scholarly journals Whole Genome Doubling mitigates Muller’s Ratchet in Cancer Evolution

2019 ◽  
Author(s):  
Saioa López ◽  
Emilia Lim ◽  
Ariana Huebner ◽  
Michelle Dietzen ◽  
Thanos Mourikis ◽  
...  
Keyword(s):  
Negative Selection ◽  
Chromosome Complement ◽  
Essential Genes ◽  
Tumour Suppressor Genes ◽  
Whole Genome ◽  
Cancer Genes ◽  
Cancer Evolution ◽  
Genome Doubling ◽  
Whole Genome Doubling ◽  
Strong Negative Selection

AbstractWhole genome doubling (WGD) is a prevalent macro-evolutionary event in cancer, involving a doubling of the entire chromosome complement. However, despite its prevalence and clinical prognostic relevance, the evolutionary selection pressures for WGD have not been investigated. Here, we explored whether WGD may act to mitigate the irreversible, inexorable ratchet-like, accumulation of deleterious mutations in essential genes. Utilizing 1050 tumor regions from 816 non-small cell lung cancers (NSCLC), we temporally dissect mutations to determine their temporal acquisition in relation to WGD. We find evidence for strong negative selection against homozygous loss of essential cancer genes prior to WGD. However, mutations in essential genes occurring after duplication were not subject to significant negative selection, consistent with WGD providing a buffering effect, decreasing the likelihood of homozygous loss. Finally, we demonstrate that loss of heterozygosity and temporal dissection of mutations can be exploited to identify signals of positive selection in lung, breast, colorectal cancer and other cancer types, enabling the elucidation of novel tumour suppressor genes and a deeper characterization of known cancer genes.

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 Use of signals of positive and negative selection to distinguish cancer genes and passenger genes

2020 ◽  
Author(s):  
László Bányai ◽  
Mária Trexler ◽  
Krisztina Kerekes ◽  
Orsolya Csuka ◽  
László Patthy
Keyword(s):  
Negative Selection ◽  
Cancer Genomics ◽  
Tumor Evolution ◽  
Cancer Genes ◽  
Cancer Evolution ◽  
Human Genes ◽  
Strong Negative Selection ◽  
Selection For ◽  
Inactivating Mutations

AbstractA major goal of cancer genomics is to identify all genes that play critical roles in carcinogenesis. Most approaches focused on genes that are positively selected for mutations that drive carcinogenesis and neglected the role of negative selection. Some studies have actually concluded that negative selection has no role in cancer evolution. In the present work we have re-examined the role of negative selection in tumor evolution through the analysis of the patterns of somatic mutations affecting the coding sequences of human genes. Our analyses have confirmed that tumor suppressor genes are positively selected for inactivating mutations. Oncogenes, however, were found to display signals of both negative selection for inactivating mutations and positive selection for activating mutations. Significantly, we have identified numerous human genes that show signs of strong negative selection during tumor evolution, suggesting that their functional integrity is essential for the growth and survival of tumor cells.

scholarly journals Interplay between whole-genome doubling and the accumulation of deleterious alterations in cancer evolution

2020 ◽  
Vol 52 (3) ◽  
pp. 283-293 ◽  
Author(s):  
Saioa López ◽  
◽  
Emilia L. Lim ◽  
Stuart Horswell ◽  
Kerstin Haase ◽  
...  
Keyword(s):  
Whole Genome ◽  
Cancer Evolution ◽  
Genome Doubling ◽  
Whole Genome Doubling

scholarly journals Use of signals of positive and negative selection to distinguish cancer genes and passenger genes

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
László Bányai ◽  
Maria Trexler ◽  
Krisztina Kerekes ◽  
Orsolya Csuka ◽  
László Patthy
Keyword(s):  
Negative Selection ◽  
Cancer Genomics ◽  
Tumor Evolution ◽  
Cancer Genes ◽  
Cancer Evolution ◽  
Human Genes ◽  
Strong Negative Selection ◽  
Selection For ◽  
Inactivating Mutations

A major goal of cancer genomics is to identify all genes that play critical roles in carcinogenesis. Most approaches focused on genes positively selected for mutations that drive carcinogenesis and neglected the role of negative selection. Some studies have actually concluded that negative selection has no role in cancer evolution. We have re-examined the role of negative selection in tumor evolution through the analysis of the patterns of somatic mutations affecting the coding sequences of human genes. Our analyses have confirmed that tumor suppressor genes are positively selected for inactivating mutations, oncogenes, however, were found to display signals of both negative selection for inactivating mutations and positive selection for activating mutations. Significantly, we have identified numerous human genes that show signs of strong negative selection during tumor evolution, suggesting that their functional integrity is essential for the growth and survival of tumor cells.

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 Differential whole-genome doubling and homologous recombination deficiencies across breast cancer subtypes from the Taiwanese population

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Chia-Hsin Wu ◽  
Chia-Shan Hsieh ◽  
Yo-Cheng Chang ◽  
Chi-Cheng Huang ◽  
Hsien-Tang Yeh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Homologous Recombination ◽  
De Novo ◽  
Chromosome Complement ◽  
Breast Cancer Subtypes ◽  
Whole Genome ◽  
Breast Cancer Patients ◽  
Cancer Subtypes ◽  
Genome Doubling ◽  
Whole Genome Doubling

AbstractWhole-genome doubling (WGD) is an early macro-evolutionary event in tumorigenesis, involving the doubling of an entire chromosome complement. However, its impact on breast cancer subtypes remains unclear. Here, we performed a comprehensive and quantitative analysis of WGD and its influence on breast cancer subtypes in patients from Taiwan and consequently highlight the genomic association between WGD and homologous recombination deficiency (HRD). A higher manifestation of WGD was reported in triple-negative breast cancer, conferring high chromosomal instability (CIN), while HER2 + tumors exhibited early WGD events, with widely varied CIN levels, compared to luminal-type tumors. An association of higher activity of de novo indel signature 2 with WGD and HRD in Taiwanese breast cancer patients was reported. A control test between WGD and pseudo non-WGD samples was further employed to support this finding. The study provides a better comprehension of tumorigenesis in breast cancer subtypes, thus assisting in personalized treatment.

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.

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