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 develop methods to identify current and former hypodiploid tumours, analyse predictors of chromosome loss patterns across tissues, and characterise the relationship between hypodiploidy and other forms of chromosomal instability.

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, chromoanagenesis, 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 unstable hypodiploidy predicts poor prognosis across cancers. Genome doubling does not confer a fitness advantage in 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 chromosomal instability, and illustrate the remarkable ability of cancer cells to tolerate and evolve under extreme dosage imbalance.