An Integrative Framework for Detecting Structural Variations in Cancer Genomes

Structural variants can contribute to oncogenesis through a variety of mechanisms, yet, 2 despite their importance, the identification of structural variants in cancer genomes remains 3 challenging. Here, we present an integrative framework for comprehensively identifying 4 structural variation in cancer genomes. For the first time, we apply next-generation optical 5 mapping and high-throughput chromosome conformation capture techniques to6 systematically detect SVs in a variety of cancer cells. Combined with whole genome 7 sequencing, we identify and characterize structural variants in up to 29 commonly used 8 normal and cancer cell lines. We find that each method has unique strengths in identifying 9 different classes of structural variants and at different scales, suggesting that integrative 10approaches are likely the only way to comprehensively identify structural variants in the 11genome. Studying the impact of the structural variants in cancer cell lines, we identify 12widespread structural variation events affecting replication timing and the functions of non-13coding sequences in the genome, including the deletion of distal regulatory sequences, 14alteration of DNA replication timing, and the creation of novel 3D chromatin structural 15domains. These results underscore the importance of comprehensive structural variant 16identification and indicate that non-coding structural variation may be an underappreciated 17mutational process in cancer genomes.