scholarly journals Mechanisms Generating Cancer Genome Complexity From A Single Cell Division Error

2019 ◽  
Author(s):  
Neil T. Umbreit ◽  
Cheng-Zhong Zhang ◽  
Luke D. Lynch ◽  
Logan J. Blaine ◽  
Anna M. Cheng ◽  
...  
Keyword(s):  
Genome Instability ◽  
Chromosome Breakage ◽  
Epigenetic Mark ◽  
Clonal Heterogeneity ◽  
Bridge Formation ◽  
Genome Complexity ◽  
Cancer Genomes ◽  
Chromosome Bridge ◽  
Bfb Cycle ◽  
Mutational Process

ABSTRACTThe chromosome breakage-fusion-bridge (BFB) cycle is a mutational process that produces gene amplification and genome instability. Signatures of BFB cycles can be observed in cancer genomes with chromothripsis, another catastrophic mutational process. Here, we explain this association by identifying a mutational cascade downstream of chromosome bridge formation that generates increasing amounts of chromothripsis. We uncover a new role for actomyosin forces in bridge breakage and mutagenesis. Chromothripsis then accumulates starting with aberrant interphase replication of bridge DNA, followed by an unexpected burst of mitotic DNA replication, generating extensive DNA damage. Bridge formation also disrupts the centromeric epigenetic mark, leading to micronucleus formation that itself promotes chromothripsis. We show that this mutational cascade generates the continuing evolution and sub-clonal heterogeneity characteristic of many human cancers.

scholarly journals Mechanisms generating cancer genome complexity from a single cell division error

Science ◽  
2020 ◽  
Vol 368 (6488) ◽  
pp. eaba0712 ◽  
Author(s):  
Neil T. Umbreit ◽  
Cheng-Zhong Zhang ◽  
Luke D. Lynch ◽  
Logan J. Blaine ◽  
Anna M. Cheng ◽  
...  
Keyword(s):  
Cell Division ◽  
Single Cell ◽  
Genome Instability ◽  
Chromosome Breakage ◽  
Genomic Complexity ◽  
Genome Complexity ◽  
Cancer Genomes ◽  
Chromosome Bridge ◽  
Bfb Cycle ◽  
Mutational Process

The chromosome breakage-fusion-bridge (BFB) cycle is a mutational process that produces gene amplification and genome instability. Signatures of BFB cycles can be observed in cancer genomes alongside chromothripsis, another catastrophic mutational phenomenon. We explain this association by elucidating a mutational cascade that is triggered by a single cell division error—chromosome bridge formation—that rapidly increases genomic complexity. We show that actomyosin forces are required for initial bridge breakage. Chromothripsis accumulates, beginning with aberrant interphase replication of bridge DNA. A subsequent burst of DNA replication in the next mitosis generates extensive DNA damage. During this second cell division, broken bridge chromosomes frequently missegregate and form micronuclei, promoting additional chromothripsis. We propose that iterations of this mutational cascade generate the continuing evolution and subclonal heterogeneity characteristic of many human cancers.

scholarly journals The Role of Dicentric Chromosome Formation and Secondary Centromere Deletion in the Evolution of Myeloid Malignancy

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Ruth N. MacKinnon ◽  
Lynda J. Campbell
Keyword(s):  
Cancer Cells ◽  
Genome Instability ◽  
Chromosome Organization ◽  
Myeloid Malignancy ◽  
Dicentric Chromosomes ◽  
Cancer Genomes ◽  
Cancer Initiation ◽  
Centromere Inactivation ◽  
Chromosome Formation

Dicentric chromosomes have been identified as instigators of the genome instability associated with cancer, but this instability is often resolved by one of a number of different secondary events. These include centromere inactivation, inversion, and intercentromeric deletion. Deletion or excision of one of the centromeres may be a significant occurrence in myeloid malignancy and other malignancies but has not previously been widely recognized, and our reports are the first describing centromere deletion in cancer cells. We review what is known about dicentric chromosomes and the mechanisms by which they can undergo stabilization in both constitutional and cancer genomes. The failure to identify centromere deletion in cancer cells until recently can be partly explained by the standard approaches to routine diagnostic cancer genome analysis, which do not identify centromeres in the context of chromosome organization. This hitherto hidden group of primary dicentric, secondary monocentric chromosomes, together with other unrecognized dicentric chromosomes, points to a greater role for dicentric chromosomes in cancer initiation and progression than is generally acknowledged. We present a model that predicts and explains a significant role for dicentric chromosomes in the formation of unbalanced translocations in malignancy.

Genome instability mechanisms and the structure of cancer genomes

2012 ◽  
Vol 22 (1) ◽  
pp. 10-13 ◽  
Author(s):  
Liam D Cassidy ◽  
Ashok R Venkitaraman
Keyword(s):  
Genome Instability ◽  
Cancer Genomes

scholarly journals Novel patterns of complex structural variation revealed across thousands of cancer genome graphs

2019 ◽  
Author(s):  
Kevin Hadi ◽  
Xiaotong Yao ◽  
Julie M. Behr ◽  
Aditya Deshpande ◽  
Charalampos Xanthopoulakis ◽  
...  
Keyword(s):  
Structural Variation ◽  
Fragile Sites ◽  
Dna Rearrangement ◽  
Genome Sequences ◽  
Cancer Genomes ◽  
Complex Structural Variation ◽  
Computational Paradigm ◽  
Complex Structural ◽  
Genome Graph ◽  
Mutational Process

SummaryCancer genomes often harbor hundreds of somatic DNA rearrangement junctions, many of which cannot be easily classified into simple (e.g. deletion, translocation) or complex (e.g. chromothripsis, chromoplexy) structural variant classes. Applying a novel genome graph computational paradigm to analyze the topology of junction copy number (JCN) across 2,833 tumor whole genome sequences (WGS), we introduce three complex rearrangement phenomena: pyrgo, rigma, and tyfonas. Pyrgo are “towers” of low-JCN duplications associated with early replicating regions and superenhancers, and are enriched in breast and ovarian cancers. Rigma comprise “chasms” of low-JCN deletions at late-replicating fragile sites in esophageal and other gastrointestinal (GI) adenocarcinomas. Tyfonas are “typhoons” of high-JCN junctions and fold back inversions that are enriched in acral but not cutaneous melanoma and associated with a previously uncharacterized mutational process of non-APOBEC kataegis. Clustering of tumors according to genome graph-derived features identifies subgroups associated with DNA repair defects and poor prognosis.

scholarly journals Absence of Brca2 causes genome instability by chromosome breakage and loss associated with centrosome amplification

1999 ◽  
Vol 9 (19) ◽  
pp. 1107-S1 ◽  
Author(s):  
Andrew Tutt ◽  
Anastasia Gabriel ◽  
David Bertwistle ◽  
Frances Connor ◽  
Hugh Paterson ◽  
...  
Keyword(s):  
Genome Instability ◽  
Chromosome Breakage ◽  
Centrosome Amplification

scholarly journals Histone H2A insufficiency causes chromosomal segregation defects due to anaphase chromosome bridge formation at rDNA repeats in fission yeast

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Takaharu G. Yamamoto ◽  
Da-Qiao Ding ◽  
Yuki Nagahama ◽  
Yuji Chikashige ◽  
Tokuko Haraguchi ◽  
...  
Keyword(s):  
Fission Yeast ◽  
Histone H2a ◽  
Bridge Formation ◽  
Chromosomal Segregation ◽  
Chromosome Bridge

scholarly journals Chromosome Instability Accounts for Reverse Metastatic Outcomes of Pediatric and Adult Synovial Sarcomas

2013 ◽  
Vol 31 (5) ◽  
pp. 608-615 ◽  
Author(s):  
Pauline Lagarde ◽  
Joanna Przybyl ◽  
Céline Brulard ◽  
Gaëlle Pérot ◽  
Gaelle Pierron ◽  
...  
Keyword(s):  
Genome Instability ◽  
Expression Profiles ◽  
Chromosome Instability ◽  
Genome Complexity ◽  
Metastasis Development ◽  
Adults And Children ◽  
Synovial Sarcomas ◽  
Chromosome Integrity ◽  
Formalin Fixed ◽  
Independent Cohort

Purpose Synovial sarcoma (SS) occurs in both children and adults, although metastatic events are much more common in adults. Whereas the importance of the t(X;18) translocation in SS oncogenesis is well established, the genetic basis of SS metastasis is still poorly understood. We recently reported expression (CINSARC; Complexity Index in Sarcoma) and Genomic Index prognostic signatures related to chromosome integrity in sarcomas and GI stromal tumors. Here we investigate whether these signatures can also predict outcomes in SS. Patients and Methods One hundred patients who had primary untreated SS tumors were selected for expression and genomic profiling in a training/validation approach. Results CINSARC and Genomic Index have strong independent and validated prognostic values (P < .001). By comparing expression profiles of tumors with or without metastasis, 14 genes that are common to the CINSARC signature were identified, and the two top-ranked genes, KIF14 and CDCA2, were validated as prognostic markers in an independent cohort. Comparing genomic profiles of adult versus pediatric SS, we show that metastasis is associated with genome complexity in both situations and that the adult genome is more frequently rearranged. Accordingly, pediatric patients with an even genomic profile do not develop metastasis. Conclusion Metastasis development in SS is strongly associated with chromosome complexity, and CINSARC and Genomic Index are validated independent prognostic factors. The differences in metastasis frequency between adults and children are associated with genome instability, which is much more frequent in adults. Genomic Index is potentially the best overall biomarker and clearly the most clinically relevant, considering that genome profiling from formalin-fixed samples is already used in pathology.

scholarly journals Mechanisms Generating Cancer Genome Complexity: Back to the Future

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3783
Author(s):  
Franck Toledo
Keyword(s):  
Genome Evolution ◽  
Fluorescent In Situ Hybridization ◽  
Chromosome Breakage ◽  
Cancer Genome ◽  
Hybridization Data ◽  
Genome Complexity ◽  
Amplification Mechanism ◽  
Cell Genome ◽  
Single Cell Genome

Understanding the mechanisms underlying cancer genome evolution has been a major goal for decades. A recent study combining live cell imaging and single-cell genome sequencing suggested that interwoven chromosome breakage-fusion-bridge cycles, micronucleation events and chromothripsis episodes drive cancer genome evolution. Here, I discuss the “interphase breakage model,” suggested from prior fluorescent in situ hybridization data that led to a similar conclusion. In this model, the rapid genome evolution observed at early stages of gene amplification was proposed to result from the interweaving of an amplification mechanism (breakage-fusion-bridge cycles) and of a deletion mechanism (micronucleation and stitching of DNA fragments retained in the nucleus).

When junk DNA turns functional: transposon-derived non-coding RNAs in plants

2021 ◽  
Author(s):  
Federico D Ariel ◽  
Pablo A Manavella
Keyword(s):  
Small Rnas ◽  
Genome Instability ◽  
Current Knowledge ◽  
Regulatory Elements ◽  
Rna Molecules ◽  
Genome Complexity ◽  
Protein Partners ◽  
Non Coding Rnas ◽  
Trans Regulation ◽  
Development And Evolution

Abstract Transposable elements (TEs) are major contributors to genome complexity in eukaryotes. TE mobilization may cause genome instability, although it can also drive genome diversity throughout evolution. TE transposition may influence the transcriptional activity of neighboring genes by modulating the epigenomic profile of the region or by altering the relative position of regulatory elements. Notably, TEs have emerged in the last few years as an important source of functional long and small non-coding RNAs. A plethora of small RNAs derived from TEs have been linked to the trans regulation of gene activity at the transcriptional and post-transcriptional levels. Furthermore, TE-derived long non-coding RNAs have been shown to modulate gene expression by interacting with protein partners, sequestering active small RNAs, and forming duplexes with DNA or other RNA molecules. In this review, we summarize our current knowledge of the functional and mechanistic paradigms of TE-derived long and small non-coding RNAs and discuss their role in plant development and evolution.

THE INDUCTION OF X-CHROMOSOMAL ANEUPLOIDY BY 5-FLUORODEOXYURIDINE (FUdR) FED TO DROSOPHILA MELANOGASTER FEMALES

1978 ◽  
Vol 20 (2) ◽  
pp. 259-263 ◽  
Author(s):  
H. Traut
Keyword(s):  
Drosophila Melanogaster ◽  
X Chromosome ◽  
Chromosome Breakage ◽  
Chromosomal Damage ◽  
X Chromosomes ◽  
Bridge Formation ◽  
Chromosomal Aneuploidy ◽  
Interphase Cells

After feeding FUdR (5-fluorodeoxyuridine) to female Drosophila melanogaster, highly significant increases in the frequencies of both XO and XXY exceptions were observed in their offspring. The XXY exceptions and part of the XO exceptions result from maternal nondisjunction of the X-chromosomes. Part of the XO exceptions can be assumed to be produced by X-chromosome breakage followed by bridge formation. The analysis of the brood pattern observed suggests that interphase cells (premeiotic oocytes, oogonia) are especially sensitive in the induction of both XO and XXY exceptions by FUdR. In addition, and contrary to the results obtained with other objects, FUdR seems to induce chromosomal damage (presumably chromatid and/or isochromatid breaks) not only in interphase but also in prophase cells. The mechanisms of the induction of X-chromosomal aneuploids by FUdR are discussed.

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