Germline Variants in Pediatric Cancer : Based on Oncogenic Pathways.

Abstract

Pathogenic germline variants (PGVs) are increasingly recognized as critical elements in pediatric cancer predisposition. Determining the pathogenicity of germline variants is a dynamic process, with advancements in next-generation sequencing (NGS) and expanding genome databases reshaping our understanding of cancer genomics. This article reviews the role of PGVs in key oncogenic pathways, including RTK/RAS/MAPK, PI3K/AKT, WNT, and Hedgehog signaling, highlighting their associations with specific cancer predisposition syndromes and neurosurgical implications. Most PGVs are inherited in an autosomal dominant pattern and are frequent in tumor suppressor genes, while autosomal recessive conditions like Ataxia-telangiectasia and Fanconi anemia are less common. Germline variants in proto-oncogenes such as PTPN11, KRAS, and HRAS are associated with RASopathies, including Noonan and Costello syndromes, which show variable cancer risks. Similarly, PTEN PGVs, linked to Cowden syndrome, and DICER1 PGVs, responsible for DICER1 syndrome, exemplify the diverse clinical presentations and risks of pediatric cancer predisposition syndromes. Medulloblastoma, a pediatric-specific brain tumor, shows an increasing proportion of PGVs, with approximately 12% of all medulloblastomas harboring PGVs in APC, PTCH1, SUFU, and ELP1 in the WNT-activated and SHH-activated subtypes. Emerging evidence suggests that approximately 8.5-20% of pediatric cancer patients harbor PGVs, with a substantial proportion arising de novo. Routine germline screening for pediatric cancer patients is increasingly recommended, as many PGVs lack family history. Programs like STREAM (Solid Tumor REsearch And Magic) in Korea underscore the importance of comprehensive pediatric genome databases for personalized precision medicine. As neurosurgeons are frequently the first to encounter central nervous system tumor manifestations, a robust understanding of genomic medicine is essential. This review emphasizes the need for international collaboration to develop actionable insights into pediatric cancer genomics, ultimately improving diagnostic, therapeutic, and preventive strategies.