Ni Leathlobhair, M. | Search bioRxiv

bioRxiv2025

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.

cancer biology↗

bioRxiv2022

Whole genome sequencing of 2,023 colorectal cancers reveals mutational landscapes, new driver genes and immune interactions

To characterise the somatic alterations in colorectal cancer (CRC), we conducted whole-genome sequencing analysis of 2,023 tumours. We provide the most detailed high-resolution map to date of somatic mutations in CRC, and demonstrate associations with clinicopathological features, in particular location in the large bowel. We refined the mutational processes and signatures acting in colorectal tumorigenesis. In analyses across the sample set or restricted to molecular subtypes, we identified 185 CRC driver genes, of which 117 were previously unreported. New drivers acted in various molecular pathways, including Wnt (CTNND1, AXIN1, TCF3), TGF-{beta}/BMP (TGFBR1) and MAP kinase (RASGRF1, RASA1, RAF1, and several MAP2K and MAP3K loci). Non-coding drivers included intronic neo-splice site alterations in APC and SMAD4. Whilst there was evidence of an excess of mutations in functionally active regions of the non-coding genome, no specific drivers were called with high confidence. Novel recurrent copy number changes included deletions of PIK3R1 and PWRN1, as well as amplification of CCND3 and NEDD9. Putative driver structural variants included BRD4 and SOX9 regulatory elements, and ACVR2A and ANKRD11 hotspot deletions. The frequencies of many driver mutations, including somatic Wnt and Ras pathway variants, showed a gradient along the colorectum. The Pks-pathogenic E. coli signature and TP53 mutations were primarily associated with rectal cancer. A set of unreported immune escape driver genes was found, primarily in hypermutated CRCs, most of which showed evidence of genetic evasion of the anti-cancer immune response. About 25% of cancers had a potentially actionable mutation for a known therapy. Thirty-three of the new driver genes were predicted to be essential, 17 possessed a druggable structure, and nine had a bioactive compound available. Our findings provide further insight into the genetics and biology of CRC, especially tumour subtypes defined by genomic instability or clinicopathological features.

genomics↗