EPCO-29. WHOLE-GENOME SEQUENCING REVEALS GENOMIC SIGNATURE OF INTRACRANIAL YOLK SAC TUMORS

Abstract Intracranial germ cell tumors (IGCTs), primarily affecting infants and children, exhibit malignancy and prognosis that largely depend on tumor histological subtypes. While somatic coding alterations have revealed activation of the MAPK and PI3K pathways in the germinoma subtype, the genetic basis of the more malignant yolk sac tumor (YST) subtype remains poorly understood. In this study, we analyzed whole-genome sequencing data from blood-tumor matched samples of 69 IGCT patients, identifying a significant enrichment of somatic chromosome 1p36 copy number loss in YST (7 out of 13 YST cases compared to 3 out of 56 non-YST cases). Further analysis of whole-genome level somatic single nucleotide variations revealed a YST-specific single base substitution signature (5 out of 13 YST cases), characterized by frequent ACG to AGG mutations. Alongside this novel signature, we observed a high burden of point mutations, structural variations, and LINE1 retrotransposition, indicating increased genomic instability in this subgroup of IGCTs. Additionally, association analyses revealed that these genomic instability events were significantly linked to the copy number loss of 1p36. These findings elucidate the distinct mutational landscape of YSTs and suggest potential treatment vulnerabilities for this subtype by targeting genomic instability.