Genomic signatures of past and present chromosomal instability in the evolution of Barrett's esophagus to esophageal adenocarcinoma
- 1. Dana-Farber Cancer Institute
Description
The progression of precancerouslesionsto malignancyis often accompanied by increasing complexity of3chromosomalalterationsbuthow these alterations arise ispoorly understood.Here weperformed4haplotype-specific analysis ofchromosomal copy-number evolution in the progression of Barrett’s5esophagus(BE) to esophageal adenocarcinoma (EAC)onmultiregional whole-genome sequencingdataof6BE withdysplasia and microscopicEACfoci.We identified distinct patterns of copy-number evolution7indicatingmultigenerational chromosomal instabilitythat isinitiated bycell division errorsbutpropagated8onlyafter p53 loss. While abnormal mitosis, including whole-genome duplication,underlieschromosomal9copy-number changes, segmental alterations display signatures ofsuccessive breakage-fusion-bridge cycles10and chromothripsisof unstable dicentric chromosomes.Ouranalysiselucidateshowmultigenerational11chromosomal instabilitygeneratescopy-number variationinBEcells,precipitatescomplexalterations12including DNA amplifications, andpromotestheir independentclonal expansion and transformation.In13particular, we suggest sloping copy-number variation as a signature of ongoing chromosomal instability14that precedes copy-number complexity.Thesefindingssuggestcopy-numberheterogeneity in advanced15cancersoriginates from chromosomal instability in precancerous cellsandsuch instability may be identified16fromthe presence ofsloping copy-numbervariationin bulk sequencing data.
Notes
Files
BE-EAC-CopyNumberAnalysis.zip
Files
(4.4 GB)
Name | Size | Download all |
---|---|---|
md5:7dda1a8abf6003e1c09e675d8c1ea8ee
|
175.0 MB | Preview Download |
md5:eec4b810d33d337866282b9510a2896b
|
2.6 GB | Preview Download |
md5:ec48a1dc94080626acfd94c536759ab9
|
1.8 MB | Preview Download |
md5:5fe8d2a6e9c70a907837d80b90cc9684
|
15.5 MB | Preview Download |
md5:192eff56141a02d3df4d059f4702a7e7
|
1.6 GB | Preview Download |
md5:45dab3c84ea91582f7837f5f1e894908
|
99.7 kB | Preview Download |
md5:8db698b08d9eb66cf831e66dc7c328f7
|
8.3 MB | Preview Download |