Pervasive Chromosomal Instability Drives the Karyotypic Evolution of Hypodiploid Tumours

Tumours frequently exhibit extreme levels of aneuploidy. While increases in ploidy are well-characterised, the opposite phenomenon--extensive chromosome loss leading to hypodiploidy-- remains underexplored. Here, we analyse over 17,000 cancer genomes from 34 cancer types and perform a pan-cancer analysis of karyotypic evolution in hypodiploid tumours. We find that hypodiploidy is widespread and associated with a generalised chromosomal instability phenotype, marked by significantly elevated rates of genome doubling, intrachromosomal copy number alterations, chromothripsis, and intra-tumour heterogeneity. These tumours are hypoxic and strongly enriched for TP53 mutations. However, we also identify a subset of cancers--acute lymphoblastic leukaemia (ALL), kidney chromophobe, and adrenocortical carcinoma--that exhibit stable hypodiploidy, with stereotyped chromosome loss patterns, low chromosomal instability, and distinct evolutionary origins. We exploit this stability to develop a simple method of distinguishing poor-prognosis masked hypodiploid from good-prognosis hyperdiploid ALL using only cytogenetic data, enabling more precise risk stratification. Finally, we show that hypodiploidy predicts poor prognosis across cancers. Genome doubling does not confer a fitness advantage in low-hypodiploid tumours, nor do these tumours evolve to avoid loss of dosage-sensitive genes. Together, these findings provide the first pan-cancer characterization of hypodiploidy as a widespread and clinically relevant phenomenon often driven by pervasive chromo-somal instability, and illustrate the remarkable ability of cancer cells to tolerate and evolve under extreme dosage imbalance.