| Autor: |
Jon M. Davison, Masayuki Watanabe, Robert D. Odze, Gad Getz, Chip Stewart, Katie S. Nason, Hideo Baba, Casey H Zhang, Kunal Jajoo, Lili Sun, Chunyang Bao, Gregory J. Brunette, Richard W. Tourdot, Kenneth K. Wang, Agoston T. Agoston, Yu Imamura, Adam J. Bass, Stachler M |
| Rok vydání: |
2021 |
| Předmět: |
|
| DOI: |
10.1101/2021.03.26.437288 |
| Popis: |
Complex chromosomal alterations are a hallmark of advanced cancers but rarely seen in normal tissue. The progression of precancerous lesions to malignancy is often accompanied by increasing complexity of chromosomal alterations that can drive their transformation through focal oncogenic amplifications. However, the etiology and evolution dynamics of these alterations are poorly understood. Here we study chromosomal copy-number evolution in the progression of Barrett’s esophagus (BE) to esophageal adenocarcinoma (EAC) by multi-regional whole-genome sequencing analysis of BE samples with dysplasia and microscopic EAC foci. Through haplotype-specific copy-number analysis of BE genome evolution, we identified distinct patterns of episodic copy-number evolution consistent with the outcomes of abnormal mitosis and dicentric chromosome breakage. While abnormal mitosis, including whole-genome duplication, accounts for most chromosome or arm-level copy-number changes, segmental copy-number alterations display signatures of multi-generational evolution of unstable dicentric chromosomes. Continuous evolution of dicentric chromosomes through breakage-fusion-bridge cycles and chromothripsis rapidly increases genomic complexity and diversity among BE cells, culminating in the generation of distinct focal amplifications. These mutational processes enable multiple subclones within small dysplastic areas to undergo parallel transformation to cancer following acquisition of distinct oncogenic amplifications. Our results demonstrate how chromosomal instability drives clonal diversification in precancer evolution and promotes tumorigenesis in primary human samples. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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