Abstract 701: Understanding the genomic landscape of pediatric cancer predisposition

Abstract Once thought to be rare, 10% of pediatric cancers can be attributed to mutations in known cancer predisposition genes (CPGs). However, given that many pediatric cancers occur sporadically without germline mutations in the ∼114 known CPGs, it is plausible that previously unidentified mutations in novel genes and non-coding regions contribute to pediatric cancer development. This research aims to uncover novel germline mutations, to use somatic “second hits” to prioritize candidates for detailed multi-faceted analysis of downstream effects contributing to pediatric cancer predisposition and pathogenesis. Here we present an analysis of the largest pediatric burden testing cohort to date (>7, 000 tumor/normal) of WGS, WES and RNAseq data to explore the genetic landscape of childhood cancers. First, we combined multiple rare-variant burden testing methods, such as TRAPD, SKAT-O, CoCoRV, RV-EXCALIBER, to identify novel germline variants associated with cancer at both within and across pediatric cancer entities. Putative CPGs were prioritized by detecting somatic second hits in tumors, leveraging multiple genomic data types (SNVs, indels, structural variants (SVs), and copy number variations (CNVs). The impact of germline mutations on the somatic landscape was explored by examining how these variants influence tumor mutational profiles, including co-occurring mutations and mutational signatures. Single-cell RNA sequencing data were interrogated when available for pediatric brain tumors and sarcomas to determine how the identified germline genes influence the cell-of-origin and its malignant transformation. We will assess whether these mutations can be observed early in development and their potential causative role in specific tumor types. The findings from our comprehensive approach will deepen our understanding of the interplay between germline and somatic mutations in cancer, enhancing risk prediction and guiding precision oncology efforts. Citation Format: Martha O'Brien, Robert J. Autry, Olaf Witt, David Jones, Stefan Pfister. Understanding the genomic landscape of pediatric cancer predisposition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 701.