Journal Article

Mechanisms generating cancer genome complexity from a single cell division error

Lynch, Luke D., Pellman, David, Tourdot, Richard, Umbreit, Neil T., Spektor, Alexander, Zhang, Cheng-Zhong, Blaine, Logan J., Sun, Lili, Almubarak, Hannah F., Mitchell, Thomas J., Judge, Kim, Cheng, Anna M.

2020

Overview

Many human tumors display scrambled genomes that arise from two distinct mutational processes. The first, the chromosome breakage-fusion-bridge (BFB) cycle, produces gene amplification and genomic instability. The second, chromothripsis, generates massive, clustered genomic rearrangements in one or a few chromosomes. Umbreit et al. hypothesized that these two processes are mechanistically related and tested this idea by recreating essential steps of the BFB cycle in cultured cells (see the Perspective by Paiano and Nussenzweig). They found that chromothripsis arises from a cascade of events that begins with aberrant chromosome bridge formation during mitosis, followed by chromosome fragmentation, DNA damage, chromosome missegregation, and the formation of micronuclei. They propose a model that explains how a single cell division error (chromosome bridge formation) can generate many hallmark features of cancer genomes. Science , this issue p. 240 ; see also p. eaba0712 The genomic complexity of a cancer cell is traced to aberrant formation of a chromosome bridge during one cell division. The chromosome breakage-fusion-bridge (BFB) cycle is a mutational process that produces gene amplification and genome instability. Signatures of BFB cycles can be observed in cancer genomes alongside chromothripsis, another catastrophic mutational phenomenon. We explain this association by elucidating a mutational cascade that is triggered by a single cell division error—chromosome bridge formation—that rapidly increases genomic complexity. We show that actomyosin forces are required for initial bridge breakage. Chromothripsis accumulates, beginning with aberrant interphase replication of bridge DNA. A subsequent burst of DNA replication in the next mitosis generates extensive DNA damage. During this second cell division, broken bridge chromosomes frequently missegregate and form micronuclei, promoting additional chromothripsis. We propose that iterations of this mutational cascade generate the continuing evolution and subclonal heterogeneity characteristic of many human cancers.

• Publisher: American Association for the Advancement of Science,The American Association for the Advancement of Science
• Subject: Actomyosin / Actomyosin - metabolism / Amplification / Breakage / Bridges / Cancer / Carcinogenesis - genetics / Carcinogenesis - pathology / Cell cycle / Cell division / Cell Line, Tumor / Chromosome 4 / Chromosome Breakage / Chromosomes / Complexity / Copy number / Damage / Deoxyribonucleic acid / DNA / DNA biosynthesis / DNA damage / DNA Damage - genetics / DNA fragmentation / DNA sequencing / Errors / Evolution / Exodeoxyribonucleases - genetics / Fragmentation / Gene amplification / Gene Dosage / Genome, Human / Genomes / Genomic analysis / Genomic instability / Genomics / Haplotypes / Heterogeneity / Humans / Iterative methods / Karyotypes / Mechanical Phenomena / Micronuclei / Mitosis / Mitosis - genetics / Mutagenesis / Mutation / Neoplasms - genetics / Neoplasms - pathology / Nucleotide sequence / Phosphoproteins - genetics / Populations / Replication / RESEARCH ARTICLE SUMMARY / Single-Cell Analysis / Stability / Tumorigenesis / Whole genome sequencing