Integrative detection and analysis of structural variation in cancer genomes

Abstract

Structural variants (SVs) can contribute to oncogenesis through a variety of mechanisms. Despite their importance, the identification of SVs in cancer genomes remains challenging. Here, we present a framework that integrates optical mapping, high-throughput chromosome conformation capture (Hi-C), and whole-genome sequencing to systematically detect SVs in a variety of normal or cancer samples and cell lines. We identify the unique strengths of each method and demonstrate that only integrative approaches can comprehensively identify SVs in the genome. By combining Hi-C and optical mapping, we resolve complex SVs and phase multiple SV events to a single haplotype. Furthermore, we observe widespread structural variation events affecting the functions of noncoding sequences, including the deletion of distal regulatory sequences, alteration of DNA replication timing, and the creation of novel three-dimensional chromatin structural domains. Our results indicate that noncoding SVs may be underappreciated mutational drivers in cancer genomes.

DLO Hi-C Tool for Digestion-Ligation-Only Hi-C Chromosome Conformation Capture Data Analysis

“…9. We confirmed the authenticity of these two translocations by the software hic_breakfinder and Hi-Ctrans [15,16]. The heatmap generated by DLO Hi-C Tool will provide a visual theoretical basis for chromatin translocation calling.…”

Intermingling of chromosome territories

“…Furthermore, investigation of the impact of neo‐TADs on gene expression revealed that across eight cancer cell lines, the genes within TADs enclosing rearrangements exhibit greater allelic bias compared with the genes located in non‐rearranged TADs. This strongly suggests that at least a part of SV's events lead to gene expression changes . Activation of silent proto‐oncogenes has been shown to appear on deeper level of chromatin structure due to insulated neighborhood boundary loss as well.…”

“…This strongly suggests that at least a part of SV's events lead to gene expression changes. 58 Activation of silent proto-oncogenes has been shown to appear on deeper level of chromatin structure due to insulated neighborhood boundary loss as well. Enhancers that are normally located outside the neighborhood changed their locations as a consequence of loss of CTCF-cohesinmediated loop and can cause altered expression of oncogenes.…”

Nanopore sequencing of DNA concatemers reveals higher-order features of chromatin structure

“…Previous work in constitutional genetics has linked the pres-ence of inherited non-coding DNA variants, such as CTCF mutations 10 or larger structural variants 11,12 , to human limb malformations through chromatin re-structuring 10 . In cancer, complex somatic genomic rearrangements can create neo-TADs 11,13 or hijack enhancers to activate oncogenes [14][15][16][17][18] .…”

“…Most notably, Hi-C enables unbiased mapping of active (A) and inactive (B) chromatin compartments, TADs, cohesin loops, and enhancer-promoter interactions among the billions of interacting locus pairs in these genome-wide contact maps. In addition, Hi-C has been applied to generate reference-grade de novo assemblies of mammalian scale genomes 25 , identify structural variants in cancer cells 13 , and study DNA replication 26,27 .…”