Extrachromosomal oncogene amplification drives tumour evolution and genetic heterogeneity

Turner, Kristen M.; Deshpande, Viraj; Beyter, Doruk; Koga, Tomoyuki; Rusert, Jessica M.; Lee, Catherine; Li, Bin; Arden, Karen C.; Ren, Bing; Nathanson, David; Kornblum, Harley I.; Taylor, Michael D.; Kaushal, Sharmeela; Cavenee, Webster K.; Wechsler‐Reya, Robert J.; Furnari, Frank B.; VandenBerg, Scott R.; Rao, P. Nagesh; Wahl, Geoffrey M.; Bafna, Vineet; Mischel, Paul S.

doi:10.1038/nature21356

Cited by 594 publications

(905 citation statements)

References 34 publications

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“…These regions were lost from the reassembled derivative chromosome 8. Remarkably, such DMs have recently been detected in nearly half of all human cancers and can lead to exceptionally high expression of the corresponding DM-located genes [29] – typically oncogenes and/or genes conferring resistance to therapy [30]. That said, the frequency at which chromothripsis directly contributes to the formation of DMs across varying cancer types is not established.…”

Section: Chromothripsis Driving Tumorigenesismentioning

confidence: 99%

Rebuilding Chromosomes After Catastrophe: Emerging Mechanisms of Chromothripsis

Cleveland

2017

Trends in Cell Biology

175

166

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Cancer genome sequencing has identified chromothripsis, a complex class of structural genomic rearrangements involving the apparent shattering of an individual chromosome into tens to hundreds of fragments. An initial error during mitosis, producing either chromosome missegregation into a micronucleus or chromatin bridge interconnecting two daughter cells, can trigger the catastrophic pulverization of the spatially isolated chromosome. The resultant chromosomal fragments are re-ligated in random order by DNA double-strand break repair during the subsequent interphase. Chromothripsis scars the cancer genome with localized DNA rearrangements that frequently generate extensive copy number alterations, oncogenic gene fusion products, and/or tumor suppressor gene inactivation. Here we review emerging mechanisms underlying chromothripsis with a focus on the contribution of cell division errors caused by centromere dysfunction.

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Section: Chromothripsis Driving Tumorigenesismentioning

confidence: 99%

Rebuilding Chromosomes After Catastrophe: Emerging Mechanisms of Chromothripsis

Cleveland

2017

Trends in Cell Biology

175

166

View full text Add to dashboard Cite

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“…For instance, Sanborn et al [22] published a method to determine full structures of double minutes using WGS data from The Cancer Genome Atlas (TCGA) glioblastoma multiforme (GBM) samples. More recently, AmpliconArchitect was developed for searching and constructing circular DNA structures based on discordant reads [32]. Recent studies have also reported the structural heterogeneity of double minutes in a tumor population in several cancer types, suggesting that they dynamically evolve [13, 14].…”

Section: Introductionmentioning

confidence: 99%

Structure and evolution of double minutes in diagnosis and relapse brain tumors

Ding

Chang

et al. 2018

Acta Neuropathol

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Double minute chromosomes are extrachromosomal circular DNA fragments frequently found in brain tumors. To understand their evolution, we characterized the double minutes in paired diagnosis and relapse tumors from a pediatric high-grade glioma and four adult glioblastoma patients. We determined the full structures of the major double minutes using a novel approach combining multiple types of supporting genomic evidence. Among the double minutes identified in the pediatric patient, only one carrying EGFR was maintained at high abundance in both samples, whereas two others were present in only trace amounts at diagnosis but abundant at relapse, and the rest were found either in the relapse sample only or in the diagnosis sample only. For the EGFR-carrying double minutes, we found a secondary somatic deletion in all copies at relapse, after erlotinib treatment. However, the somatic mutation was present at very low frequency at diagnosis, suggesting potential resistance to the EGFR inhibitor. This mutation caused an in-frame RNA transcript to skip exon 16, a novel transcript isoform absent in EST database, as well as about 700 RNA-seq of normal brains that we reviewed. We observed similar patterns involving longitudinal copy number shift of double minutes in another four pairs (diagnosis/relapse) of adult glioblastoma. Overall, in three of five paired tumor samples, we found that although the same oncogenes were amplified at diagnosis and relapse, they were amplified on different double minutes. Our results suggest that double minutes readily evolve, increasing tumor heterogeneity rapidly. Understanding patterns of double minute evolution can shed light on future therapeutic solutions to brain tumors carrying such variants.Electronic supplementary materialThe online version of this article (10.1007/s00401-018-1912-1) contains supplementary material, which is available to authorized users.

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“…This entire procedure is illustrated in Figure 1. Although this strategy is very effective for small eccDNAs (like microDNA and spcDNA) it remains difficult to extract the entire circular DNA for the large DMs, for which alternative methods like microdissection (13), array-CGH (39) or direct sequencing of the total DNA (40) can be applied, as sequences on DMs are highly amplified. As the quantity of cfDNAs obtained from body fluids is very limited, when using cfDNAs as starting material, eccDNA enrichment method may need further improvement to increase sensitivity.…”

Section: Methods For Identification and Enrichment Of Eccdnasmentioning

confidence: 99%

Cell-Free eccDNAs: A New Type of Nucleic Acid Component for Liquid Biopsy?

et al. 2018

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Extrachromosomal circular DNAs (eccDNAs) are circular DNAs that are originated from chromosomes, but are independent from chromosomal DNA. The eccDNAs are commonly found in various tissues and cell types, and in both normal and diseased conditions. Due to their highly heterogeneous origins and being widely spread in nearly all eukaryotes, the eccDNAs are believed to reflect the genome's plasticity and instability. With the assistance of next-generation sequencing, more eccDNAs have been characterized at the molecular level. Recently, eccDNAs have been reported as cell-free DNAs in the circulation system. Importantly, these circulating eccDNAs have shown some evidence with disease associations, suggesting their potential utility as a new type of biomarker for disease detection, treatment assessment and progress surveillance. However, many challenges need to be addressed before implementing the eccDNAs as a new source of genetic material for liquid biopsy.

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Extrachromosomal oncogene amplification drives tumour evolution and genetic heterogeneity

Cited by 594 publications

References 34 publications

Rebuilding Chromosomes After Catastrophe: Emerging Mechanisms of Chromothripsis

Rebuilding Chromosomes After Catastrophe: Emerging Mechanisms of Chromothripsis

Structure and evolution of double minutes in diagnosis and relapse brain tumors

Cell-Free eccDNAs: A New Type of Nucleic Acid Component for Liquid Biopsy?

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