Complex structural variation is prevalent and highly pathogenic in pediatric solid tumors

Abstract

AbstractBackgroundIn pediatric cancer, structural variants (SVs) and copy number alterations can contribute to cancer initiation and progression, and hence aid diagnosis and treatment stratification. The few studies into complex rearrangements have found associations with tumor aggressiveness or poor outcome. Yet, their prevalence and biological relevance across pediatric solid tumors remains unknown.ResultsIn a cohort of 120 primary tumors, we systematically characterized patterns of extrachromosomal DNA, chromoplexy and chromothripsis across five pediatric solid cancer types: neuroblastoma, Ewing sarcoma, Wilms tumor, hepatoblastoma and rhabdomyosarcoma. Complex SVs were identified in 56 tumors (47%) and different classes occurred across multiple cancer types. Recurrently mutated regions tend to be cancer-type specific and overlap with cancer genes, suggesting that selection contributes to shaping the SV landscape. In total, we identified potentially pathogenic complex SVs in 42 tumors that affect cancer driver genes or result in unfavorable chromosomal alterations. Half of which were known drivers, e.g.MYCNamplifications due to ecDNA andEWSR1::FLI1fusions due to chromoplexy. Recurrent novel candidate complex events include chromoplexy inWT1in Wilms tumors, focal chromothripsis with 1p loss in hepatoblastomas and complexMDM2amplifications in rhabdomyosarcomas.ConclusionsComplex SVs are prevalent and pathogenic in pediatric solid tumors. They represent a type of genomic variation which currently remains unexplored. Moreover, carrying complex SVs seems to be associated with adverse clinical events. Our study highlights the potential for complex SVs to be incorporated in risk stratification or exploited for targeted treatments.