Germline Predisposition in Pediatric Central Nervous System Tumors: Insights from a Multigene Panel Study.

Objectives

Germline variants in cancer predisposition genes have been increasingly recognized in pediatric cancers. However, their spectrum in East Asian children with central nervous system (CNS) tumors remains insufficiently defined. This study investigated the prevalence and clinical significance of pathogenic or likely pathogenic (P/LP) germline mutations in Korean children, adolescents, and young adults (AYAs) with CNS tumors.

Methods

We performed targeted next-generation sequencing of 358 cancer-associated genes using peripheral blood DNA from 108 patients. Germline variants were classified according to ACMG/AMP guidelines and curated using ClinVar and relevant literature.

Results

Among 108 patients, 17 (15.7%) carried P/LP germline variants. The median age at diagnosis was 7.7 years (range, 1.0-24.0), and 64.7% were male. P/LP variants were most frequent in other CNS tumors (4/11, 36.4%), including 2 glioneuronal tumors, 1 schwannoma, 1 atypical teratoid rhabdoid tumor (ATRT), and gliomas (9/32, 28.1%), followed by medulloblastomas (3/31, 9.7%). In gliomas, P/LP variants in MLH1, NF1, MUTYH, PALB2, PMS2, FANCM, and TP53 were observed, while medulloblastomas carried alterations in SUFU, BRIP1, and FANCI. SMARCB1 variant was found in ATRT. Among 25 patients with intracranial germ cell tumors, only a single case carried a P/LP germline variant, identified in FANCI.

Conclusion

Germline P/LP mutations were identified in 15.7% of Korean children and AYAs with CNS tumors, most commonly in gliomas and other CNS tumors. Our findings highlight the molecular heterogeneity of germline predisposition in CNS tumors and emphasize the importance of germline testing for risk assessment and surveillance.