scholarly journals Generalizing Few-Shot Classification of Whole-Genome Doubling Across Cancer Types

2021 ◽  
Author(s):  
Sherry Chao ◽  
David Belanger
Keyword(s):  
Whole Genome ◽  
Genome Doubling ◽  
Shot Classification ◽  
Whole Genome Doubling ◽  
Cancer Types

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.

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 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.

scholarly journals High prevalence of TP53 loss and whole-genome doubling in early-onset colorectal cancer

2021 ◽  
Author(s):  
Jeong Eun Kim ◽  
Jaeyong Choi ◽  
Chang-Ohk Sung ◽  
Yong Sang Hong ◽  
Sun Young Kim ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Early Onset ◽  
Large Scale ◽  
Late Onset ◽  
Age Groups ◽  
The Cancer Genome Atlas ◽  
Whole Genome ◽  
Genome Doubling ◽  
Whole Genome Doubling ◽  
Early Onset Colorectal Cancer

AbstractThe global incidence of early-onset colorectal cancer (EO-CRC) is rapidly rising. However, the reason for this rise in incidence as well as the genomic characteristics of EO-CRC remain largely unknown. We performed whole-exome sequencing in 47 cases of EO-CRC and targeted deep sequencing in 833 cases of CRC. Mutational profiles of EO-CRC were compared with previously published large-scale studies. EO-CRC and The Cancer Genome Atlas (TCGA) data were further investigated according to copy number profiles and mutation timing. We classified colorectal cancer into three subgroups: the hypermutated group consisted of mutations in POLE and mismatch repair genes; the whole-genome doubling group had early functional loss of TP53 that led to whole-genome doubling and focal oncogene amplification; the genome-stable group had mutations in APC and KRAS, similar to conventional colon cancer. Among non-hypermutated samples, whole-genome doubling was more prevalent in early-onset than in late-onset disease (54% vs 38%, Fisher’s exact P = 0.04). More than half of non-hypermutated EO-CRC cases involved early TP53 mutation and whole-genome doubling, which led to notable differences in mutation frequencies between age groups. Alternative carcinogenesis involving genomic instability via loss of TP53 may be related to the rise in EO-CRC.

scholarly journals Origin, Conservation, and Loss of Alternative Splicing Events that Diversify the Proteome in Saccharomycotina Budding Yeasts

2020 ◽  
Author(s):  
Jennifer E. Hurtig ◽  
Minseon Kim ◽  
Luisa J. Orlando-Coronel ◽  
Jellisa Ewan ◽  
Michelle Foreman ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Low Frequency ◽  
Common Mechanism ◽  
Duplicate Genes ◽  
Whole Genome ◽  
Genome Doubling ◽  
Whole Genome Doubling ◽  
Functional Consequences ◽  
Alternatively Spliced ◽  
Mammalian Genes

AbstractMany eukaryotes use alternative splicing to express multiple proteins from the same gene. However, while the majority of mammalian genes are alternatively spliced, other eukaryotes use this process less frequently. The budding yeast Saccharomyces cerevisiae has been successfully used to study the mechanism of splicing and the splicing machinery, but alternative splicing in yeast is relatively rare and has not been extensively studied. We have recently shown that the alternative splicing of SKI7/HBS1 is widely conserved, but that yeast and a few other eukaryotes have replaced this one alternatively spliced gene with a pair of duplicated unspliced genes as part of a whole genome doubling (WGD). Here we show that other examples of alternative splicing that were previously found to have functional consequences are widely conserved within the Saccharomycotina. We also show that the most common mechanism by which alternative splicing has disappeared is by the replacement of an alternatively spliced gene with duplicate genes. Saccharomycetaceae that diverged before WGD use alternative splicing more frequently than S. cerevisiae. This suggests that the WGD is a major reason for the low frequency of alternative splicing in yeast. We anticipate that whole genome doublings in other lineages may have had the same effect.

scholarly journals Loss of USP28 and SPINT2 expression promotes cancer cell survival after whole genome doubling

2021 ◽  
Author(s):  
Sara Vanessa Bernhard ◽  
Katarzyna Seget-Trzensiok ◽  
Christian Kuffer ◽  
Dragomir B. Krastev ◽  
Lisa-Marie Stautmeister ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cancer Cell ◽  
Cancer Cell Line ◽  
Colorectal Cancer Cell Line ◽  
Whole Genome ◽  
Cancer Evolution ◽  
Genome Doubling ◽  
Whole Genome Doubling ◽  
Frequent Event

Abstract Background Whole genome doubling is a frequent event during cancer evolution and shapes the cancer genome due to the occurrence of chromosomal instability. Yet, erroneously arising human tetraploid cells usually do not proliferate due to p53 activation that leads to CDKN1A expression, cell cycle arrest, senescence and/or apoptosis. Methods To uncover the barriers that block the proliferation of tetraploids, we performed a RNAi mediated genome-wide screen in a human colorectal cancer cell line (HCT116). Results We identified 140 genes whose depletion improved the survival of tetraploid cells and characterized in depth two of them: SPINT2 and USP28. We found that SPINT2 is a general regulator of CDKN1A transcription via histone acetylation. Using mass spectrometry and immunoprecipitation, we found that USP28 interacts with NuMA1 and affects centrosome clustering. Tetraploid cells accumulate DNA damage and loss of USP28 reduces checkpoint activation, thus facilitating their proliferation. Conclusions Our results indicate three aspects that contribute to the survival of tetraploid cells: (i) increased mitogenic signaling and reduced expression of cell cycle inhibitors, (ii) the ability to establish functional bipolar spindles and (iii) reduced DNA damage signaling.

scholarly journals Excision Dominates Pseudogenization During Fractionation After Whole Genome Duplication and in Gene Loss After Speciation in Plants

2020 ◽  
Vol 11 ◽  
Author(s):  
Zhe Yu ◽  
Chunfang Zheng ◽  
Victor A. Albert ◽  
David Sankoff
Keyword(s):  
Whole Genome Duplication ◽  
Gene Loss ◽  
Genome Duplication ◽  
Duplicate Genes ◽  
Whole Genome ◽  
Coding Sequence ◽  
Genome Doubling ◽  
Whole Genome Doubling ◽  
Synteny Blocks ◽  
Genomic Divergence

We take advantage of synteny blocks, the analytical construct enabled at the evolutionary moment of speciation or polyploidization, to follow the independent loss of duplicate genes in two sister species or the loss through fractionation of syntenic paralogs in a doubled genome. By examining how much sequence remains after a contiguous series of genes is deleted, we find that this residue remains at a constant low level independent of how many genes are lost—there are few if any relics of the missing sequence. Pseudogenes are rare or extremely transient in this context. The potential exceptions lie exclusively with a few examples of speciation, where the synteny blocks in some larger genomes tolerate degenerate sequence during genomic divergence of two species, but not after whole genome doubling in the same species where fractionation pressure eliminates virtually all non-coding sequence.

scholarly journals Oncogenic BRAF Induces Whole-Genome Doubling Through Suppression of Cytokinesis

2021 ◽  
Author(s):  
Revati Darp ◽  
Marc A Vittoria ◽  
Neil J Ganem ◽  
Craig J Ceol
Keyword(s):  
Mapk Pathway ◽  
Common Mutation ◽  
Whole Genome ◽  
Negative Consequences ◽  
Genome Doubling ◽  
Whole Genome Doubling ◽  
High Prevalence ◽  
Melanoma Model ◽  
Diploid Cells

Melanomas and other solid tumors commonly have increased ploidy, with near tetraploid karyotypes being most frequently observed. Such karyotypes have been shown to arise through whole genome doubling events that occur during early stages of tumor progression. The generation of tetraploid cells via whole genome doubling is proposed to allow nascent tumor cells the ability to sample various protumorigenic genomic configurations while avoiding the negative consequences that chromosomal gains or losses have in diploid cells. Whereas a high prevalence of whole genome doubling events has been established, the means by which whole genome doubling arises is unclear. Here, we find that BRAFV600E, the most common mutation in melanomas, can induce whole genome doubling via cytokinesis failure in vitro and in a zebrafish melanoma model. Mechanistically, BRAFV600E causes decreased activation and localization of RhoA, a critical cytokinesis regulator. BRAFV600E activity during G1/S phases of the cell cycle is required to suppress cytokinesis. During G1/S, BRAFV600E activity causes inappropriate centriole amplification, which is linked in part to inhibition of RhoA and suppression of cytokinesis. Together these data suggest that common abnormalities of melanomas linked to tumorigenesis; amplified centrosomes and whole-genome doubling events can be induced by oncogenic BRAF and other mutations that increase RAS/MAPK pathway activity.

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