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

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.

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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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  • DOI: https://doi.org/10.1007/s00401-019-02111-y

Keywords

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