Transient genomic instability drives tumorigenesis through accelerated clonal evolution
- Ofer Shoshani1,5,
- Bjorn Bakker2,
- Lauren de Haan1,2,
- Andréa E. Tijhuis2,
- Yin Wang1,
- Dong Hyun Kim1,
- Marcus Maldonado1,
- Matthew A. Demarest1,
- Jon Artates1,
- Ouyang Zhengyu3,
- Adam Mark4,
- René Wardenaar2,
- Roman Sasik4,
- Diana C.J. Spierings2,
- Benjamin Vitre1,6,
- Kathleen Fisch4,
- Floris Foijer2 and
- Don W. Cleveland1
- 1Ludwig Cancer Research, Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California 92093, USA;
- 2European Research Institute for the Biology of Ageing (ERIBA), University of Groningen, University Medical Center Groningen, 9713 AV Groningen, The Netherlands;
- 3Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California 92093, USA;
- 4Center for Computational Biology and Bioinformatics, Department of Medicine, University of California at San Diego, La Jolla, California 92093, USA
- Corresponding authors: dcleveland{at}health.ucsd.edu, f.foijer{at}umcg.nl, ofer.shoshani{at}weizmann.ac.il
Abstract
Abnormal numerical and structural chromosome content is frequently found in human cancer. To test the role of aneuploidy in tumor initiation and progression, we generated mice with random aneuploidies by transient induction of polo-like kinase 4 (Plk4), a master regulator of centrosome number. Short-term chromosome instability (CIN) from transient Plk4 induction resulted in formation of aggressive T-cell lymphomas in mice with heterozygous inactivation of one p53 allele and accelerated tumor development in the absence of p53. Transient CIN increased the frequency of lymphoma-initiating cells with a specific karyotype profile, including trisomy of chromosomes 4, 5, 14, and 15 occurring early in tumorigenesis. Tumor development in mice with chronic CIN induced by an independent mechanism (through inactivation of the spindle assembly checkpoint) gradually trended toward a similar karyotypic profile, as determined by single-cell whole-genome DNA sequencing. Overall, we show how transient CIN generates cells with random aneuploidies from which ones that acquire a karyotype with specific chromosome gains are sufficient to drive cancer formation, and that distinct CIN mechanisms can lead to similar karyotypic cancer-causing outcomes.
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Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.348319.121.
- Received February 2, 2021.
- Accepted June 10, 2021.
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