Negative selection may cause grossly altered but broadly stable karyotypes in metastatic colorectal cancer

Abstract

Aneuploidy, defined as the loss and gain of whole and part chromosomes, is a near-ubiquitous feature of cancer genomes, is prognostic, and likely an important determinant of cancer cell biology. In colorectal cancer (CRC), aneuploidy is found in virtually all tumours, including precursor adenomas. However, the temporal evolutionary dynamics that select for aneuploidy remain broadly uncharacterised. Here we perform genomic analysis of 755 samples from a total of 167 patients with colorectal-derived neoplastic lesions that cross-sectionally represent the distinct stages of tumour evolution, and longitudinally track individual tumours through metastasis and treatment. Precancer lesions (adenomas) exhibited low levels of aneuploidy but high intra-tumour heterogeneity, whereas cancers had high aneuploidy but low heterogeneity, indicating that progression is through a genetic bottleneck that suppresses diversity. Individual CRC glands from the same tumour have similar karyotypes, despite prior evidence of ongoing instability at the cell level. Pseudo-stable aneuploid genomes were observed in metastatic lesions sampled from liver and other organs, after chemo- or targeted therapies, and late recurrences detected many years after the diagnosis of a primary tumour. Modelling indicates that these data are consistent with the action of stabilising selection that ‘traps’ cancer cell genomes on a fitness peak defined by the specific pattern of aneuploidy. These data show that the initial progression of CRC requires the traversal of a rugged fitness landscape and subsequent genomic evolution, including metastatic dissemination and therapeutic resistance, is constrained by stabilising selection.

Breast tumours maintain a reservoir of subclonal diversity during expansion

“…Our data further shows that after the MRCA, a period of transient instability generates a large number of subclones before transitioning to a basal rate of ongoing copy number evolution that persists during the expansion of the primary tumor mass. These data suggest that while there may be some stabilizing selection 22 , the tumor cells continue to explore the fitness landscape during the growth and expansion of the primary tumor. Based on our new data, we propose a revised model for TNBC evolution after PCNE ( Extended Data Fig.…”

Reconstructing single-cell karyotype alterations in colorectal cancer identifies punctuated and gradual diversification patterns

“…Fresh-frozen CRC tissue specimens. Fresh-frozen tissue samples were collected from University College London Hospitals under ethical approval 11/LO/1613 and via the University College London Hospital Biobank (15/YH/0311) and processed as previously described 41 . All surgically resected samples were collected from patients who had given informed consent.…”

Evolutionary tracking of cancer haplotypes at single-cell resolution

“…Meanwhile, we suggest that pervasive parallel copy number events 10,14,29 in general are a consequence of underlying levels of instability rather than positive selection. On the other hand, how rarer events modify tumour cell fitness remains uncertain, and will require integration of single cell data with evolutionary models of genomic instability 30,31 .…”