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


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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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 (, 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.).


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

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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

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Correspondence to Annie Huang.

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The authors declare no conflict of interest.

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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).

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  • Pineoblastoma
  • Pineal parenchymal tumors of intermediate differentiation
  • DNA methylation profiling
  • Molecular groups
  • Consensus
  • Risk-stratification