Huang

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

    Bryan K. Li, Cynthia Hawkins & Annie Huang

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

    Bryan K. Li, Cynthia Hawkins & Annie Huang

  6. Hopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany

    Elke Pfaff, Felix Sahm, Marcel Kool, Stefan M. Pfister & David T. W. Jones

  7. Pediatric Glioma Research Group (B360), German Cancer Research Center (DKFZ), Hopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany

    Elke Pfaff & David T. W. Jones

  8. Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany

    Elke Pfaff & Stefan M. Pfister

  9. Faculté de Médecine Lyon Est, Université Claude Bernard, Lyon 1, Lyon, France

    Alexandre Vasiljevic

  10. Service D’Anatomie Et Cytologie Pathologiques, CHU de Lyon, Lyon, France

    Alexandre Vasiljevic

  11. Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Brent A. Orr

  12. Department of Pediatric and Adolescent Oncology, Gustave Roussy, Villejuif, France

    Christelle Dufour

  13. INSERM, Molecular Predictors and New Targets in Oncology, Paris-Saclay University, Villejuig, France

    Christelle Dufour

  14. Division of Neuropathology, NYU Langone Health, New York, USA

    Matija Snuderl

  15. Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, USA

    Matija Snuderl

  16. Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, USA

    Matthias A. Karajannis, Max Levine & Nancy Bouvier

  17. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA

    Marc K. Rosenblum

  18. Children’s National Medical Center, Washington, DC, USA

    Eugene I. Hwang

  19. Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China

    Ho-Keung Ng

  20. Children’s Cancer Centre, The Royal Children’s Hospital; Murdoch Children’s Research Institute; Department of Pediatrics, University of Melbourne, Melbourne, VIC, Australia

    Jordan R. Hansford

  21. Département de Neurochirurgie Pédiatrique, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France

    Alexandru Szathmari

  22. Institut D’Hématologie Et D’Oncologie Pédiatrique, IHOPe, Lyon, France

    Cécile Faure-Conter

  23. Department of Radiation Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Thomas E. Merchant

  24. Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany

    Katja von Hoff

  25. Department of Paediatric Haematology and Oncology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany

    Martin Mynarek & Stefan Rutkowski

  26. Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany

    Felix Sahm

  27. Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany

    Felix Sahm

  28. Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Marcel Kool & Stefan M. Pfister

  29. Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands

    Marcel Kool

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

    Cynthia Hawkins

  31. Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Arzu Onar-Thomas

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

    Annie Huang

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  1. Anthony P. Y. Liu
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Contributions

Study Design: APYL, BKL, EP, BG, PAN, DTWJ, AH Data generation: APYL, BKL, EP, BG, AV, BAO, CD, MS, MAK, MKR, ML, NB, EIH, HKN, MK, CH, PAN, DTWJ, AH Data analysis: APYL, BKL, EP, BG, AOT Project support: AV, BAO, CD, MS, MAK, MKR, ML, NB, EIH, HKN, JRH, AS, CFC, TEM, KvH, MM, SR, FS, MK, CH, AOT, GWR, AG, SMP, EB Manuscript preparation (with feedback from all authors): APYL, BKL, EP, BG, PAN, DTWJ, AH Study supervision and funding: PAN, DTWJ, AH

Corresponding author

Correspondence to Annie Huang.

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The authors declare no conflict of interest.

Ethics committee approval

Clinical data and tumor material were obtained according to Institutional Review Board approval from St. Jude Children's Research Hospital, Hospital for Sick Children, and contributing sites to German Cancer Research Center.

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Anthony P. Y. Liu, Bryan K. Li, Elke Pfaff and Brian Gudenas shared first authors.

Paul A. Northcott, David T.W. Jones and Annie Huang shared senior authors.

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Liu, A.P.Y., Li, B.K., Pfaff, E. et al. Clinical and molecular heterogeneity of pineal parenchymal tumors: a consensus study. Acta Neuropathol 141, 771–785 (2021). https://doi.org/10.1007/s00401-021-02284-5

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