Mechanisms generating cancer genome complexity from a single cell division error
Apr 1, 2020·,,
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0 min read
Neil T. Umbreit
Cheng-Zhong Zhang
Luke D. Lynch
Logan Blaine
Anna M. Cheng
Richard Tourdot
Lili Sun
Hannah F. Almubarak
Kim Judge
Thomas J. Mitchell
Alexander Spektor
David Pellman
Abstract
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.
Type
Publication
Science, 368
Status
Peer-reviewed
Authors
Logan Blaine
(he/him)
PhD Candidate in Bioinformatics and Integrative Genomics
Logan is a Ph.D. candidate in Biomedical Informatics at Harvard Medical School building probabilistic machine learning systems that reason over large-scale biological data. His work in the Pinello Lab develops Bayesian & deep learning models — spanning representation learning, generative modeling, and causal inference — to turn high-throughput single-cell experiments into testable hypotheses about biological mechanism, with the broader goal of building computational systems that can reason under uncertainty and close the loop with experimental biology.
Outside of lab, he enjoys training for marathons (and the occasional IRONMAN triathlon) and bikepacking around Vermont.