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

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.Github repo: https://github.com/chunyangbao/NC_ESAD7