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The Life History of Neochromosomes Revealed

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The Life History of Neochromosomes Revealed AUTHOR'S VIEW Molecular & Cellular Oncology 2:4, e1000698; October/November/December 2015; Published with license by Taylor & Francis Group, LLC The life history of neochromosomes revealed Anthony T Papenfuss1,2,3,4,* and David M Thomas2,5,6,* 1Bioinformatics Division; The Walter & Eliza Hall Institute of Medical Research; Parkville, Australia; 2Peter MacCallum Cancer Centre; East Melbourne, Australia; 3Department of Medical Biology; University of Melbourne; Melbourne, Australia; 4Sir Peter MacCallum Department of Oncology; University of Melbourne; Melbourne, Australia; 5The Kinghorn Cancer Centre, Garvan Institute of Medical Research; Sydney, Australia; 6University of New South Wales; Sydney, Australia Keywords: neochromosome, chromothripsis, breakage-fusionbridge mechanism, liposarcoma, cancer evolution, computational modelling Neochromosomes are a little-studied class of chromosome-scale mutations that drive some cancers. By sequencing isolated neochromosomes from liposarcomas, we recently defined their structure at single-nucleotide resolution and proposed a model for their life history. Here, we summarize that work, highlighting significant aspects and providing historical context and insight into the discovery process. Neochromosomes are giant extra chro- leads to the formation of a ring chromo- specialized method because of the unusual mosomes that are found in 3% of cancers some. During replication, DNA crossover nature of the complex data generated. overall1 but are particularly common in events between the sister chromatids can This included the copy number analysis, certain cancer subtypes, including well- occur. An odd number of crossovers leads which integrated information from spec- differentiated and de-differentiated lipo- to an interlocked and dicentric ring. tral karyotyping to calibrate the copy sarcomas (WD/DD-LPS). Neochromo- Dicentric chromosomes form anaphase number on the neochromosome, fusion somes may be circular or linear, possess bridges and are torn apart during cell divi- detection, classification of neochromoso- centromeres and telomeres (in the linear sion. This leads to unequal inheritance of mal material, and finally a mathematical form), and can harbor oncogenes at high DNA by daughter cells and possible selec- model of the mutational mechanisms that copy number that drive tumor develop- tion of some cell subpopulations.1 shaped the neochromosome over time. In ment. They were probably first observed In our recent publication,5 we describe a similar vein, we repeatedly found that in the 1950s by the Swedish geneticist the analysis of sequencing data from puri- we had to invent new terms to describe Albert Levan as ring chromosomes in fied neochromosomes obtained from and discuss the data—including the term tumors,2 but were not identified as a dis- WD/DD-LPS cell lines by flow cytomet- ‘neochromosome’ itself. tinct cancer-causing entity until the ric cell sorting and whole-genome The sequencing data provided the 1990s.3 How neochromosomes form has sequence data from patient tumors. Flow first high-resolution view of a neochro- remained a mystery. sorting of chromosomes works by select- mosome, allowing us to describe their Low-resolution analyses of WD/DD- ing DNA molecules based on the intensity architecture in detail (Fig. 1B). Several LPS neochromosomes using fluorescent in of 2 fluorescent dyes that are markers of observations suggested the involvement situ hybridization (FISH) and copy num- size and GC-content. We purified neo- of chromothripsis, the shattering of a ber arrays provided an approximate idea chromosomal DNA in order to sequence chromosome in a single catastrophic of DNA content, and an (under-) estimate the neochromosome at high coverage. event6 that was first identified in tumors of their size and copy number. This led to Unavoidably, the rest of the genome was that were otherwise genomically stable. the hypothesis that the breakage-fusion- sequenced at low coverage. This can be The occurrence of a chromothriptic bridge (BFB) mechanism4 might be seen in plots of the neochromosome copy event is not observed directly, but rather involved in their formation,1,3 but no number, which highlight multiple fasci- inferred from the ruins of the chromo- solid proof of this existed. BFB was dis- nating features in the background of the somes that remain. A set of statistical covered by Barbara McClintock in maize normal chromosomes (e.g., Fig. 1). criteria have been proposed to test for in 1951. It is initiated by telomere loss: Analysis and interpretation of the neo- chromothripsis,7 but they are strongly single telomere loss leads to the formation chromosome sequencing data required a motivated by the ideal case of a largely of a dicentric linear chromosome during high level of creativity. Almost every quiescent genome and must be adapted replication, whereas loss of both telomeres aspect of analysis (see Fig. 1A) required a for more complex cases (see the © Anthony T Papenfuss and David M Thomas *Correspondence to: Anthony T Papenfuss; Email: [email protected]; David M Thomas; Email: [email protected] Submitted: 12/10/2014; Revised: 12/17/2014; Accepted: 12/17/2014 http://dx.doi.org/10.1080/23723556.2014.1000698 This is an Open Access article distributed under the terms of the Creative Commons Attribution-Non-Commercial License (http://creativecommons.org/licenses/ by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted. www.tandfonline.com Molecular & Cellular Oncology e1000698-1 Figure 1. Integration of multiple omics data and computational modeling provides insight into the life history of neochromosomes. (A) Schematic of the analysis of next-generation sequencing data from flow sorted neochromosomes, integration of fluorescent in situ hybridization (FISH) and ChIP-seq against centromere protein A (CENPA), and computational modeling. (B) Copy number profile for neochromosomal material derived from chromosome 12 in the T1000 cell line. This shows high levels of amplification and enrichment compared to a low background. Copy numbers are calibrated for the neochromosome; copy numbers less than one correspond to normal chromosomes. The highly amplified contiguous genomic regions (CGRs), which are the building blocks of the neochromosome, are indicated. (C)A“normal” or “background” chromosome from the T1000 cell line. Low coverage sequencing of this chromosome provides evidence for linear breakage-fusion-bridge. Supplementary Information of references other lines of evidence supported the an intrachromosomal walk, suggestive of 5 and 8 for a detailed discussion). Our notion that chromothripsis underlies the an early chromothriptic event involving data were the antithesis of this: nearly highly amplified regions of chromosome chromosome 12 only. every chromosome was involved and 12 present in all neochromosomes. In par- The key to demonstrating that both showed extreme copy number amplifica- ticular, we discovered that the fundamental chromothripsis and BFB were involved in tion. Nevertheless, the telomeric regions building blocks (we used the term contigu- the formation of the neochromosome was of the neochromosome showed the classic ous genomic regions or CGRs; Fig. 1B) the development of a mathematical model signature of chromothripsis and multiple were rearranged and fused edge-to-edge in of these mechanisms. There were really 4 e1000698-2 Molecular & Cellular Oncology Volume 2 Issue 4 components to our model: a stochastic chromothripsis model easily fitted the Funding simulation of circular BFB, a simple data. DMT and ATP were supported by a model of selection, a model of chromo- Through detailed analysis of National Health and Medical Research thripsis, and a way to compare the model sequencing data from liposarcoma neo- Council (NHMRC) Project Grant with the data. Because of the lack of chromosomes, development of special- (1004022) and the Liddy Shriver Sar- detailed information about these mecha- ized methods for genotyping, hypothesis coma Initiative. DMT was supported nisms, our approach was to try to make testing using computational modeling, by an NHMRC Senior Research Fel- few assumptions, keep the models simple, and integration with observations of lowship (1003929). ATP was supported and use empirical data where possible. centromeres across multiple neochromo- by an NHMRC Career Development How we compared the model results to somes, we were able to infer the life Fellowship (1003856) and an NHMRC the data was the most critical part. We ran history of these oncogenic chromo- Program Grant (1054618). The work the model hundreds of times and com- somal-scale mutations. benefitted from support by the Victo- pared summary statistics of the predictions rian State Government Operational from each run with summary statistics of Infrastructure Support and Australian Disclosure of Potential Conflicts of Interest the data. We found that we could not fit Government NHMRC IRIISS. the BFB-only model to the data for any No potential conflicts of interest were parameter choices, whereas the BFB plus disclosed. References 4. McClintock B. The Behavior in Successive Nuclear single catastrophic event during cancer development. 1. Garsed DW, Holloway AJ, Thomas DM. Cancer-associ- Divisions of a Chromosome Broken at Meiosis. Proc Cell 2011; 144:27-40; PMID:21215367; http://dx.doi. ated neochromosomes: a novel mechanism of oncogene- Natl Acad Sci
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