Chromothripsis from DNA damage in micronuclei

Chen, Ken; Spektor, Alexander; Cornils, Hauke; Francis, Joshua M.; Jackson, Emily; Liu, Shiwei; Meyerson, Matthew; Pellman, David

doi:10.1038/nature14493

Cited by 995 publications

(1,119 citation statements)

References 46 publications

Supporting

Mentioning

1,054

Contrasting

Unclassified

Order By: Relevance

“…This is the first DNA evaluation directly in intact EVs. Similar size DNA has been reported to derive from DNA damage and likely chromosomal fragmentation that occurs in micronuclei, which can induce chromothripsis [42]. Chromothripsis consists of massive clustered chromosomal rearrangements usually involving one chromosome.…”

Section: Discussionmentioning

confidence: 81%

Large extracellular vesicles carry most of the tumour DNA circulating in prostate cancer patient plasma

Vagner

Spinelli

Minciacchi

et al. 2018

J of Extracellular Vesicle

313

332

View full text Add to dashboard Cite

Cancer-derived extracellular vesicles (EVs) are membrane-enclosed structures of highly variable size. EVs contain a myriad of substances (proteins, lipid, RNA, DNA) that provide a reservoir of circulating molecules, thus offering a good source of biomarkers. We demonstrate here that large EVs (L-EV) (large oncosomes) isolated from prostate cancer (PCa) cells and patient plasma are an EV population that is enriched in chromosomal DNA, including large fragments up to 2 million base pair long. While L-EVs and small EVs (S-EV) (exosomes) isolated from the same cells contained similar amounts of protein, the DNA was more abundant in L-EV, despite S-EVs being more numerous. Consistent with in vitro observations, the abundance of DNA in L-EV obtained from PCa patient plasma was variable but frequently high. Conversely, negligible amounts of DNA were present in the S-EVs from the same patients. Controlled experimental conditions, with spike-ins of L-EVs and S-EVs from cancer cells in human plasma from healthy subjects, showed that circulating DNA is almost exclusively enclosed in L-EVs. Whole genome sequencing revealed that the DNA in L-EVs reflects genetic aberrations of the cell of origin, including copy number variations of genes frequently altered in metastatic PCa (i.e. MYC, AKT1, PTK2, KLF10 and PTEN). These results demonstrate that L-EV-derived DNA reflects the genomic make-up of the tumour of origin. They also support the conclusion that L-EVs are the fraction of plasma EVs with DNA content that should be interrogated for tumour-derived genomic alterations.

show abstract

Section: Discussionmentioning

confidence: 81%

Large extracellular vesicles carry most of the tumour DNA circulating in prostate cancer patient plasma

Vagner

Spinelli

Minciacchi

et al. 2018

J of Extracellular Vesicle

313

332

View full text Add to dashboard Cite

show abstract

“…Although recent advances have been made in understanding the mechanisms underlying chromothripsis, no specific therapeutic intervention has yet been identified for chromothriptic cancers or for other chromotypes (11)(12)(13)(14).…”

Section: Tp53mentioning

confidence: 99%

The tandem duplicator phenotype as a distinct genomic configuration in cancer

Menghi

Inaki

Woo

et al. 2016

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

107

102

View full text Add to dashboard Cite

Next-generation sequencing studies have revealed genome-wide structural variation patterns in cancer, such as chromothripsis and chromoplexy, that do not engage a single discernable driver mutation, and whose clinical relevance is unclear. We devised a robust genomic metric able to identify cancers with a chromotype called tandem duplicator phenotype (TDP) characterized by frequent and distributed tandem duplications (TDs). Enriched only in triple-negative breast cancer (TNBC) and in ovarian, endometrial, and liver cancers, TDP tumors conjointly exhibit tumor protein p53 (TP53) mutations, disruption of breast cancer 1 (BRCA1), and increased expression of DNA replication genes pointing at rereplication in a defective checkpoint environment as a plausible causal mechanism. The resultant TDs in TDP augment global oncogene expression and disrupt tumor suppressor genes. Importantly, the TDP strongly correlates with cisplatin sensitivity in both TNBC cell lines and primary patient-derived xenografts. We conclude that the TDP is a common cancer chromotype that coordinately alters oncogene/tumor suppressor expression with potential as a marker for chemotherapeutic response.

show abstract

“…proposed to explain the rearrangements in chromothripsis and chromoanasynthesis 21 . The role of MYC and MYCN in replication stress 22 may represent a causative factor in the occurrence of catastrophic events.…”

Section: Discussionmentioning

confidence: 99%

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

Ratnaparkhe

Wong

Wei

et al. 2018

Preprint

View full text Add to dashboard Cite

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...

show abstract

Chromothripsis from DNA damage in micronuclei

Cited by 995 publications

References 46 publications

Large extracellular vesicles carry most of the tumour DNA circulating in prostate cancer patient plasma

Large extracellular vesicles carry most of the tumour DNA circulating in prostate cancer patient plasma

The tandem duplicator phenotype as a distinct genomic configuration in cancer

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

Contact Info

Product

Resources

About