Biology subjects

Zhang, C.-Z.

Publications and source records attributed to Zhang, C.-Z..

3 recordsLinked to original sources

bioRxiv2018

Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing

Chromothripsis is a newly discovered mutational phenomenon involving massive, clustered genomic rearrangements that occurs in cancer and other diseases. Recent studies in cancer suggest that chromothripsis may be far more common than initially inferred from low resolution DNA copy number data. Here, we analyze the patterns of chromothripsis across 2,658 tumors spanning 39 cancer types using whole-genome sequencing data. We find that chromothripsis events are pervasive across cancers, with a frequency of >50% in several cancer types. Whereas canonical chromothripsis profiles display oscillations between two copy number states, a considerable fraction of the events involves multiple chromosomes as well as additional structural alterations. In addition to non-homologous end-joining, we detect signatures of replicative processes and templated insertions. Chromothripsis contributes to oncogene amplification as well as to inactivation of genes such as mismatch-repair related genes. These findings show that chromothripsis is a major process driving genome evolution in human cancer.

genomics↗

bioRxiv2017

Selective and mechanistic sources of recurrent rearrangements across the cancer genome

Cancer cells can acquire profound alterations to the structure of their genomes, including rearrangements that fuse distant DNA breakpoints. We analyze the distribution of somatic rearrangements across the cancer genome, using whole-genome sequencing data from 2,693 tumor-normal pairs. We observe substantial variation in the density of rearrangement breakpoints, with enrichment in open chromatin and sites with high densities of repetitive elements. After accounting for these patterns, we identify significantly recurrent breakpoints (SRBs) at 52 loci, including novel SRBs near BRD4 and AKR1C3. Taking into account both loci fused by a rearrangement, we observe different signatures resembling either single breaks followed by strand invasion or two separate breaks that become joined. Accounting for these signatures, we identify 90 pairs of loci that are significantly recurrently juxtaposed (SRJs). SRJs are primarily tumor-type specific and tend to involve genes with tissue-specific expression. SRJs were frequently associated with disruption of topology-associated domains, juxtaposition of enhancer elements, and increased expression of neighboring genes. Lastly, we find that the power to detect SRJs decreases for short rearrangements, and that reliable detection of all driver SRJs will require whole-genome sequencing data from an order of magnitude more cancer samples than currently available.

cancer biology↗

bioRxiv2017

Genome-wide detection of structural variants and indels by local assembly

Structural variants (SVs), including small insertion and deletion variants (indels), are challenging to detect through standard alignment-based variant calling methods. Sequence assembly offers a powerful approach to identifying SVs, but is difficult to apply at-scale genome-wide for SV detection due to its computational complexity and the difficulty of extracting SVs from assembly contigs. We describe SvABA, an efficient and accurate method for detecting SVs from short-read sequencing data using genome-wide local assembly with low memory and computing requirements. We evaluated SvABAs performance on the NA12878 human genome and in simulated and real cancer genomes. SvABA demonstrates superior sensitivity and specificity across a large spectrum of SVs, and substantially improved detection performance for variants in the 20-300 bp range, compared with existing methods. SvABA also identifies complex somatic rearrangements with chains of short (< 1,000 bp) templated-sequence insertions copied from distant genomic regions. We applied SvABA to 344 cancer genomes from 11 cancer types, and found that templated-sequence insertions occur in ~4% of all somatic rearrangements. Finally, we demonstrate that SvABA can identify sites of viral integration and cancer driver alterations containing medium-sized SVs.

genomics↗