PT - JOURNAL ARTICLE AU - Sheltzer, Jason M. AU - Ko, Julie H. AU - Habibe Burgos, Nicole C. AU - Chung, Erica S. AU - Meehl, Colleen M. AU - Passerini, Verena AU - Storchova, Zuzana AU - Amon, Angelika TI - Single-chromosome aneuploidy commonly functions as a tumor suppressor AID - 10.1101/040162 DP - 2016 Jan 01 TA - bioRxiv PG - 040162 4099 - http://biorxiv.org/content/early/2016/02/19/040162.short 4100 - http://biorxiv.org/content/early/2016/02/19/040162.full AB - Whole-chromosome aneuploidy is a hallmark of human malignancies. The prevalence of chromosome segregation errors in cancer – first noted more than 100 years ago – has led to the widespread belief that aneuploidy plays a crucial role in tumor development. Here, we set out to test this hypothesis. We transduced congenic euploid and trisomic fibroblasts with 14 different oncogenes or oncogene combinations, thereby creating genetically-matched cancer cell lines that differ only in karyotype. Surprisingly, nearly all aneuploid cell lines divided slowly in vitro, formed few colonies in soft agar, and grew poorly as xenografts, relative to matched euploid lines. Similar results were obtained when comparing a near-diploid human colorectal cancer cell line with derivatives of that line that harbored extra chromosomes. Only a few aneuploid lines grew at close to wild-type levels, and no aneuploid line exhibited greater tumorigenic capabilities than its euploid counterpart. These results demonstrate that rather than promoting tumorigenesis, aneuploidy, particularly single chromosome gains, can very often function as a tumor suppressor. Moreover, our results suggest one potential way that cancers can overcome the tumor suppressive effects of aneuploidy: rapidly-growing aneuploid cell lines that had evolved in vitro or in vivo demonstrated recurrent karyotype changes that were absent from their euploid counterparts. Thus, the genome-destabilizing effects of single-chromosome aneuploidy may facilitate the development of balanced, high-complexity karyotypes that are frequently found in advanced malignancies.