The landscape of structural variation in pediatric cancer

作者：Robert Greenhalgh, Wentao Yang, Samuel W. Brady, Diane A. Flasch, Yanling Liu, Karol Szlachta, Liqing Tian, Pandurang Kolekar, Jian Wang, Xin Zhou, Daniela S. Gerhard, Xiaotu Ma, Jinghui Zhang · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2025 · DOI：10.1101/2025.04.24.650284 · 被引用次数：3 · 研究领域：Acute Lymphoblastic Leukemia research、Cancer Genomics and Diagnostics、DNA Repair Mechanisms

Structural variants (SVs) account for over 60% of the driver variants in pediatric cancer, and in many cases act as the cancer initiating event. To study SVs from a pan-cancer perspective, we analyzed 1,616 pediatric cancer genomes in 16 major cancer types of hematological malignancies (n = 908), brain tumors (n = 183), and solid tumors (n = 525) and compared their profiles to those of 2,203 adult cancers. The SV burden varied ~100-fold across pediatric cancer types and demonstrated an 8- to 16-fold reduction compared to adult brain and solid tumors but was comparable in pediatric versus adult hematological malignancies. Recurrent SV hotspots occurred uniquely in pediatric acute lymphoblastic leukemias (ALLs) in proximity to RAG-mediated recombination signal sequences (RSS) and disrupted multiple immune-related loci as well as 69 genes, which often involved cryptic RSS sites. By contrast, such hotspots affected only immune-related loci but not driver genes in adult lymphoid cancers. Eight SV signatures extracted from the cohort had varying distributions across cancer types, with clustered translocations reflecting templated insertions in osteosarcoma, and medium-sized deletions (10 kb to 1 Mb) enriched in cancers with RAG-mediated deletions. Intra-patient evolutionary analysis in 13 patients with multiple spatiotemporally distinct samples revealed that RAG-mediated recombination in leukemia and complex rearrangements in solid tumors occurred both early in disease initiation a...