Risk-adapted therapy and biological heterogeneity in pineoblastoma: integrated clinico-pathological analysis from the prospective, multi-center SJMB03 and SJYC07 trials
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Pineoblastoma 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.
KeywordsPineoblastoma Clinical trial Molecular subgroups DICER1 MicroRNA processing FOXR2
We thank all patients and families, physicians, and nursing, research, and administrative staff from all participating institutions. We appreciate the following core facilities at St Jude Children’s Research Hospital: the Biorepository, for providing and processing study tissues; the Diagnostic Biomarkers Shared Resource, for nucleic acid extractions; the Hartwell Center, for conducting DNA-methylation profiling and next-generation sequencing. We thank Brandon Stelter for assistance with figure preparation and artwork and Cherise Guess, PhD, ELS, for editing the manuscript.
Conception and design: Anthony P.Y. Liu, Arzu Onar-Thomas, David Ellison, Frederick A. Boop, Thomas E. Merchant, Giles W. Robinson, Paul A. Northcott, Amar Gajjar. Provision of study material or patients: Brent A. Orr, Paul Klimo Jr., Eric Bouffet, Sridharan Gururangan, John R. Crawford, Stewart J. Kellie, Murali Chintagumpala, Michael Fisher, Daniel C. Bowers, Tim Hassall, David Ellison, Frederick A. Boop, Thomas E. Merchant, Giles W. Robinson, Paul A. Northcott, and Amar Gajjar. Collection and assembly of data: All authors. Data analysis and interpretation: Anthony P.Y. Liu, Brian Gudenas, Tong Lin, Brent A. Orr, Arzu Onar-Thomas, Giles W. Robinson, Paul A. Northcott, and Amar Gajjar. Manuscript writing: All authors. Final approval of manuscript: All authors. Accountable for all aspects of the work: All authors.
This work was sponsored by the American Lebanese Syrian Associated Charities, the National Cancer Institute (Grant No. CA21765), and Musicians Against Childhood Cancer. P.A.N. is a Pew-Stewart Scholar for Cancer Research (Margaret and Alexander Stewart Trust) and recipient of The Sontag Foundation Distinguished Scientist Award. P.A.N. was also supported by the National Cancer Institute (Grant no. R01CA232143-01), American Association for Cancer Research (NextGen Grant for Transformative Cancer Research), The Brain Tumour Charity (Quest for Cures), the American Lebanese Syrian Associated Charities (ALSAC), and St. Jude.
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Conflict of interest
The author declares that they have no competing interests.
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