Abstract
Methylation profiling has radically transformed our understanding of tumors previously called central nervous system primitive neuro-ectodermal tumors (CNS-PNET). While this marks a momentous step toward defining key differences, reclassification has thrown treatment into disarray. To shed light on response to therapy and guide clinical decision-making, we report outcomes and molecular features of children with CNS-PNETs from two multi-center risk-adapted studies (SJMB03 for patients ≥ 3 years; SJYC07 for patients < 3 years) complemented by a non-protocol institutional cohort. Seventy patients who had a histological diagnosis of CNS-PNET or CNS embryonal tumor from one of the new categories that has supplanted CNS-PNET were included. This cohort was molecularly characterized by DNA methylation profiling (n = 70), whole-exome sequencing (n = 53), RNA sequencing (n = 20), and germline sequencing (n = 28). Clinical characteristics were detailed, and treatment was divided into craniospinal irradiation (CSI)-containing (SJMB03 and SJMB03-like) and CSI-sparing therapy (SJYC07 and SJYC07-like). When the cohort was analyzed in its entirety, no differences were observed in the 5-year survival rates even when CSI-containing therapy was compared to CSI-sparing therapy. However, when analyzed by DNA methylation molecular grouping, significant survival differences were observed, and treatment particulars provided suggestions of therapeutic response. Patients with CNS neuroblastoma with FOXR2 activation (CNS-NB-FOXR2) had a 5-year event-free survival (EFS)/overall survival (OS) of 66.7% ± 19.2%/83.3% ± 15.2%, and CIC rearranged sarcoma (CNS-SARC-CIC) had a 5-year EFS/OS both of 57.1% ± 18.7% with most receiving regimens that contained radiation (focal or CSI) and multidrug chemotherapy. Patients with high-grade neuroepithelial tumor with BCOR alteration (HGNET-BCOR) had abysmal responses to upfront chemotherapy-only regimens (5-year EFS = 0%), but survival extended with salvage radiation after progression [5-year OS = 53.6% ± 20.1%]. Patients with embryonal tumor with multilayered rosettes (ETMR) or high-grade glioma/glioblastoma multiforme (HGG/GBM) did not respond favorably to any modality (5-year EFS/OS = 10.7 ± 5.8%/17.9 ± 7.2%, and 10% ± 9.0%/10% ± 9.0%, respectively). As an accompaniment, we have assembled this data onto an interactive website to allow users to probe and query the cases. By reporting on a carefully matched clinical and molecular cohort, we provide the needed insight for future clinical management.
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Acknowledgements
The authors acknowledge patients and families, nursing, and research staff from all participating institutions. In particular, we thank the St. Jude Biorepository for archiving and preservation of patient samples, the Cancer Biomarkers Lab for the processing of samples, the St. Jude Hartwell Center for next-generation sequencing, the St Jude Center for Applied Bioinformatics for assistance with bioinformatic analysis. Funding was provided by American Lebanese Syrian Associated Charities and National Cancer Institute Cancer Center Grant (P30CA021765), St. Jude Comprehensive Cancer Center Developmental Funds, and The Press on Fund.
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Supplementary Fig. S1
Schematic summary of treatment approach from (a) SJMB03 and (b) SJYC07 (PNG 197 KB)
Supplementary Fig. S2
Overall survival analysis for whole cohort, by gender, metastatic status, age, extent of resection, histology, enrollment on protocol, protocol, receipt of CSI, receipt of CSI or focal RT. Abbreviations: Biop, biopsy; CNS, central nervous system; CNS-ET, CNS-embryonal tumor; CSI, craniospinal irradiation; EFS, event-free survival; EOR, extent of resection; GTR, gross-total resection; HGNET, high-grade neuroepithelial tumor; M0, non-metastatic; M+, metastatic; NPTP, non-protocol treatment plan; NTR, near-total resection; OS, overall survival; PNET, primitive neuro-ectodermal tumor; RT, radiation therapy (PNG 760 KB)
Supplementary Fig. S3
Event-free survival and overall survival by primary treatment risk. Abbreviations: AR, average risk, EFS, event-free survival; HR, high-risk; IR, intermediate-risk; LR, low-risk; OS, overall survival; PNET, primitive neuro-ectodermal tumor (PNG 499 KB)
Supplementary Fig. S4
Molecular and clinical characteristics of CNS-SARC-DICER tumors. (a) Oncoprint aligning clinical features with molecular findings. (b-c) EFS and OS by treatment category. Abbreviations: CNS, central nervous system, CNS-SARC-DICER, CNS sarcoma with DICER mutation; CSI, craniospinal irradiation; F, female; GTR, gross-total resection; HGNET, high-grade neuroepithelial tumor; M, male; M0, non-metastatic; M+, metastatic; MNP classifier, Molecular Neuropathology brain tumor classifier; NPTP, non-protocol treatment plan; PNET, primitive neuro-ectodermal tumor; TSNE, t-stochastic neighbor embedding (PNG 453 KB)
Supplementary Fig. S5
Molecular and clinical characteristics of HGG tumors. (a) Oncoprint aligning clinical features with molecular findings. (b-c) EFS and OS by treatment category. Abbreviations: CNS, central nervous system; CSI, craniospinal irradiation; DHG-G34, diffuse hemispheric glioma H3 G34 mutant; F, female; G34, high-grade glioma subclass G34; GTR, gross-total resection; HGG, high-grade glioma; HGNET, high-grade neuroepithelial tumor; M, male; M0, non-metastatic; M+, metastatic; MID, high-grade glioma subclass MID; MNP classifier, Molecular Neuropathology brain tumor classifier; MYCN, high-grade glioma subclass MYCN; NPTP, non-protocol treatment plan; NTR, near-total resection; pedHGG-MYCN, pediatric-type high-grade glioma, subclass MYCN; pedHGG-RTK1C, pediatric-type high-grade glioma, subclass RTK1C; PNET, primitive neuro-ectodermal tumor; RT, radiation therapy; RTK_III, high-grade glioma subclass RTKIII; STR, subtotal resection; TSNE, t-stochastic neighbor embedding (PNG 651 KB)
Supplementary Fig. S6
Molecular and clinical characteristics of CNS-ET-NEC/NOS tumors. (a) Oncoprint aligning clinical features with molecular findings. (b-c) EFS and OS by treatment category. Abbreviations: CNS, central nervous system; CSI, craniospinal irradiation; F, female; GTR, gross-total resection; HGNET, high-grade neuroepithelial tumor; HGNET-PLAG, high-grade neuroepithelial tumor with PLAG alteration; M, male; M0, non-metastatic; MNP classifier, Molecular Neuropathology brain tumor classifier; pedHGG-MYCN, pediatric-type high-grade glioma, subclass MYCN; PNET, primitive neuro-ectodermal tumor; RT, radiation therapy; STR, subtotal resection; TSNE, t-stochastic neighbor embedding (PNG 558 KB)
Supplementary Fig. S7
Fusion plots for (a) ETMR: TTYH1 is fused with MIR512 (SJBT031447) and MIR373 (SJHGG030284) on chromosome 19; (b) HGNET-BCOR: BCOR-ITD is shown in 3 cases (SJBT032267, SJBT032239, SJHGG030319); KDM2B-NUTM1 is shown in 1 (SJBT30377); and BCOR-EP300 and BCOR-L3MBTL2 are shown in 2 (SJBT031672, SJBT076946). (c) CNS-SARC-CIC: CIC is involved in 3 cases (SJBT030809, SJBT030477, SJBT030086, SJBT032239) and ATXN1 in one (SJBT030703) (PNG 535 KB)
Supplementary Table S1
Metadata for the study cohort. (XLSX 25 KB)
Supplementary Table S2
Filtered list of variants called from whole-exome sequencing (XLSX 19 KB)
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Liu, A.P.Y., Dhanda, S.K., Lin, T. et al. Molecular classification and outcome of children with rare CNS embryonal tumors: results from St. Jude Children’s Research Hospital including the multi-center SJYC07 and SJMB03 clinical trials. Acta Neuropathol 144, 733–746 (2022). https://doi.org/10.1007/s00401-022-02484-7
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DOI: https://doi.org/10.1007/s00401-022-02484-7