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Article: Risk-adapted therapy and biological heterogeneity in pineoblastoma: integrated clinico-pathological analysis from the prospective, multi-center SJMB03 and SJYC07 trials

TitleRisk-adapted therapy and biological heterogeneity in pineoblastoma: integrated clinico-pathological analysis from the prospective, multi-center SJMB03 and SJYC07 trials
Authors
KeywordsPineoblastoma
Clinical trial
Molecular subgroups
DICER1
MicroRNA processing
Issue Date2020
PublisherSpringer Verlag. The Journal's web site is located at http://link.springer.de/link/service/journals/00401/index.htm
Citation
Acta Neuropathologica, 2020, v. 139, p. 259-271 How to Cite?
AbstractPineoblastoma is a rare embryonal tumor of childhood that is conventionally treated with high-dose craniospinal irradiation (CSI). Multi-dimensional molecular evaluation of pineoblastoma and associated intertumoral heterogeneity is lacking. Herein, we report outcomes and molecular features of children with pineoblastoma from two multi-center, risk-adapted trials (SJMB03 for patients ≥ 3 years; SJYC07 for patients < 3 years) complemented by a non-protocol institutional cohort. The clinical cohort consisted of 58 patients with histologically diagnosed pineoblastoma (SJMB03 = 30, SJYC07 = 12, non-protocol = 16, including 12 managed with SJMB03-like therapy). The SJMB03 protocol comprised risk-adapted CSI (average-risk = 23.4 Gy, high-risk = 36 Gy) with radiation boost to the primary site and adjuvant chemotherapy. The SJYC07 protocol consisted of induction chemotherapy, consolidation with focal radiation (intermediate-risk) or chemotherapy (high-risk), and metronomic maintenance therapy. The molecular cohort comprised 43 pineal parenchymal tumors profiled by DNA methylation array (n = 43), whole-exome sequencing (n = 26), and RNA-sequencing (n = 16). Respective 5-year progression-free survival rates for patients with average-risk or high-risk disease on SJMB03 or SJMB03-like therapy were 100% and 56.5 ± 10.3% (P = 0.007); respective 2-year progression-free survival rates for those with intermediate-risk or high-risk disease on SJYC07 were 14.3 ± 13.2% and 0% (P = 0.375). Of patients with average-risk disease treated with SJMB03/SJMB03-like therapy, 17/18 survived without progression. DNA-methylation analysis revealed four clinically relevant pineoblastoma subgroups: PB-A, PB-B, PB-B–like, and PB-FOXR2. Pineoblastoma subgroups differed in age at diagnosis, propensity for metastasis, cytogenetics, and clinical outcomes. Alterations in the miRNA-processing pathway genes DICER1, DROSHA, and DGCR8 were recurrent and mutually exclusive in PB-B and PB-B–like subgroups; PB-FOXR2 samples universally overexpressed the FOXR2 proto-oncogene. Our findings suggest superior outcome amongst older children with average-risk pineoblastoma treated with reduced-dose CSI. The identification of biologically and clinically distinct pineoblastoma subgroups warrants consideration of future molecularly-driven treatment protocols for this rare pediatric brain tumor entity.
Descriptioneid_2-s2.0-85077202384
Persistent Identifierhttp://hdl.handle.net/10722/287690
ISSN
2019 Impact Factor: 14.251
2015 SCImago Journal Rankings: 6.610
PubMed Central ID
Errata

 

DC FieldValueLanguage
dc.contributor.authorLiu, APY-
dc.contributor.authorGudenas, B-
dc.contributor.authorLin, T-
dc.contributor.authorOrr, BA-
dc.contributor.authorKlimo, P-
dc.contributor.authorKumar, R-
dc.contributor.authorBouffet, E-
dc.contributor.authorGururangan, S-
dc.contributor.authorCrawford, JR-
dc.contributor.authorKellie, SJ-
dc.contributor.authorChintagumpala, M-
dc.contributor.authorFisher, MJ-
dc.contributor.authorBowers, DC-
dc.contributor.authorHassall, T-
dc.contributor.authorIndelicato, DJ-
dc.contributor.authorOnar-Thomas, A-
dc.contributor.authorEllison, DW-
dc.contributor.authorBoop, FA-
dc.contributor.authorMerchant, TE-
dc.contributor.authorRobinson, GW-
dc.contributor.authorNorthcott, PA-
dc.contributor.authorGajjar, A-
dc.date.accessioned2020-10-05T12:01:49Z-
dc.date.available2020-10-05T12:01:49Z-
dc.date.issued2020-
dc.identifier.citationActa Neuropathologica, 2020, v. 139, p. 259-271-
dc.identifier.issn0001-6322-
dc.identifier.urihttp://hdl.handle.net/10722/287690-
dc.descriptioneid_2-s2.0-85077202384-
dc.description.abstractPineoblastoma is a rare embryonal tumor of childhood that is conventionally treated with high-dose craniospinal irradiation (CSI). Multi-dimensional molecular evaluation of pineoblastoma and associated intertumoral heterogeneity is lacking. Herein, we report outcomes and molecular features of children with pineoblastoma from two multi-center, risk-adapted trials (SJMB03 for patients ≥ 3 years; SJYC07 for patients < 3 years) complemented by a non-protocol institutional cohort. The clinical cohort consisted of 58 patients with histologically diagnosed pineoblastoma (SJMB03 = 30, SJYC07 = 12, non-protocol = 16, including 12 managed with SJMB03-like therapy). The SJMB03 protocol comprised risk-adapted CSI (average-risk = 23.4 Gy, high-risk = 36 Gy) with radiation boost to the primary site and adjuvant chemotherapy. The SJYC07 protocol consisted of induction chemotherapy, consolidation with focal radiation (intermediate-risk) or chemotherapy (high-risk), and metronomic maintenance therapy. The molecular cohort comprised 43 pineal parenchymal tumors profiled by DNA methylation array (n = 43), whole-exome sequencing (n = 26), and RNA-sequencing (n = 16). Respective 5-year progression-free survival rates for patients with average-risk or high-risk disease on SJMB03 or SJMB03-like therapy were 100% and 56.5 ± 10.3% (P = 0.007); respective 2-year progression-free survival rates for those with intermediate-risk or high-risk disease on SJYC07 were 14.3 ± 13.2% and 0% (P = 0.375). Of patients with average-risk disease treated with SJMB03/SJMB03-like therapy, 17/18 survived without progression. DNA-methylation analysis revealed four clinically relevant pineoblastoma subgroups: PB-A, PB-B, PB-B–like, and PB-FOXR2. Pineoblastoma subgroups differed in age at diagnosis, propensity for metastasis, cytogenetics, and clinical outcomes. Alterations in the miRNA-processing pathway genes DICER1, DROSHA, and DGCR8 were recurrent and mutually exclusive in PB-B and PB-B–like subgroups; PB-FOXR2 samples universally overexpressed the FOXR2 proto-oncogene. Our findings suggest superior outcome amongst older children with average-risk pineoblastoma treated with reduced-dose CSI. The identification of biologically and clinically distinct pineoblastoma subgroups warrants consideration of future molecularly-driven treatment protocols for this rare pediatric brain tumor entity.-
dc.languageeng-
dc.publisherSpringer Verlag. The Journal's web site is located at http://link.springer.de/link/service/journals/00401/index.htm-
dc.relation.ispartofActa Neuropathologica-
dc.rightsThis is a post-peer-review, pre-copyedit version of an article published in [insert journal title]. The final authenticated version is available online at: https://doi.org/[insert DOI]-
dc.subjectPineoblastoma-
dc.subjectClinical trial-
dc.subjectMolecular subgroups-
dc.subjectDICER1-
dc.subjectMicroRNA processing-
dc.titleRisk-adapted therapy and biological heterogeneity in pineoblastoma: integrated clinico-pathological analysis from the prospective, multi-center SJMB03 and SJYC07 trials-
dc.typeArticle-
dc.identifier.emailLiu, APY: apyliu@hku.hk-
dc.identifier.authorityLiu, APY=rp01357-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1007/s00401-019-02106-9-
dc.identifier.pmid31802236-
dc.identifier.pmcidPMC7065912-
dc.identifier.scopuseid_2-s2.0-85077202384-
dc.identifier.hkuros315664-
dc.identifier.volume139-
dc.identifier.spage259-
dc.identifier.epage271-
dc.publisher.placeGermany-
dc.relation.erratumdoi:10.1007/s00401-019-02115-8-

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