Published July 31, 2023 | Version v1
Journal article Open

Genomic signatures of past and present chromosomal instability in the evolution of Barrett's esophagus to esophageal adenocarcinoma

  • 1. Dana-Farber Cancer Institute

Contributors

Researcher:

  • 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

Github repo: https://github.com/chunyangbao/NC_ESAD75

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