Signatures of copy number alterations in human cancer

Steele, Christopher D.; Abbasi, Ammal; Islam, S. M. Ashiqul; Bowes, Amy L; Khandekar, Azhar; Haase, Kerstin; Hames-Fathi, Shadi; Ajayi, Dolapo; Verfaillie, Annelien; Dhami, Pawan; McLatchie, Alex P.; Lechner, Matt; Light, Nicholas; Shlien, Adam; Malkin, David; Feber, Andrew; Proszek, Paula; Lesluyes, Tom; Mertens, Fredrik; Flanagan, Adrienne M.; Tarabichi, Maxime; Loo, Peter Van; Alexandrov, Ludmil B.; Pillay, Nischalan

doi:10.1038/s41586-022-04738-6

Cited by 260 publications

(222 citation statements)

References 75 publications

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“…11 A-C ). In low TOPBP1/CIP2A expressing chromothriptic samples in TCGA, there was a significant depletion (OR=0.48, q=3.2e -4 ) of chromothripsis-amplification type copy number signatures 40 and a trend (OR=1.5, p = 0.14) towards enrichment in high expressing samples ( Extended Data Fig. 11 D ), an outcome confirmed by enrichment of multiple classes of amplicon structures 41 only in high expressing samples of both non- and chromothriptic designation ( Fig.…”

Section: Resultsmentioning

confidence: 93%

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Mitotic tethering enables en masse inheritance of a shattered micronuclear chromosome

Cleveland

Trivedi

Steele

et al. 2022

Preprint

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Chromothripsis, the shattering and imperfect reassembly of one (or a few) chromosome(s)1, is an ubiquitous2 mutational process generating localized complex chromosomal rearrangements that drive genome evolution in cancer. Chromothripsis can be initiated by missegregation errors in mitosis3,4 or DNA metabolism5-7 that lead to entrapment of chromosomes within micronuclei and their subsequent fragmentation in the next interphase or upon mitotic entry6,8-10. Here, we use inducible degrons to demonstrate that chromothriptically produced pieces of a micronucleated chromosome are tethered together in mitosis by a protein complex consisting of Mediator of DNA damage checkpoint 1 (MDC1), DNA Topoisomerase II Binding Protein 1 (TOPBP1), and Cellular Inhibitor of PP2A (CIP2A), thereby enabling en masse segregation to the same daughter cell. Such tethering is shown to be crucial for the viability of cells undergoing chromosome missegregation and shattering after transient inactivation of the spindle assembly checkpoint. Pan-cancer analysis of transcriptome and whole-genome sequencing data revealed that chromothriptic genome rearrangements were accompanied by elevated expression of MDC1, TOPBP1, and CIP2A. Thus, chromatin-bound tethers maintain proximity of fragments of a shattered chromosome enabling their re-encapsulation into, and religation within, a daughter cell nucleus to form heritable, chromothriptically rearranged chromosomes found in the majority of human cancers.

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Section: Resultsmentioning

confidence: 93%

“…Copy number signature exposures for TCGA copy number profiles were downloaded from Steele et al . 2022 40 . Associations between categorized CIP2A/TOPBP1 expression and chromothripsis-associated copy number signatures (CN4:9) were performed using Fisher’s exact tests.…”

Section: Materials and Methods Cell Culturementioning

confidence: 99%

Mitotic tethering enables en masse inheritance of a shattered micronuclear chromosome

Cleveland

Trivedi

Steele

et al. 2022

Preprint

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“…We anticipate further utility of spike-in normalized chromatin architectural sequencing in the context of chromosomal imbalances (e.g., aneuploidy), which occur in as much as 90% of human tumors [ 36 ]. Studies of childhood cancers which rarely exhibit signatures of high mutational frequencies but often display signs of chromothripsis [ 37 , 38 ] may benefit from these new approaches.…”

Section: Main Textmentioning

confidence: 99%

Chromatin structure in cancer

Wang

Sunkel

Ray

2022

BMC Mol and Cell Biol

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In the past decade, we have seen the emergence of sequence-based methods to understand chromosome organization. With the confluence of in situ approaches to capture information on looping, topological domains, and larger chromatin compartments, understanding chromatin-driven disease is becoming feasible. Excitingly, recent advances in single molecule imaging with capacity to reconstruct “bulk-cell” features of chromosome conformation have revealed cell-to-cell chromatin structural variation. The fundamental question motivating our analysis of the literature is, can altered chromatin structure drive tumorigenesis? As our community learns more about rare disease, including low mutational frequency cancers, understanding “chromatin-driven” pathology will illuminate the regulatory structures of the genome. We describe recent insights into altered genome architecture in human cancer, highlighting multiple pathways toward disruptions of chromatin structure, including structural variation, noncoding mutations, metabolism, and de novo mutations to architectural regulators themselves. Our analysis of the literature reveals that deregulation of genome structure is characteristic in distinct classes of chromatin-driven tumors. As we begin to integrate the findings from single cell imaging studies and chromatin structural sequencing, we will be able to understand the diversity of cells within a common diagnosis, and begin to define structure–function relationships of the misfolded genome.

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“…CNV is a chromosomal structural variation, often caused by genome rearrangement, resulting in duplication, deletion, or copy number change in specific regions of the genome [ 41 ]. We downloaded the CNV of the TP63 gene from UCSC Xena ( (accessed on 20 June 2022)).…”

Section: Tp63 Copy Number Variation (Cnv) and Mir-944mentioning

confidence: 99%

Novel Insights into miR-944 in Cancer

Shen

Wang

Liang

et al. 2022

Cancers

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miRNA is a class of endogenous short-chain non-coding RNAs consisting of about 22 nucleotides. miR-944 is located in the fourth intron of the TP63 gene in the 3q28 region. miR-944 is abnormally expressed in cancers in multiple systems including neural, endocrine, respiratory, reproductive, and digestive systems. miR-944 can target at least 27 protein-coding genes. miR-944 can regulate a series of cell behaviors, such as cell cycle, proliferation, invasion and migration, EMT, apoptosis, etc. miR-944 participates in the networks of 11 ceRNAs, including six circRNAs and five lncRNAs. miR-944 is involved in three signaling pathways. The abnormal expression of miR-944 is closely related to the clinicopathological conditions of various cancer patients. Deregulated expression of miR-944 is significantly associated with clinicopathology and prognosis in cancer patients. In addition, miR-944 is also associated with the development of DDP, RAPA, DOX, and PTX resistance in cancer cells. miR-944 is involved in the anticancer molecular mechanisms of matrine and Rhenium-liposome drugs. In conclusion, this work systematically summarizes the related findings of miR-944, which will provide potential hints for follow-up research on miR-944.

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Signatures of copy number alterations in human cancer

Cited by 260 publications

References 75 publications

Mitotic tethering enables en masse inheritance of a shattered micronuclear chromosome

Mitotic tethering enables en masse inheritance of a shattered micronuclear chromosome

Chromatin structure in cancer

Novel Insights into miR-944 in Cancer

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