ID #452 DNA Repair Gene Variants of the RAD Family in Pediatric CNS Tumors: Clinical and Molecular Insights
Giada Del Baldo, Selene Cipri, Antonella Cacchione, Emanuele Agolini, Sabrina Rossi, Andrea Carai, Giovanna Stefania Colafati, Marco Tartaglia, Luigi Boccuto, Angela MastronuzziAbstract
Background
Defects in the DNA damage response, particularly within the homologous recombination (HR) pathway, are increasingly recognized as drivers of cancer predisposition. Members of the RAD gene family are central to HR-mediated DNA repair, yet their role in pediatric central nervous system (CNS) tumor susceptibility remains poorly characterized.
Methods
We performed a descriptive analysis of 84 pediatric patients with CNS tumors who underwent germline testing including RAD family genes. Clinical, histopathological, and family history data were collected. Variants were classified according to ACMG criteria. Trio analysis was performed when available, and tumor tissue sequencing was conducted in selected cases.
Results
Thirteen patients (15.5%) harbored germline variants in RAD genes. The most frequently involved genes were RAD54L (35.7%), RAD51D (28.7%), RAD50 (21.4%), RAD51B (7.1%), and RAD52 (7.1%). Diagnoses included high- and low-grade gliomas, medulloblastomas, ependymomas, germ cell tumors, and meningiomas. Pathogenic or likely pathogenic variants were identified in 3/13 patients (23.1%), while 10/13 (76.9%) carried variants of uncertain significance. A positive family history of cancer was present in 69.2% of cases. In selected patients, tumor sequencing confirmed the presence of HR-related alterations, supporting a biological role of these variants in tumorigenesis.
Conclusions
This study provides the first systematic description of germline RAD family gene variants in pediatric CNS tumors. Although limited by cohort size and heterogeneity, our findings suggest that inherited defects in HR may contribute to genomic instability and cancer predisposition in a subset of pediatric CNS tumor patients. Larger, dedicated studies integrating functional assays and familial segregation analyses are warranted to define the clinical relevance of RAD alterations and their implications for genetic counseling and surveillance.