Talk Title:
Dynamic changes of unstable chromosomes: insights from in vitro genome evolution and cancer sequencing

Talk Summary:

Copy-number alterations and chromosomal translocations are widespread in cancer and frequently causing oncogenic mutations that drive tumorigenesis and therapy resistance. Despite their prevalence, how these alterations arise during tumor development remains a mystery. We have gained significant insight into this question by two lines of research. In the first approach, we analyzed genomic alterations induced by unstable chromosomes and their evolution over multiple generations by single-cell sequencing. We found that even a single broken chromosome in an ancestor cell can cause highly dynamic evolution and generate extensive genetic diversity in the progeny population, giving rise to all forms of alterations in cancer genomes, including focal amplification and deletion, arm-level copy-number changes, and complex rearrangements. This finding led us to hypothesize that the genetic diversity due to unstable chromosomes may fuel the transition from pre-malignancy to cancer. In the second approach, we performed whole-genome sequencing on esophageal adenocarcinomas and matching precursor lesions from the same patients to track the evolution of chromosomal alterations during disease progression. The analysis of tumor genomes revealed a trajectory of genome evolution from benign to malignancy that bears a striking similarity to the evolution of unstable chromosomes in the in vitro experiments. Together, our results suggest that a few simple mechanisms of chromosomal evolution may be sufficient to create the enormous complexity of cancer genomes and the evolution of unstable genomes may be not completely chaotic after all.