Cortés-Ciriano I, Lee JJK, Xi R, Jain D, Jung YL, Yang L, Gordenin D, Klimczak LJ, Zhang CZ, Pellman DS, Group PCAWGSVW, Park PJ, Consortium PCAWG.
Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing. Nature Genetics 2020;52(3):331-341.
AbstractChromothripsis is a mutational phenomenon characterized by massive, clustered genomic rearrangements that occurs in cancer and other diseases. Recent studies in selected cancer types have suggested that chromothripsis may be more common than initially inferred from low-resolution copy-number data. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we analyze patterns of chromothripsis across 2,658 tumors from 38 cancer types using whole-genome sequencing data. We find that chromothripsis events are pervasive across cancers, with a frequency of more than 50% in several cancer types. Whereas canonical chromothripsis profiles display oscillations between two copy-number states, a considerable fraction of events involve multiple chromosomes and additional structural alterations. In addition to non-homologous end joining, we detect signatures of replication-associated processes and templated insertions. Chromothripsis contributes to oncogene amplification and to inactivation of genes such as mismatch-repair-related genes. These findings show that chromothripsis is a major process that drives genome evolution in human cancer.
pdf Wang S, Lee S, Chu C, Jain D, Kerpedjiev P, Nelson GM, Walsh JM, Alver BH, Park PJ.
HiNT: a computational method for detecting copy number variations and translocations from Hi-C data. Genome Biology 2020;21(1):73.
AbstractThe three-dimensional conformation of a genome can be profiled using Hi-C, a technique that combines chromatin conformation capture with high-throughput sequencing. However, structural variations often yield features that can be mistaken for chromosomal interactions. Here, we describe a computational method HiNT (Hi-C for copy Number variation and Translocation detection), which detects copy number variations and interchromosomal translocations within Hi-C data with breakpoints at single base-pair resolution. We demonstrate that HiNT outperforms existing methods on both simulated and real data. We also show that Hi-C can supplement whole-genome sequencing in structure variant detection by locating breakpoints in repetitive regions.
pdf Horton CA, Alver B, Park PJ.
GiniQC: a measure for quantifying noise in single-cell Hi-C data. Bioinformatics 2020;
AbstractSingle-cell Hi-C (scHi-C) allows the study of cell-to-cell variability in chromatin structure and dynamics. However, the high level of noise inherent in current scHi-C protocols necessitates careful assessment of data quality before biological conclusions can be drawn. Here we present GiniQC, which quantifies unevenness in the distribution of inter-chromosomal reads in the scHi-C contact matrix to measure the level of noise. Our examples show the utility of GiniQC in assessing the quality of scHi-C data as a complement to existing quality control measures. We also demonstrate how GiniQC can help inform the impact of various data processing steps on data quality.
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