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bioRxiv · 10.1101/2021.03.26.437288

Origins of cancer genome complexity revealed by haplotype-resolved genomic analysis of evolution of Barretts esophagus to esophageal adenocarcinoma

Zhang, C.-Z.·Stachler, M.·Bao, C.·Tourdot, R.·Brunette, G. J.·Stewart, C.·Sun, L.·Baba, H.·Watanabe, M.·Agoston, A.·Jajoo, K.·Nason, K.·Davison, J.·Getz, G.·Wang, K.·Imamura, Y.·Odze, R.·Bass, A.
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Abstract

The progression of precancerous lesions to malignancy is often accompanied by increasing complexity of chromosomal alterations but how these alterations arise is poorly understood. Here we performed haplotype-specific analysis of chromosomal copy-number evolution in the progression of Barretts esophagus (BE) to esophageal adenocarcinoma (EAC) on multiregional whole-genome sequencing data of BE with dysplasia and microscopic EAC foci. We identified distinct patterns of copy-number evolution indicating multigenerational chromosomal instability that is initiated by cell division errors but propagated only after p53 loss. While abnormal mitosis, including whole-genome duplication, underlies chromosomal copy-number changes, segmental alterations display signatures of successive breakage-fusion-bridge cycles and chromothripsis of unstable dicentric chromosomes. Our analysis elucidates how multigenerational chromosomal instability generates copy-number variation in BE cells, precipitates complex alterations including DNA amplifications, and promotes their independent clonal expansion and transformation. In particular, we suggest sloping copy-number variation as a signature of ongoing chromosomal instability that precedes copy-number complexity. These findings suggest copy-number heterogeneity in advanced cancers originates from chromosomal instability in precancerous cells and such instability may be identified from the presence of sloping copy-number variation in bulk sequencing data.

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Zhang, C.-Z., Stachler, M., Bao, C., Tourdot, R., Brunette, G. J., Stewart, C., Sun, L., Baba, H., Watanabe, M., Agoston, A., Jajoo, K., Nason, K., Davison, J., Getz, G., Wang, K., Imamura, Y., Odze, R., Bass, A.. 2021-03-28. Origins of cancer genome complexity revealed by haplotype-resolved genomic analysis of evolution of Barretts esophagus to esophageal adenocarcinoma. https://doi.org/10.1101/2021.03.26.437288

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