Journal Article

Integrative detection and analysis of structural variation in cancer genomes

Kaul, Rajinder, Zhan, Ye, Bann, Darrin V., Wang, Yanli, Lajoie, Bryan R., Ernst, Christina, Clark, Royden, Iyyanki, Sriranga, Hardison, Ross C., Buckley, Michael, Diegel, Morgan, Le, Victoria T., Pool, Christopher, Noble, William Stafford, Gilbert, David M., Song, Fan, Dileep, Vishnu, Ozadam, Hakan, Hadjur, Suzana, Stamatoyannopoulos, John A., Ay, Ferhat, Sasaki, Takayo, Odom, Duncan T., Dixon, Jesse R., Pezic, Dubravka, Yang, Hongbo, Chakraborty, Abhijit, Dekker, Job, Xu, Jie, Broach, James R., Liu, Tingting, An, Lin, Yue, Feng, Zhang, Lijun, Yardımcı, Galip Gürkan, Rivera-Mulia, Juan Carlos, Lee, Kristen

2018

Overview

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. The authors present an integrative framework for identifying structural variants (SVs) in cancer that applies optical mapping, Hi-C, and whole-genome sequencing. They find SVs affecting distal regulatory sequences, DNA replication, and three-dimensional chromatin structure.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 38 / 38/39 / 45/15 / 45/23 / 45/91 / 631/208 / 631/208/212 / A549 Cells / Agriculture / Algorithms / Animal Genetics and Genomics / Biomedical and Life Sciences / Biomedicine / Cancer / Cancer genetics / Cancer Research / Carcinogenesis / Cell Line, Tumor / Chromatin / Chromosome Mapping / Chromosomes / Clonal deletion / Conformation / Deoxyribonucleic acid / DNA / DNA biosynthesis / DNA replication / DNA sequencing / DNA, Neoplasm - analysis / DNA, Neoplasm - genetics / Domains / Gene expression / Gene Function / Gene mapping / Gene sequencing / Genes, Neoplasm / Genetic Variation / Genome, Human / Genomes / Genomic Structural Variation / Genomic structural variations / Genomics / Haplotypes / High-Throughput Nucleotide Sequencing - methods / Human Genetics / Humans / K562 Cells / Linkage Disequilibrium / Mapping / Methods / Mutation / Neoplasms - genetics / Nucleotide sequence / Pipelines / Regulatory sequences / Sequence Analysis, DNA - methods / Software / Systems Biology - methods / Systems Integration / Tumor cell lines / Tumorigenesis