Context is everything: aneuploidy in cancer

Ben‐David, Uri; Amon, Angelika

doi:10.1038/s41576-019-0171-x

Cited by 437 publications

(354 citation statements)

References 215 publications

(324 reference statements)

Supporting

Mentioning

344

Contrasting

Order By: Relevance

“…The spatial-temporal evolutionary dynamics that produce the aneuploidy observed in cancer genomes remain poorly understood 17 . In part this is because longitudinal measurement is often not clinically feasible, and is compounded by the lack of effective cancer-specific evolutionary tools to reconstruct ancestral history of chromosome gains and losses 18 .…”

Section: Introductionmentioning

confidence: 99%

Stabilising selection causes grossly altered but stable karyotypes in metastatic colorectal cancer

Cross

Mossner

Nowinski

et al. 2020

Preprint

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 99%

Stabilising selection causes grossly altered but stable karyotypes in metastatic colorectal cancer

Cross

Mossner

Nowinski

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Both focal and broad CNAs are important in oncogenesis. While broad CNAs often manifest through dosage effects 13 , focal CNAs often target driver genes directly and result in protein structural changes 63 .…”

Section: Methodsmentioning

confidence: 99%

“…Various efforts have been made to obtain comprehensive knowledge of CNAs responsible for cancer diagnostics, prognostics and targeted therapeutics. Systematic CNA analysis in over 10,000 primary tumor samples in the cancer genome atlas (TCGA) and 2,500 samples in the International Cancer Genome Consortium (ICGC) revealed distinct CNA landscapes in different cancer types 11–13 . Comparison of CNAs amongst autologous tumors obtained at different stage from different histology revealed that CNAs are critical for tumor evolution across time and space.…”

Section: Introductionmentioning

confidence: 99%

Single-cell copy number lineage tracing enabling gene discovery

Wang

Mohanty

et al. 2020

Preprint

View full text Add to dashboard Cite

Aneuploidy plays critical roles in genome evolution.Alleles, whose dosages affect the fitness of an ancestor, will have altered frequencies in the descendant populations upon perturbation.Single-cell sequencing enables comprehensive genome-wide copy number profiling of thousands of cells at various evolutionary stage and lineage. That makes it possible to discover dosage effects invisible at tissue level, provided that the cell lineages can be accurately reconstructed.Here, we present a Minimal Event Distance Aneuploidy Lineage Tree (MEDALT) algorithm that infers the evolution history of a cell population based on single-cell copy number (SCCN) profiles. We also present a statistical routine named lineage speciation analysis (LSA), which facilitates discovery of fitness-associated alterations and genes from SCCN lineage trees.We assessed our approaches using a variety of single-cell datasets. Overall, MEDALT appeared more accurate than phylogenetics approaches in reconstructing copy number lineage.From the single-cell DNA-sequencing data of 20 triple-negative breast cancer patients, our approaches effectively prioritized genes that are essential for breast cancer cell fitness and are predictive of patient survival, including those implicating convergent evolution. Similar benefits Recent advances in single-cell DNA sequencing (e.g., tagmentation based approach 15 and single-cell CNV solution by the 10X Genomics) have enabled large-scale acquisition of singlecell copy number (SCCN) profiles in tens of thousands of cells at around 100 kb resolution (~0.1X sequencing coverage per cell) [16][17][18][19] . Other platforms such as single-cell RNA-sequencing 20, 21 and single-cell ATAC-sequencing 22 have also been utilized for SCCN profiling.These SCCN profiles not only present a rich pool of genetic perturbations that are invisible at tissue level, but also potentiate reconstruction of cellular lineage, based on which the impact of an allele on cellular fitness can be measured. Thus, statistical approaches that integrate cellular lineage tracing with population genetic analysis 23 can enable discovery of novel disease genes and mechanisms of disease progression.So far, studies performing retrospective lineage tracing from single-cell data have largely been utilizing phylogenetics approaches designed to model species evolution, which is quite different from cellular evolution in terms of duration, scale, genetics and dynamics 24, 25 . Many existing phylogenetics approaches assume that genomic sites evolve independently and follow the socalled infinite site assumption (ISA) 26 . But in the context of aneuploidy, a genome site can often be altered repeatedly by different CNAs, due partly to constraints on genome and chromatin structures, properties of DNA replication/repairing 27 and functional selection. To apply conventional maximum parsimony approaches on SCCN data, one has to over-segment genomic regions and represent copy numbers as characters in disjoint intervals, which illrepresents the properties of DNAs and dis...

show abstract

“…Faithful chromosome segregation during mitosis ensures genome stability and defects in this process may lead to imbalance in chromosomal composition named aneuploidy or polyploidy, which have been causally linked to cellular transformation (1). The kinetochore is a large proteinaceous structure built onto centromere regions of sister chromatids of all chromosomes where spindle microtubules attach, thereby driving faithful sister chromatid separation at the transition from metaphase to anaphase.…”

Section: Introductionmentioning

confidence: 99%

Deubiquitylase UCHL3 drives error correction at kinetochores and chromosome segregation independent of spindle assembly checkpoint

Jeřábková

Liao

Kleiss

et al. 2020

Preprint

View full text Add to dashboard Cite

Equal segregation of chromosomes during mitosis ensures euploidy of daughter cells. Defects in this process may result in imbalance in chromosomal composition and cellular transformation. Two surveillance pathways, the spindle assembly checkpoint (SAC) and the error-correction (EC), exist at kinetochores that monitor microtubule attachment and faithful segregation of chromosomes at the metaphase to anaphase transition. However, the molecular understanding of the interplay between EC and SAC signaling remains limited. Here we describe a role of deubiquitylase UCHL3 in the regulation of EC pathway during mitosis. Downregulation or inhibition of UCHL3 leads to improper attachments of chromosomes to spindle microtubules and to chromosome alignment defects during metaphase. Frequent segregation errors during anaphase and consequently aneuploidy is also observed upon inactivation of UCHL3. Surprisingly, UCHL3 is not involved in SAC signaling as both recruitment of SAC proteins to kinetochores and timely anaphase onset are not perturbed in UCHL3-deficient cells. Mechanistically, UCHL3 interacts with and deubiquitylates the mitotic kinase Aurora B known to drive both SAC and EC signaling. UCHL3 promotes interaction of Aurora B with MCAK, important EC factor but does not regulate Aurora B binding to other interacting partners or subcellular localization of Aurora B. Our results thus suggest that UCHL3-mediated deubiquitylation functionally separates EC from SAC signaling during mitosis and is critical for maintenance of euploidy in human cells.

show abstract

Context is everything: aneuploidy in cancer

Cited by 437 publications

References 215 publications

Stabilising selection causes grossly altered but stable karyotypes in metastatic colorectal cancer

Stabilising selection causes grossly altered but stable karyotypes in metastatic colorectal cancer

Single-cell copy number lineage tracing enabling gene discovery

Deubiquitylase UCHL3 drives error correction at kinetochores and chromosome segregation independent of spindle assembly checkpoint

Contact Info

Product

Resources

About