Genomic signatures of past and present chromosomal instability in Barrett’s esophagus and early esophageal adenocarcinoma

Chunyang Bao, Richard W. Tourdot, Gregory J. Brunette, Chip Stewart, Lili Sun, Hideo Baba, Masayuki Watanabe, Agoston T. Agoston, Kunal Jajoo, Jon M. Davison, Katie S. Nason, Gad Getz, Kenneth K. Wang, Yu Imamura, Robert Odze, Adam J. Bass (), Matthew D. Stachler () and Cheng-Zhong Zhang ()
Additional contact information
Chunyang Bao: Dana-Farber Cancer Institute
Richard W. Tourdot: Dana-Farber Cancer Institute
Gregory J. Brunette: Dana-Farber Cancer Institute
Chip Stewart: Broad Institute of MIT and Harvard
Lili Sun: Dana-Farber Cancer Institute
Hideo Baba: Kumamoto University
Masayuki Watanabe: Cancer Institute Hospital of Japanese Foundation of Cancer Research
Agoston T. Agoston: Brigham and Women’s Hospital
Kunal Jajoo: Brigham and Women’s Hospital
Jon M. Davison: University of Pittsburgh School of Medicine
Katie S. Nason: University of Massachusetts Medical School
Gad Getz: Brigham and Women’s Hospital
Kenneth K. Wang: Mayo Clinic
Yu Imamura: Cancer Institute Hospital of Japanese Foundation of Cancer Research
Robert Odze: Brigham and Women’s Hospital
Adam J. Bass: Dana-Farber Cancer Institute
Matthew D. Stachler: Dana-Farber Cancer Institute
Cheng-Zhong Zhang: Dana-Farber Cancer Institute

Nature Communications, 2023, vol. 14, issue 1, 1-22

Abstract: 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 perform haplotype-specific analysis of chromosomal copy-number evolution in the progression of Barrett’s esophagus (BE) to esophageal adenocarcinoma (EAC) on multiregional whole-genome sequencing data of BE with dysplasia and microscopic EAC foci. We identify 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.

Date: 2023
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DOI: 10.1038/s41467-023-41805-6

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