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

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.

Fig. 1

Cohort composition and key clinical outcomes. (a) The cohort was assembled from two multi-center studies (SJMB03, SJYC07) and a NPTP cohort. Patients were included based on histology and molecular grouping. All samples were molecularly characterized by DNA methylation profiling into methylation classes. Treatment was divided into CSI-containing (SJMB03 and SJMB03-like) and CSI-sparing therapy (SJYC07 and SJYC07-like) and palliative therapy. (b) EFS and OS of the whole cohort. EFS by (c) metastatic status (M0 vs M+); (d) age [< 3years (red), 3–6 years (blue) >6 years (yellow)]; (e) surgical EOR (STR/Biop vs GTR/NTR; (f) histology [PNET/HGNET/CNS-Embryonal Tumor (blue); non-PNET (red)]; (g) enrollment on protocol [Protocol, (SJMB03 or SJYC07) vs NPTP]; (h) type of protocol (SJYC07 vs SJMB03); (i) CSI (blue) vs no CSI in frontline therapy (red). (j) CSI (blue) vs Focal RT (orange) vs Chemotherapy only (red) in frontline therapy. Abbreviations: AR, average-risk; Biop, biopsy; CNS, central nervous system; CNS-ET-NEC/NOS, CNS embryonal tumor not elsewhere defined/not otherwise specified; CNS-SARC-CIC, CNS sarcoma with CIC rearrangement; CNS-SARC-DICER, CNS sarcoma with DICER mutation; CNS-NB-FOXR2, CNS neuroblastoma with FOXR2 activation; CSI, craniospinal irradiation; EFS, event-free survival; ETMR, embryonal tumor with multilayered rosettes; GBM, glioblastoma; GTR, gross-total resection; HGNET, high-grade neuroepithelial tumor; HGNET-BCOR, high-grade neuroepithelial tumor with BCOR alteration; HR, high-risk; IR, intermediate-risk; LR low-risk; M0, non-metastatic; M+, metastatic; NPTP, non-protocol treatment plan; NTR, near-total resection; PNET, primitive neuro-ectodermal tumor; RT, radiation therapy.

Fig. 2

Categorization of cohort into molecular groups with outcomes and genomic alterations. (a) TSNE clustering of cohort samples against reference classes in the Capper dataset [1]. Samples from this study appear as solid-colored circles over reference samples shown in faded colors. Entities unto which our cohort samples matched or clustered near are highlighted in boxes with increased font size. (b) Alluvial plot shows the relationship between histology, TSNE clustering, TSNE category (where HGG entities are consolidated), and MNP classifier. (c-d) EFS and overall OS by TSNE category. (e) Oncoprint aligning clinical features (age, gender, metastasis, histology, primary treatment, extent of resection, type of study, progressive disease, death) with molecular findings (TSNE classification, MNP classification, mutational burden, cytogenetic whole-chromosomal arm alterations, gene fusions, focal copy number alterations, germline mutations and somatic mutations). Abbreviations: CNS, central nervous system, CNS-BCOR-FUS, CNS tumor with BCOR fusion; CNS-BCOR-ITD, CNS tumor with BCOR ITD; CNS-ET-NEC/NOS, CNS embryonal tumor not elsewhere defined/not otherwise specified; CNS-SARC-CIC, CNS sarcoma with CIC rearrangement; CNS-SARC-DICER, CNS sarcoma with DICER mutation, CNS-NB-FOXR2, CNS neuroblastoma with FOXR2 activation; CPC, choroid plexus carcinoma; CPC-AD, choroid plexus carcinoma adult subtype; CSI, craniospinal irradiation; DHG-G34, diffuse hemispheric glioma H3 G34 mutant; ETMR, embryonal tumor with multilayered rosettes; ETMR-C19MC, embryonal tumor with multilayered rosettes with C19 microRNA cluster; ETMR-Atyp, embryonal tumor with multilayered rosettes atypical; EWS, Ewing’s Sarcoma; F, female; G34, high-grade glioma subclass G34; GTR, gross-total resection; HGG, high-grade glioma; HGNET, high-grade neuroepithelial tumor; HGNET-BCOR, high-grade neuroepithelial tumor with BCOR alteration; HGNET-PLAG, high-grade neuroepithelial tumor with PLAG alteration; ITD, internal tandem duplication; M, male; M0, non-metastatic; M+, metastatic; MB, medulloblastoma; MID, high-grade glioma subclass MID; MNP, 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; PXA, pleomorphic xanthoastrocytoma; RT, radiation therapy; RTK_III, high-grade glioma subclass RTKIII; STR, subtotal resection; TSNE, t-stochastic neighbor embedding.

Fig. 3

Molecular and clinical characteristics of ETMR tumors. (a) Oncoprint aligning clinical features with molecular findings. (b-c) EFS and OS by treatment category. Abbreviations: CNS, central nervous system, ETMR, embryonal tumor with multilayered rosettes; ETMR-C19MC, embryonal tumor with multilayered rosettes with C19 microRNA cluster; ETMR-Atyp, embryonal tumor with multilayered rosettes atypical; F, female; HGNET, high-grade neuroepithelial tumor; M, male; M0, non-metastatic; M+, metastatic; MB, medulloblastoma; MNP Classifier, Molecular Neuropathology brain tumor classifier; NTR, near-total resection; PNET, primitive neuro-ectodermal tumor; RT, radiation therapy; STR, subtotal resection; TSNE, t-stochastic neighbor embedding.

Fig. 4

Molecular and clinical characteristics of HGNET-BCOR tumors. (a) Oncoprint aligning clinical features with molecular findings. (b-c) EFS and OS by treatment category. (d) Swimmer plot depicting all the different therapies (surgery, primary and relapse treatment) received from diagnosis through follow up by patients in this cohort. Abbreviations: AR, average risk; CNS, central nervous system, CNS-BCOR-FUS, CNS tumor with BCOR fusion; CNS-BCOR-ITD, CNS tumor with BCOR ITD; CSI, craniospinal irradiation; F, female; GTR, gross-total resection; HGG, high-grade glioma; HGNET, high-grade neuroepithelial tumor; HGNET-BCOR, high-grade neuroepithelial tumor with BCOR alteration; IR, intermediate-risk; ITD, internal tandem duplication; LR, low-risk; M, male; M0, non-metastatic; M+, metastatic; MNP classifier, Molecular Neuropathology brain tumor classifier; NPTP, non-protocol treatment plan; PNET, primitive neuro-ectodermal tumor; RT, radiation therapy; STR, subtotal resection; TSNE, t-stochastic neighbor embedding.

Fig. 5

Molecular and clinical characteristics of CNS-SARC-CIC tumors. (a) Oncoprint aligning clinical features with molecular findings. (b-c) EFS and OS by treatment category. Abbreviations: CNS, central nervous system, CNS-SARC-CIC, CNS sarcoma with CIC rearrangement; CSI, craniospinal irradiation; F, female; GTR, gross-total resection; HGG, high-grade glioma; HGNET, high-grade neuroepithelial tumor; M, male; M0, non-metastatic; MNP, Molecular Neuropathology brain tumor classifier; NPTP, non-protocol treatment plan; PNET, primitive neuro-ectodermal tumor; RT, radiation therapy; TSNE, t-stochastic neighbor embedding.

Fig. 6

Molecular and clinical characteristics of CNS-NB-FOXR2 tumors. (a) Oncoprint aligning clinical features with molecular findings. (b) Box plots for FOXR2 and SOX10 genes show higher expression (transcript per million, TPM) in CNS-NB-FOXR2 samples than in other CNS embryonal tumors (c-d) EFS and OS by treatment category. Abbreviations: CNS, central nervous system, CNS-SARC-CIC, CNS sarcoma with CIC rearrangement; CNS-SARC-DICER, CNS sarcoma with DICER mutation, CNS-NB-FOXR2, CNS neuroblastoma with FOXR2 activation; CSI, craniospinal irradiation; ETMR, embryonal tumor with multilayered rosettes; F, female; GTR, gross-total resection; HGG, high-grade glioma; HGNET, high-grade neuroepithelial tumor; HGNET-BCOR, high-grade neuroepithelial tumor with BCOR alteration; M, male; M0, non-metastatic; MNP classifier, Molecular Neuropathology brain tumor classifier; NPTP, non-protocol treatment plan; NTR, near-total resection; PNET, primitive neuro-ectodermal tumor; RT, radiation therapy; STR, subtotal resection; TSNE, t-stochastic neighbor embedding.