Chromothripsis and beyond: rapid genome evolution from complex chromosomal rearrangements

Chen, Ken; Leibowitz, Mitchell L.; Pellman, David

doi:10.1101/gad.229559.113

Cited by 225 publications

(229 citation statements)

References 153 publications

(242 reference statements)

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“…The mechanisms underlying these differences are poorly understood. Chromothripsis is a possible mechanism to explain these genomic amplifications (28). Other multistep evolutionary process starting from single chromosome ancestral amplicons could explain the process (29).…”

Section: Discussionmentioning

confidence: 99%

The RNA binding protein FXR1 is a new driver in the 3q26-29 amplicon and predicts poor prognosis in human cancers

Qian

Hassanein

Hoeksema

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

111

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Aberrant expression of RNA-binding proteins has profound implications for cellular physiology and the pathogenesis of human diseases such as cancer. We previously identified the Fragile X-Related 1 gene (FXR1) as one amplified candidate driver gene at 3q26-29 in lung squamous cell carcinoma (SCC). FXR1 is an autosomal paralog of Fragile X mental retardation 1 and has not been directly linked to human cancers. Here we demonstrate that FXR1 is a key regulator of tumor progression and its overexpression is critical for nonsmall cell lung cancer (NSCLC) cell growth in vitro and in vivo. We identified the mechanisms by which FXR1 executes its regulatory function by forming a novel complex with two other oncogenes, protein kinase C, iota and epithelial cell transforming 2, located in the same amplicon via distinct binding mechanisms. FXR1 expression is a candidate biomarker predictive of poor survival in multiple solid tumors including NSCLCs. Because FXR1 is overexpressed and associated with poor clinical outcomes in multiple cancers, these results have implications for other solid malignancies.

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Section: Discussionmentioning

confidence: 99%

The RNA binding protein FXR1 is a new driver in the 3q26-29 amplicon and predicts poor prognosis in human cancers

Qian

Hassanein

Hoeksema

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

111

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“…The role of isolated structural variants in tumorigenesis is well studied (Forment et al 2012), but complete characterization of large-scale CGRs still present challenges that existing methods do not solve. In order to understand chromothripsis at a mechanistic level, Zhang et al (2013) recently demonstrated, using a combination of live cell imaging and single-cell genome sequencing, that micronucleus formation can indeed generate a spectrum of genomic rearrangements, some of which recapitulate all known features of chromothripsis. Recent reports have shown evidence for an independent cellular "path" to chromothripsis via telomere shortening and processing of the resulting dicentric chromosomes (Maciejowski et al 2015;Mardin et al 2015).…”

Section: [Supplemental Materials Is Available For This Article]mentioning

confidence: 99%

“…Chromoplexy, a phenomenon where complex genomic rearrangements typically involving up to 10 chromosomes is not uncommon, is known to occur extensively in prostate cancers (Baca et al 2013;Zhang et al 2013). We therefore looked at the distribution of contigs that span single, double, or multiple chromosomes For each of the identified contigs, we report their copy count, size, their type, and whether it was also identified by two other approaches.…”

Section: High Incidence Of Chromoplexy In Prostate and Bladder Cancersmentioning

confidence: 99%

Identification of complex genomic rearrangements in cancers using CouGaR

et al. 2016

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The genomic alterations associated with cancers are numerous and varied, involving both isolated and large-scale complex genomic rearrangements (CGRs). Although the underlying mechanisms are not well understood, CGRs have been implicated in tumorigenesis. Here, we introduce CouGaR, a novel method for characterizing the genomic structure of amplified CGRs, leveraging both depth of coverage (DOC) and discordant pair-end mapping techniques. We applied our method to whole-genome sequencing (WGS) samples from The Cancer Genome Atlas and identify amplified CGRs in at least 5.2% (10+ copies) to 17.8% (6+ copies) of the samples. Furthermore, ∼95% of these amplified CGRs contain genes previously implicated in tumorigenesis, indicating the importance and widespread occurrence of CGRs in cancers. Additionally, CouGaR identified the occurrence of ‘chromoplexy’ in nearly 63% of all prostate cancer samples and 30% of all bladder cancer samples. To further validate the accuracy of our method, we experimentally tested 17 predicted fusions in two pediatric glioma samples and validated 15 of these (88%) with precise resolution of the breakpoints via qPCR experiments and Sanger sequencing, with nearly perfect copy count concordance. Additionally, to further help display and understand the structure of CGRs, we have implemented CouGaR-viz, a generic stand-alone tool for visualization of the copy count of regions, breakpoints, and relevant genes.

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“…Chromothripsis and chromoanasynthesis are two forms of genomic instability that lead to complex genomic rearrangements affecting one or very few chromosomes [1][2][3] . These two types of catastrophic events play a role in numerous tumor entities as well as in some congenital diseases 3,4 .…”

mentioning

confidence: 99%

“…4, 2018; 3 Chromothripsis and chromoanasynthesis are two forms of genomic instability that lead to complex genomic rearrangements affecting one or very few chromosomes [1][2][3] . These two types of catastrophic events play a role in numerous tumor entities as well as in some congenital diseases 3,4 . The first form, chromothripsis, is characterized by the simultaneous occurrence of tens to hundreds of clustered DNA double-strand breaks 1,5 .…”

mentioning

confidence: 99%

Defective DNA damage repair leads to frequent catastrophic genomic events in murine and human tumors

Ratnaparkhe

Wong

Wei

et al. 2018

Preprint

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Chromothripsis and chromoanasynthesis are catastrophic events leading to clustered genomic rearrangements. Whole-genome sequencing revealed frequent chromothripsis or chromoanasynthesis (n= 16/26) in brain tumors developing in mice deficient for factors involved in homologous-recombination-repair or nonhomologous-end-joining. Catastrophic events were tightly linked to Myc/Mycn amplification, with increased DNA damage and inefficient apoptotic response already observable at early postnatal stages. Inhibition of repair processes and comparison of the mouse tumors with human medulloblastomas (n=68) and glioblastomas (n=32) identified chromothripsis as associated with MYC/MYCN gains and with DNA repair deficiencies, pointing towards therapeutic opportunities to target DNA repair defects in tumors with complex genomic rearrangements.All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/314518 doi: bioRxiv preprint first posted online May. 4, 2018; 3 Chromothripsis and chromoanasynthesis are two forms of genomic instability that lead to complex genomic rearrangements affecting one or very few chromosomes [1][2][3] . These two types of catastrophic events play a role in numerous tumor entities as well as in some congenital diseases 3,4 . The first form, chromothripsis, is characterized by the simultaneous occurrence of tens to hundreds of clustered DNA double-strand breaks 1,5 . The DNA fragments resulting from this shattering event are re-ligated by error-prone repair processes, with some of the fragments being lost. The outcome is a highly rearranged derivative chromosome, with oscillations between two or three copy-number states 6 . Conversely, the local rearrangements arising from chromoanasynthesis exhibit altered copy number due to serial microhomologymediated template switching during DNA replication 2 . Resynthesis of fragments from one chromatid and frequent insertions of short sequences between the rearrangement junctions are associated with copy number gains and retention of heterozygosity 2 .The availability of murine tumor models recapitulating these phenomena would substantially facilitate the investigation of the mechanistic aspects underlying chromothripsis and chromoanasynthesis. We showed previously the role of constitutive and somatic DNA repair defects in catastrophic genomic events in the context of TP53 and ATM mutations 5,7 . Further factors essential to the biochemical and signaling context of occurrence of these catastrophic events remain to be identified, and the role of repair processes in chromothripsis and chromoanasynthesis needs to be better defined.Homologous recombination repair (HR) and canonical non-homologous endjoining (cNHEJ) represent the two major repair processes for DNA double-strand breaks in mammalian cells. Conditional inactivation of key repair factors of either of these t...

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Chromothripsis and beyond: rapid genome evolution from complex chromosomal rearrangements

Cited by 225 publications

References 153 publications

The RNA binding protein FXR1 is a new driver in the 3q26-29 amplicon and predicts poor prognosis in human cancers

The RNA binding protein FXR1 is a new driver in the 3q26-29 amplicon and predicts poor prognosis in human cancers

Identification of complex genomic rearrangements in cancers using CouGaR

Defective DNA damage repair leads to frequent catastrophic genomic events in murine and human tumors

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