Abstract 1203: The structural variation landscape of pediatric cancer
Authors: Robert Greenhalgh, Wentao Yang, Diane A. Flasch, Samuel W. Brady, Yanling Liu, Karol A. Szlachta, Liqing Tian, Jian Wang, Xin Zhou, Daniela S. Gerhard, Xiaotu Ma, Jinghui Zhang
Journal: Cancer Research (2025)

Abstract Despite contributing to over 60% of the driver variants in pediatric cancer, and in many cases acting as the cancer initiating event, structural variants (SVs) from a pediatric pan-cancer perspective remain understudied compared to those in adults. To explore the SV landscape of pediatric cancer, we mapped the SV burden, recurrence, signatures, and target genes of 1,616 pediatric cancer genomes encompassing 16 major cancer types: hematological malignancies (n=908), brain tumors (n=183), and solid tumors (n=525). These results were compared against SVs from an adult cohort (n=2,203) compiled by the Pan-Cancer Analysis of Whole Genomes (PCAWG) consortium. The SV burden in pediatric cases exhibited over 100-fold variability across cancer types, demonstrated a 7-8 fold reduction compared to adult solid and brain tumors, and remained at a comparable level in hematological malignancies. Complex genomic rearrangements (CGRs) and chromothripsis were detected at the highest rates in osteosarcoma (100% CGR; 53% chromothripsis), adrenocortical tumor (35%; 25%), and high-grade glioma (29%; 32%), and were significantly associated with TP53 mutation status. Unique to pediatric lymphoid cancers was the presence of recurrent hotspots of inter-tumor SV breakpoints. These hotspots, which were absent in the adult PCAWG samples, were associated with recombination-activating gene (RAG) signal sequences and disrupted 63 known driver genes as well as multiple immune-related loci. Signature analysis of the pediatric cohort yielded eight SV signatures — one of which was unique to pediatric cancer — with varying distributions across cancer types. Clustered translocations were abundant in osteosarcoma (likely caused by templated interchromosomal insertions), while medium-sized deletions (10 kb to 1 Mb), an SV signature with a currently unknown mechanism, appeared to be caused by RAG-mediated recombination given their enrichment in lymphoid cancers. An exploratory analysis of multiple spatiotemporally distinct samples also revealed that RAG-mediated recombination and templated insertions continued to play an ongoing role in the evolution of pediatric leukemia and solid tumors, respectively. When considering the frequency of SV breakpoints in gene coding regions, we found that fragile sites and driver genes (including those activated by enhancer hijacking) were the two genomic regions most frequently disrupted by pediatric SVs. The unique and diverse SV landscapes that emerged from this comprehensive analysis will serve as a valuable resource for guiding future functional studies and the design of clinical genomic testing in pediatric cancer. Citation Format: Robert Greenhalgh, Wentao Yang, Diane A. Flasch, Samuel W. Brady, Yanling Liu, Karol A. Szlachta, Liqing Tian, Jian Wang, Xin Zhou, Daniela S. Gerhard, Xiaotu Ma, Jinghui Zhang. The structural variation landscape of pediatric cancer [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 1203.