scholarly journals Signatures of copy number alterations in human cancer

2021 ◽  
Author(s):  
Christopher D Steele ◽  
Ammal Abbasi ◽  
Ashiqul S M Islam ◽  
Azhar Khandekar ◽  
Kerstin Haase ◽  
...  
Keyword(s):  
Copy Number ◽  
Human Cancer ◽  
Whole Genome ◽  
Copy Number Alterations ◽  
Cancer Risk Factors ◽  
Genome Doubling ◽  
Whole Genome Doubling ◽  
Cancer Types ◽  
Copy Number Changes ◽  
Gains And Losses

The gains and losses of DNA that emerge as a consequence of mitotic errors and chromosomal instability are prevalent in cancer. These copy number alterations contribute to cancer initiaition, progression and therapeutic resistance. Here, we present a conceptual framework for examining the patterns of copy number alterations in human cancer using whole-genome sequencing, whole-exome sequencing, and SNP6 microarray data making it widely applicable to diverse datasets. Deploying this framework to 9,873 cancers representing 33 human cancer types from the TCGA project revealed a set of 19 copy number signatures that explain the copy number patterns of 93% of TCGA samples. 15 copy number signatures were attributed to biological processes of whole-genome doubling, aneuploidy, loss of heterozygosity, homologous recombination deficiency, and chromothripsis. The aetiology of four copy number signatures are unexplained and some cancer types have unique patterns of amplicon signatures associated with extrachromosomal DNA, disease-specific survival, and gains of proto-oncogenes such as MDM2. In contrast to base-scale mutational signatures, no copy number signature associated with known cancer risk factors. The results provide a foundation for exploring patterns of copy number changes in cancer genomes and synthesise the global landscape of copy number alterations in human cancer by revealing a diversity of mutational processes giving rise to copy number changes.

Abstract 5759: The landscape of copy-number changes across multiple human cancer types

2010 ◽  
Author(s):  
Rameen Beroukhim ◽  
Matthew Meyerson ◽  
Levi Garraway ◽  
John Prensner
Keyword(s):  
Copy Number ◽  
Human Cancer ◽  
Cancer Types ◽  
Copy Number Changes

scholarly journals Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing

2018 ◽  
Author(s):  
Isidro Cortés-Ciriano ◽  
June-Koo Lee ◽  
Ruibin Xi ◽  
Dhawal Jain ◽  
Youngsook L. Jung ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Copy Number ◽  
Human Cancer ◽  
Whole Genome Sequencing Data ◽  
Whole Genome ◽  
Sequencing Data ◽  
End Joining ◽  
Cancer Types ◽  
Non Homologous End Joining

SummaryChromothripsis is a newly discovered mutational phenomenon involving massive, clustered genomic rearrangements that occurs in cancer and other diseases. Recent studies in cancer suggest that chromothripsis may be far more common than initially inferred from low resolution DNA copy number data. Here, we analyze the patterns of chromothripsis across 2,658 tumors spanning 39 cancer types using whole-genome sequencing data. We find that chromothripsis events are pervasive across cancers, with a frequency of >50% in several cancer types. Whereas canonical chromothripsis profiles display oscillations between two copy number states, a considerable fraction of the events involves multiple chromosomes as well as additional structural alterations. In addition to non-homologous end-joining, we detect signatures of replicative processes and templated insertions. Chromothripsis contributes to oncogene amplification as well as to inactivation of genes such as mismatch-repair related genes. These findings show that chromothripsis is a major process driving genome evolution in human cancer.

scholarly journals Whole genome doubling confers unique genetic vulnerabilities on tumor cells

2020 ◽  
Author(s):  
Ryan J. Quinton ◽  
Amanda DiDomizio ◽  
Marc A. Vittoria ◽  
Carlos J. Ticas ◽  
Sheena Patel ◽  
...  
Keyword(s):  
Spindle Assembly Checkpoint ◽  
Human Cancer ◽  
Tumor Development ◽  
Whole Genome ◽  
Sequencing Data ◽  
Genetic Traits ◽  
Checkpoint Signaling ◽  
Genome Doubling ◽  
Whole Genome Doubling ◽  
Replication Factors

SummaryWhole genome doubling (WGD) occurs early in tumorigenesis and generates genetically unstable tetraploid cells that fuel tumor development. Cells that undergo WGD (WGD+) must adapt to accommodate their abnormal tetraploid state; however, the nature of these adaptations, and whether they confer vulnerabilities that can subsequently be exploited therapeutically, is unclear. Using sequencing data from ∼10,000 primary human cancer samples and essentiality data from ∼600 cancer cell lines, we show that WGD gives rise to common genetic traits that are accompanied by unique vulnerabilities. We reveal that WGD+ cells are more dependent on spindle assembly checkpoint signaling, DNA replication factors, and proteasome function than WGD− cells. We also identify KIF18A, which encodes for a mitotic kinesin, as being specifically required for the viability of WGD+ cells. While loss of KIF18A is largely dispensable for accurate chromosome segregation during mitosis in WGD− cells, its loss induces dramatic mitotic errors in WGD+ cells, ultimately impairing cell viability. Collectively, our results reveal new strategies to specifically target WGD+ cancer cells while sparing the normal, non-transformed WGD− cells that comprise human tissue.

scholarly journals Thermodynamic energetics underlying genomic instability and whole-genome doubling in cancer

2020 ◽  
Vol 117 (31) ◽  
pp. 18880-18890
Author(s):  
Francoise Remacle ◽  
Thomas G. Graeber ◽  
R. D. Levine
Keyword(s):  
Genomic Instability ◽  
Stable State ◽  
Whole Genome ◽  
Driver Genes ◽  
Selection Pressures ◽  
Cancer Driver ◽  
Genome Doubling ◽  
Whole Genome Doubling ◽  
High Ploidy ◽  
Cancer Types

Genomic instability contributes to tumorigenesis through the amplification and deletion of cancer driver genes. DNA copy number (CN) profiling of ensembles of tumors allows a thermodynamic analysis of the profile for each tumor. The free energy of the distribution of CNs is found to be a monotonically increasing function of the average chromosomal ploidy. The dependence is universal across several cancer types. Surprisal analysis distinguishes two main known subgroups: tumors with cells that have or have not undergone whole-genome duplication (WGD). The analysis uncovers that CN states having a narrower distribution are energetically more favorable toward the WGD transition. Surprisal analysis also determines the deviations from a fully stable-state distribution. These deviations reflect constraints imposed by tumor fitness selection pressures. The results point to CN changes that are more common in high-ploidy tumors and thus support altered selection pressures upon WGD.

scholarly journals Whole-genome doubling-aware copy number phylogenies for cancer evolution with MEDICC2

2021 ◽  
Author(s):  
Marina Petkovic ◽  
Thomas BK Watkins ◽  
Emma C Colliver ◽  
Sofya Laskina ◽  
Charles Swanton ◽  
...  
Keyword(s):  
Copy Number ◽  
Phylogenetic Trees ◽  
Evolutionary Process ◽  
Recent Common Ancestor ◽  
Whole Genome ◽  
Cancer Evolution ◽  
Minimum Evolution ◽  
Genome Doubling ◽  
Most Recent Common Ancestor ◽  
Whole Genome Doubling

Chromosomal instability (CIN) and somatic copy number alterations (SCNA) play a key role in the evolutionary process that shapes cancer genomes. SCNAs comprise many classes of clinically relevant events, such as localised amplifications, gains, losses, loss-of-heterozygosity (LOH) events, and recently discovered parallel evolutionary events revealed by multi-sample phasing. These events frequently appear jointly with whole genome doubling (WGD), a transformative event in tumour evolution, which generates tetraploid or near-tetraploid cells. WGD events are often clonal, occuring before the emergence of the most recent common ancestor, and have been associated with increased CIN, poor patient outcome and are currently being investigated as potential therapeutic targets. While SCNAs can provide a rich source of phylogenetic information, so far no method exists for phylogenetic inference from SCNAs that includes WGD events. Here we present MEDICC2, a new phylogenetic algorithm for allele-specific SCNA data based on a minimum-evolution criterion that explicitly models clonal and subclonal WGD events and that takes parallel evolutionary events into account. MEDICC2 can identify WGD events and quantify SCNA burden in single-sample studies and infer phylogenetic trees and ancestral genomes in multi-sample scenarios. In this scenario, it accurately locates clonal and subclonal WGD events as well as parallel evolutionary events in the evolutionary history of the tumour, timing SCNAs relative to each other. We use MEDICC2 to detect WGD events in 2778 tumours with 98.8% accuracy and show its ability to correctly place subclonal WGD events in simulated and real-world multi-sample tumours, while accurately inferring its phylogeny and parallel SCNA events. MEDICC2 is implemented in Python 3 and freely available under GPLv3 at https://bitbucket.org/schwarzlab/medicc2.

scholarly journals USP28 and SPINT2 mediate cell cycle arrest after whole genome doubling

2020 ◽  
Author(s):  
Katarzyna Seget-Trzensiok ◽  
Sara Vanessa Bernhard ◽  
Christian Kuffer ◽  
Dragomir B Krastev ◽  
Mirko Theis ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Human Cancer ◽  
Cancer Cell Line ◽  
Whole Genome ◽  
Genome Doubling ◽  
Cycle Arrest ◽  
Whole Genome Doubling ◽  
Mediate Cell

AbstractTetraploidy is frequent in cancer and whole genome doubling shapes the evolution of cancer genomes, thereby driving the transformation, metastasis and drug resistance. Yet, human cells usually arrest when they become tetraploid due to p53 activation that leads to CDKN1A expression, cell cycle arrest, senescence or apoptosis. To uncover the barriers that block proliferation of tetraploids, we performed an RNAi mediated genome-wide screen in a human cancer cell line. We identified 140 genes whose depletion improved survival of tetraploids and characterized in depth two of them: SPINT2 and USP28. We show that SPINT2 is a general regulator of CDKN1A, regulating its transcription via histone acetylation. By mass spectrometry and immunoprecipitation, we show that USP28 interacts with NuMA1 and affects centrosome clustering. Moreover, tetraploid cells accumulate DNA damage and loss of USP28 reduces checkpoint activation. Our results indicate three aspects that contribute to survival of tetraploid cells: i) increased mitogenic signaling and reduced expression of cell cycle inhibitors, ii) the ability to establish functional bipolar spindle, and iii) reduced DNA damage signaling.

scholarly journals Whole-Genome Doubling Affects Pre-miRNA Expression in Plants

Plants ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1004
Author(s):  
Salvatore Esposito ◽  
Riccardo Aversano ◽  
Pasquale Tripodi ◽  
Domenico Carputo
Keyword(s):  
Dna Repair ◽  
Mirna Expression ◽  
Building Blocks ◽  
Nucleotide Metabolism ◽  
Integrative Approach ◽  
Whole Genome ◽  
Solanum Commersonii ◽  
Genome Doubling ◽  
Whole Genome Doubling ◽  
Micro Rnas

Whole-genome doubling (polyploidy) is common in angiosperms. Several studies have indicated that it is often associated with molecular, physiological, and phenotypic changes. Mounting evidence has pointed out that micro-RNAs (miRNAs) may have an important role in whole-genome doubling. However, an integrative approach that compares miRNA expression in polyploids is still lacking. Here, a re-analysis of already published RNAseq datasets was performed to identify microRNAs’ precursors (pre-miRNAs) in diploids (2x) and tetraploids (4x) of five species (Arabidopsis thaliana L., Morus alba L., Brassica rapa L., Isatis indigotica Fort., and Solanum commersonii Dun). We found 3568 pre-miRNAs, three of which (pre-miR414, pre-miR5538, and pre-miR5141) were abundant in all 2x, and were absent/low in their 4x counterparts. They are predicted to target more than one mRNA transcript, many belonging to transcription factors (TFs), DNA repair mechanisms, and related to stress. Sixteen pre-miRNAs were found in common in all 2x and 4x. Among them, pre-miRNA482, pre-miRNA2916, and pre-miRNA167 changed their expression after polyploidization, being induced or repressed in 4x plants. Based on our results, a common ploidy-dependent response was triggered in all species under investigation, which involves DNA repair, ATP-synthesis, terpenoid biosynthesis, and several stress-responsive transcripts. In addition, an ad hoc pre-miRNA expression analysis carried out solely on 2x vs. 4x samples of S. commersonii indicated that ploidy-dependent pre-miRNAs seem to actively regulate the nucleotide metabolism, probably to cope with the increased requirement for DNA building blocks caused by the augmented DNA content. Overall, the results outline the critical role of microRNA-mediated responses following autopolyploidization in plants.

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