Molecular subclassification and CSF liquid biopsy guide risk-adapted therapy in infant CNS embryonal tumors
The study reports that molecular profiling using DNA methylation arrays and next-generation sequencing now redefines diagnostic classification and risk stratification for infant central nervous system embryonal tumors. Investigators found that distinct molecular subgroups, including SHH-activated medulloblastoma and AT/RT variants, directly inform treatment paradigms that increasingly aim to delay or avoid craniospinal irradiation to protect the developing brain. The authors note that cerebrospinal fluid liquid biopsy and targeted therapies are being integrated into risk-adapted clinical approaches. For molecular diagnostic laboratories, the review underscores the necessity of routine methylation and sequencing-based subclassification to enable precision oncology and guide enrollment in collaborative pediatric trials.
The original study
Infant Embryonal CNS Tumors: Molecular Insights and Treatment Considerations for Contemporary Pediatric Neuro-Oncology.
- Authors
- Damodharan S, Wright-Nadkarni M, Abdelbaki MS, Dhall G
- Journal
- Pediatric blood & cancer
- Type
- Journal Article, Review
- PMID
- 42622520
Original abstract
BACKGROUND: Embryonal tumors comprise the majority of malignant central nervous system (CNS) neoplasms diagnosed in children under 3 years of age. Compared with their counterparts in older children, these tumors exhibit distinct molecular biology and a more aggressive clinical phenotype, while their management is complicated by the heightened vulnerability of the developing brain to acute toxicity and long-term sequelae from surgery, chemotherapy, and radiotherapy. OBJECTIVES: To summarize the contemporary understanding of infant CNS embryonal tumors, including molecular classification, treatment paradigms, and emerging therapeutic strategies, and to outline a framework for molecularly driven, risk-adapted management. DESIGN AND METHODS: We performed a narrative review of published cooperative-group, consortium, and single-institution trials in medulloblastoma, atypical teratoid/rhabdoid tumor (AT/RT), embryonal tumor with multilayered rosettes (ETMR), pineoblastoma, and other infant CNS embryonal entities, integrating findings with the 2021 WHO Classification of CNS Tumors and recent DNA methylation- and next-generation sequencing-based subclassifications. RESULTS: Molecular profiling has reshaped diagnosis and risk stratification across all infant embryonal entities, identifying clinically actionable subgroups (e.g., SHH-I/II in medulloblastoma; AT/RT-TYR, -SHH, -MYC; ETMR with C19MC or DICER1 alterations; pineoblastoma molecular subgroups). Multimodal regimens that delay or avoid craniospinal irradiation have achieved durable survival in favorable-risk SHH-activated medulloblastoma, while outcomes remain poor for Group 3 medulloblastoma, ETMR, pineoblastoma, and metastatic AT/RT. Investigational targeted and immunotherapeutic strategies, intraventricular methotrexate, proton-beam radiotherapy, and cerebrospinal fluid liquid biopsy are increasingly being incorporated into risk-adapted approaches. CONCLUSION: Molecularly driven, risk-adapted clinical trials and international collaborative registries are essential to advance care for infants with CNS embryonal tumors, with the dual goals of improving survival and reducing treatment-related neurodevelopmental morbidity.