Biology subjects

Schumacher, S. E.

Publications and source records attributed to Schumacher, S. E..

3 recordsLinked to original sources

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

Pan-cancer analysis of whole genomes reveals driver rearrangements promoted by LINE-1 retrotransposition in human tumours

About half of all cancers have somatic integrations of retrotransposons. To characterize their role in oncogenesis, we analyzed the patterns and mechanisms of somatic retrotransposition in 2,954 cancer genomes from 37 histological cancer subtypes. We identified 19,166 somatically acquired retrotransposition events, affecting 35% of samples, and spanning a range of event types. L1 insertions emerged as the first most frequent type of somatic structural variation in esophageal adenocarcinoma, and the second most frequent in head-and-neck and colorectal cancers. Aberrant L1 integrations can delete megabase-scale regions of a chromosome, sometimes removing tumour suppressor genes, as well as inducing complex translocations and large-scale duplications. Somatic retrotranspositions can also initiate breakage-fusion-bridge cycles, leading to high-level amplification of oncogenes. These observations illuminate a relevant role of L1 retrotransposition in remodeling the cancer genome, with potential implications in the development of human tumours.

genomics↗

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↗