PT  - JOURNAL ARTICLE
AU  - Ofer Shoshani
AU  - Bjorn Bakker
AU  - Yin Wang
AU  - Dong Hyun Kim
AU  - Marcus Maldonado
AU  - Matthew A. Demarest
AU  - Jon Artates
AU  - Ouyang Zhengyu
AU  - Adam Mark
AU  - Rene Wardenaar
AU  - Roman Sasik
AU  - Diana C.J. Spierings
AU  - Benjamin Vitre
AU  - Kathleen Fisch
AU  - Floris Foijer
AU  - Don W. Cleveland
TI  - Transient genomic instability drives tumorigenesis through accelerated clonal evolution
AID  - 10.1101/2020.11.17.387753
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.11.17.387753
4099  - http://biorxiv.org/content/early/2020/11/18/2020.11.17.387753.short
4100  - http://biorxiv.org/content/early/2020/11/18/2020.11.17.387753.full
AB  - Abnormal numerical and structural chromosome content is frequently found in human cancer. To test the role of aneuploidy in tumor initiation and progression, we compared tumor development in mice with chronic chromosome instability (CIN) induced by inactivation of the spindle assembly checkpoint (produced by Mad2 deficiency) and mice with transient CIN through transiently increased expression of polo-like kinase 4 (PLK4), a master regulator of centrosome number. Tumors forming under chronic CIN gradually trended toward chromosomal gains producing a specific karyotype profile that could only be partially maintained in end-stage tumors, as determined by single-cell whole genome DNA sequencing. Short term CIN from transient PLK4 induction generated significant centrosome amplification and aneuploidy resulting in formation of aggressive T cell lymphomas in mice with heterozygous inactivation of one p53 allele or accelerated tumor development in the absence of p53. Transient CIN increased the frequency of lymphomainitiating cells (as revealed by T cell receptor sequencing) with a specific karyotype profile containing triploid chromosomes 4, 5, 14, and 15 occurring early in tumorigenesis. Overall, our evidence demonstrates that distinct CIN mechanisms drive cancers presenting specific, complex chromosomal alterations with transient CIN rapidly enhancing tumor formation by accelerating the generation of such events.Competing Interest StatementThe authors have declared no competing interest.