CANCER PREDISPOSITION SYNDROMES AND BRAIN TUMORS IN CHILDHOOD

Pediatric brain tumors are the most common solid malignancies in childhood and remain a leading cause of cancer-related morbidity and mortality. A substantial proportion of these tumors arise in the context of cancer predisposition syndromes (CPS), a heterogeneous group of inherited genetic conditions characterized by increased lifetime cancer risk, early-onset tumor, and distinctive biological and clinical features. This PhD project addresses the major CPS of pediatric neuro-oncology relevance, neurofibromatosis type 1 (NF1), NF2-related schwannomatosis (NF2-SWN), Li–Fraumeni syndrome (LFS), Gorlin syndrome, constitutional mismatch repair deficiency (CMMRD), and von Hippel–Lindau (VHL) syndrome, with the aims of (i) extending knowledge on tumor spectra, (ii) optimizing risk-adapted surveillance strategies, (iii) supporting multidisciplinary management, and (iv) improving the access to innovative targeted therapies. A major component of the thesis focuses on NF1-associated optic pathway gliomas (OPG), a frequent CNS manifestation and a primary determinant of long-term visual morbidity. In a homogeneous monocentric cohort of pediatric patients with anterior OPG, longitudinal visual acuity (VA) and optical coherence tomography (OCT) assessments were integrated with MRI-derived, segmentation-based shape radiomics. Shape- and diameter-related radiomic features derived from 3D tumor segmentation were found to be correlated with visual and OCT outcomes over time, possibly indicating that tumor morphology and growth patterns con be informative in identifying eyes at risk for visual deterioration, especially when combined with quadrant-specific retinal nerve fiber layer thickness. Conversely, global RNFL measures did not show a consistent predictive relationship with VA decline across the cohort. A collaborative multicenter cohort of pediatric NF1-associated high-grade gliomas (HGG) is presented, supporting an aggressive clinical behavior comparable to sporadic HGG and highlighting recurrent alterations involving CDKN2A, TP53, and ATRX. Beyond NF1, the thesis incorporates complementary original contributions across other CPS. A rare, mechanistically informative report describes the first pediatric pleural mesothelioma occurring in NF2-SWN without asbestos exposure, characterized through combined germline and tumor profiling and showing atypical chromosomal alterations suggestive of a distinct pediatric genomic signature. In LFS, a large multinational cohort of pediatric medulloblastoma demonstrates poor survival overall, a strong enrichment for the SHH_3 methylation subgroup, and a significant survival benefit associated with radiotherapy, whereas chemotherapy intensity did not clearly modify outcome. An international collaborative analysis of LFS-related choroid plexus carcinoma indicates a poor prognosis, with outcomes broadly comparable to non-LFS TP53-mutated cases. For Gorlin syndrome, a paradigmatic case with synchronous medulloblastoma and cardiac fibroma and long-term follow-up supports prioritization of oncologic therapy with conservative, closely monitored cardiac management in selected patients, emphasizing multidisciplinary coordination. Finally, a VHL-related case report documents a very rapid response to belzutifan in intracranial and retinal hemangioblastomas, providing clinically relevant evidence for early functional and radiological monitoring during targeted therapy. Overall, this doctoral work supports the clinical value of a multimodal and integrated approach combining genetic background, advanced neuroimaging, and functional assessments in pediatric CPS. Furthermore, it emphasizes the critical importance of active participation in international collaborative networks and multicenter studies, which are essential to aggregate meaningful patient populations affected by rare genetic conditions and by even rarer oncological manifestations. The findings contribute to refining risk stratification, surveillance strategies, and timing of therapeutic interventions, with the ultimate goal of improving long-term outcomes and quality of life within structured, multidisciplinary care pathways.