Chromothripsis

Last updated
Chromothripsis: Single catastrophic event in a cell's history Chromothripsis the result of a single catastrophic event in a cells history.png
Chromothripsis: Single catastrophic event in a cell's history

Chromothripsis is a mutational process by which up to thousands of clustered chromosomal rearrangements occur in a single event in localised and confined genomic regions in one or a few chromosomes, and is known to be involved in both cancer and congenital diseases. It occurs through one massive genomic rearrangement during a single catastrophic event in the cell's history. It is believed that for the cell to be able to withstand such a destructive event, the occurrence of such an event must be the upper limit of what a cell can tolerate and survive. [1] The chromothripsis phenomenon opposes the conventional theory that cancer is the gradual acquisition of genomic rearrangements and somatic mutations over time. [2]

Contents

The simplest model as to how these rearrangements occur is through the simultaneous fragmentation of distinct chromosomal regions (breakpoints show a non-random distribution) and then subsequent imperfect reassembly by DNA repair pathways or aberrant DNA replication mechanisms. Chromothripsis occurs early in tumour development and leads to cellular transformation by loss of tumour suppressors and oncogene amplifications. [3] In 2015, it was found that chromothripsis can also be curative: a woman who had WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome, an extremely rare autosomal dominant combined immunodeficiency disease, found her symptoms disappeared during her 30s after chromothripsis of chromosome 2 deleted the disease allele. [4]

The term chromothripsis is a neologism coined by scientists at the Wellcome Trust Sanger Institute [2] that comes from the Greek words χρῶμα, khrôma 'color' (representing chromosomes because they are strongly stained by particular dyes), and θρίψις, thrípsis 'shattering into pieces'. [2]

First observation

Chromothripsis was first observed in sequencing the genome of a chronic lymphocytic leukaemia. Through paired end sequencing, 55 chromosomal rearrangements were found in the long arm of chromosome 8 and a significant number of rearrangements were found in regions of chromosomes 7, 12, and 15. [2] Subsequent investigations using genome-wide paired-end sequencing and SNP array analysis [5] have found similar patterns of chromothripsis in various human cancers, e.g., melanomas, sarcomas and colorectal, lung and thyroid cancers. In subsequent investigations, about 25% of studied bone cancers displayed evidence of chromothripsis. Chromothripsis has been linked to the generation of oncogenic fusions in supratentorial ependymoma, chondromyxoid fibroma, and Ewing sarcoma, the latter two being bone tumours. [6] [7] Chromothripsis has been seen in 2–3% of cancers across all subtypes. [3]

Characteristic features

Breakage and repair of chromosomes

Non homologous end joining and Microhomology mediated end joining Non homologous end joining and microhomology mediated end joining.png
Non homologous end joining and Microhomology mediated end joining

The most widely accepted and straightforward model for chromothripsis is that within a single chromosome, distinct chromosomal regions become fragmented/shattered almost simultaneously and subsequently rejoined in an incorrect orientation. Deletion of certain fragments, including deletions that are a few hundred base pairs long, and hence gene segments is possible and consequently the production of double minute chromosomes. [2] When multiple chromosomes are involved in chromothripsis, fragments of both chromosomes are joined together by paired end joining and the exchange of fragments between the original chromosomes. [3]

Rejoining of fragments require very minimal or even no sequence homology and consequently suggesting that nonhomologous or microhomologous repair mechanisms such as non-homologous end joining (NHEJ) and microhomology-mediated break induced repair (MMBIR) dominate double stranded break repair and are involved in modelling the chromothriptic landscape, opposed to homologous recombination which requires sequence homology. Joining of fragments and rearrangements have also been shown to take place on paternal chromosomes. [5]

As well as in cancer cells, chromothripsis has also been reported in patients with developmental and congenital defects, i.e. germ line cells. Using multiple molecular techniques of these germ line cells that have appeared to have undergone a chromothripsis like process, as well as inversions and translocations, duplications and triplications were also seen and hence increases in copy number. This can be attributed to replicative processes that involve the restoration of collapsed replication forks such as fork stalling and template switching model (FoSTeS) or microhomology mediated break induced replication (MMBIR). [9] This makes it seem that it would be more appropriate to name the phenomenon 'chromoanasynthesis' which means chromosome reconstitution rather than chromothripsis. [9] However most samples displaying chromothripsis that are analysed have low copy states and hence have paired end joining predominating repair mechanisms. [2]

Further study of chromothripsis events and chromothriptic samples is required in order to understand the relative importance of paired end joining and replicative repair in chromothripsis. [3]

Mechanism

One of the main characteristic features of chromothripsis is large numbers of complex rearrangements occurring in localised regions of single chromosomes. The ability to cause such confined damage suggests that chromosomes need to be condensed e.g. in mitosis, for chromothripsis and chromosome rearrangements to be initiated. [1] [3]

The mechanisms of chromothripsis are not well understood. There are multiple ideas of how chromothripsis occurs.[ citation needed ]

Micronuclei model

Schematic of Micronucleus model of chromothripsis Micronucleus Model.png
Schematic of Micronucleus model of chromothripsis

The Micronuclei model is the most accepted model as to how and when the breakage and repair in chromothripsis occurs. In cancer cells, fragmentation of chromosomes has been correlated with the presence of micronuclei. [3] Micronuclei are structures formed by mitotic errors in the transition from metaphase to anaphase. Cells with defective chromosome segregation will form micronuclei which contain whole chromosomes or fragments of chromosomes. The segregation of single chromosomes into individual micronuclei explains why DNA fragmentation is isolated to single chromosomes in chromothripsis. [10]

These micronuclei undergo defective DNA replication, which is slower than DNA replication in the main nucleus and causes a proximal DNA damage response (DDR) to be initiated. However, DNA repair and cell cycle checkpoint activation fail to follow. [11] Consequently, chromosomes that are not correctly replicated in micronuclei become fragmented. [10] The mechanism by which the pulverization of these chromosomes occurs is not fully understood, but it is thought to be caused either by aberrant DNA replication or by premature chromosome condensation, which entails semi-replicated chromosomes being compacted by cyclin-dependent kinase activity. [12] The resulting fragmented chromosome segments can be joined together to give rise to a rearranged chromosome, which can subsequently be reincorporated into the main nucleus of a daughter cell. The new chromosome can persist for several generations of cell cycle divisions and contribute to the development of a cancer cell. [3] [10]

Although the micronucleus model is appropriate, other factors are likely to contribute towards chromothripsis for various cancer genomes. [3]

Ionising radiation during mitosis

Chromosome shattering is triggered and reassembly of chromosome fragments in close proximity is caused by environmental stimuli such as high energy ionising radiation encountered during mitosis. [1]

Aborted apoptosis

Stress stimuli such as radiation, nutrient deprivation or oxygen deprivation which causes apoptosis will lead to fragmentation of chromatin and cause most cells to apoptose. However a small subset of cells will survive apoptosis. This cleaved DNA will require repair, and when this is done incorrectly, rearrangements will be introduced into the chromosome. There is currently speculation that chromothripsis might be driven by viruses such as γ-herpes viruses which cause cancer, possibly by the inhibition of apoptosis. However this speculation requires further investigation. [13]

Telomeric dysfunction

Telomeric double stranded breaks or telomeric dysfunction is generated by exogenous agents or replicative stress. Telomeric dysfunctions are known to promote chromosomal abnormalities associated with cancer cells. For example, Telomeric double stranded breaks/ telomeric dysfunctions can cause sister chromatid/ end to end fusion and the formation of anaphase bridges resulting in dicentric chromosomes that can result in further rearrangements. This is a more plausible explanation as chromothripsis has been seen to mostly involve telomeric regions. [13]

Predispositions

Mutations in the TP53 gene can predispose a cell to chromothripsis.[ citation needed ]

Through genome sequencing of a Sonic hedgehog medulloblastoma (SHH-MB) brain tumour, a significant link between TP53 mutations and chromothripsis in SHH-MBs has been found. Further studies on the association between TP53 and chromothripsis has signified a role for p53, a tumour suppressor protein, in the massive genomic rearrangement which take place which takes place in chromothripsis. Hence there is a strong association between p53 status and chromothripsis, giving an insight into why some cancers are more aggressive. [14] [15]


It has also been shown that TP53 mutation-containing cells show a preference for low-fidelity repair mechanisms such as non-homologous end joining. TP53 mutations have also been expressed in cells that exhibit shorter[ clarification needed ] and are more end-end fusion prone. It is also hypothesized that TP53 mutations may be implicated in premature chromosome condensation. TP53 may also contribute to the ability of cells to survive the catastrophic event that normally would be considered to be too destructive to withstand. [1]

Relationship to carcinogenesis

Chromothripsis has been seen to cause oncogene amplification, amplification of oncogene containing regions and the loss of tumour suppressors. [3]

Chromosome segregation errors can lead to DNA damage and chromosomal aberrations such as aneuploidy which is linked to tumour development. [3] [16] The formation of micronuclei generally occurs concurrently with aneuploidy and aneuploidy cells are controlled by mechanisms involving p53. In order for micronuclei to progress through the cell cycle and induce chromosome damage, diminished levels of p53 have been seen to be needed. Through further investigation, chromothriptic tumours have been seen to occur in patients with p53 mutations. [17] [18]

Defects in DNA damage response can cause increased frequency of micronucleus formation and hence the occurrence of chromothripsis. There are numerous examples of how DDR pathways affect chromothripsis and hence cause tumour development and cancers. [3]

As well as cells encompassing DDR defects, they are likely to have repressed apoptotic mechanisms which will further enhance the occurrence of mutations and aneuploidy. [3]

Prognostics and diagnostics

Research in patients with chromothripsis-associated cancers may provide some information about prognosis. TP53 mutations and chromothripsis have been linked in SHH medulloblastoma patients. [1] Poor clinical outcomes in neuroblastomas (such as those caused by deletion of the FANC gene in Fanconi anaemia) have been linked to frequent chromothripsis occurrence. [22] Screening biopsy materials for chromothripsis can lead to good prognosis estimates and better outcomes for patients.[ citation needed ]

Criticism

It was pointed out that initial computational simulations underpinning the single-event nature of chromothripsis, which are central to the theory, did not necessarily prove the existence of a single event, and that known models of progressive cancer development do not contradict the occurrence of complex rearrangements. [23] It has also been suggested that there is no single traumatic event, but that repeated breakage-fusion-bridge cycles might cause the complex genetic patterns. [24]

Experimental evidence for chromothripsis

In 2015, several research groups presented experimental evidence that chromothripsis is indeed caused by a single catastrophic event. Using a combination of live cell imaging and single-cell genome sequencing of manually isolated cells, it was shown that micronucleus formation can generate a spectrum of genomic rearrangements, some of which recapitulate all known features of chromothripsis. [25] Additionally, research studies inducing telomere crises followed by sequencing the resultant clones demonstrated complex DNA rearrangements that directly recapitulated the one-off chromosomal catastrophe model of chromothripsis. [26] [27]

See also

Related Research Articles

Mutagenesis is a process by which the genetic information of an organism is changed by the production of a mutation. It may occur spontaneously in nature, or as a result of exposure to mutagens. It can also be achieved experimentally using laboratory procedures. A mutagen is a mutation-causing agent, be it chemical or physical, which results in an increased rate of mutations in an organism's genetic code. In nature mutagenesis can lead to cancer and various heritable diseases, and it is also a driving force of evolution. Mutagenesis as a science was developed based on work done by Hermann Muller, Charlotte Auerbach and J. M. Robson in the first half of the 20th century.

p53 Mammalian protein found in Homo sapiens

p53, also known as Tumor protein P53, cellular tumor antigen p53, or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins are crucial in vertebrates, where they prevent cancer formation. As such, p53 has been described as "the guardian of the genome" because of its role in conserving stability by preventing genome mutation. Hence TP53 is classified as a tumor suppressor gene.

<span class="mw-page-title-main">Tumor suppressor gene</span> Gene that inhibits expression of the tumorigenic phenotype

A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or reduction in its function. In combination with other genetic mutations, this could allow the cell to grow abnormally. The loss of function for these genes may be even more significant in the development of human cancers, compared to the activation of oncogenes.

Genotoxicity is the property of chemical agents that damage the genetic information within a cell causing mutations, which may lead to cancer. While genotoxicity is often confused with mutagenicity, all mutagens are genotoxic, but some genotoxic substances are not mutagenic. The alteration can have direct or indirect effects on the DNA: the induction of mutations, mistimed event activation, and direct DNA damage leading to mutations. The permanent, heritable changes can affect either somatic cells of the organism or germ cells to be passed on to future generations. Cells prevent expression of the genotoxic mutation by either DNA repair or apoptosis; however, the damage may not always be fixed leading to mutagenesis.

<span class="mw-page-title-main">DNA repair</span> Cellular mechanism

DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA damage, resulting in tens of thousands of individual molecular lesions per cell per day. Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to transcribe the gene that the affected DNA encodes. Other lesions induce potentially harmful mutations in the cell's genome, which affect the survival of its daughter cells after it undergoes mitosis. As a consequence, the DNA repair process is constantly active as it responds to damage in the DNA structure. When normal repair processes fail, and when cellular apoptosis does not occur, irreparable DNA damage may occur. This can eventually lead to malignant tumors, or cancer as per the two-hit hypothesis.

<span class="mw-page-title-main">Li–Fraumeni syndrome</span> Autosomal dominant cancer syndrome

Li–Fraumeni syndrome is a rare, autosomal dominant, hereditary disorder that predisposes carriers to cancer development. It was named after two American physicians, Frederick Pei Li and Joseph F. Fraumeni Jr., who first recognized the syndrome after reviewing the medical records and death certificates of 648 childhood rhabdomyosarcoma patients. This syndrome is also known as the sarcoma, breast, leukaemia and adrenal gland (SBLA) syndrome.

Double minutes (DMs)are small fragments of extrachromosomal DNA, which have been observed in a large number of human tumors including breast, lung, ovary, colon, and most notably, neuroblastoma. They are a manifestation of gene amplification as a result of chromothripsis, during the development of tumors, which give the cells selective advantages for growth and survival. This selective advantage is as a result of double minutes frequently harboring amplified oncogenes and genes involved in drug resistance. DMs, like actual chromosomes, are composed of chromatin and replicate in the nucleus of the cell during cell division. Unlike typical chromosomes, they are composed of circular fragments of DNA, up to only a few million base pairs in size, and contain no centromere or telomere. Further to this, they often lack key regulatory elements, allowing genes to be constitutively expressed. The term ecDNA may be used to refer to DMs in a more general manner. The term Double Minute originates from the visualization of these features under microscope; double because the dots were found in pairs, and minute because they were minuscule.

<span class="mw-page-title-main">Micronucleus</span> Small nucleus in the cells of some organisms

A micronucleus is a small nucleus that forms whenever a chromosome or a fragment of a chromosome is not incorporated into one of the daughter nuclei during cell division. It usually is a sign of genotoxic events and chromosomal instability. Micronuclei are commonly seen in cancerous cells and may indicate genomic damage events that can increase the risk of developmental or degenerative diseases.

<span class="mw-page-title-main">Clastogen</span> Substance that can cause breaks in chromosomes

A clastogen is a mutagenic agent that disturbs normal DNA related processes or directly causes DNA strand breakages, thus causing the deletion, insertion, or rearrangement of entire chromosome sections. These processes are a form of mutagenesis which if left unrepaired, or improperly repaired, can lead to cancer. Known clastogens include acridine yellow, benzene, ethylene oxide, arsenic, phosphine, mimosine, actinomycin D, camptothecin, methotrexate, methyl acrylate, resorcinol and 5-fluorodeoxyuridine. Additionally, 1,2-dimethylhydrazine is a known colon carcinogen and shows signs of possessing clastogenic activity. There are many clastogens not listed here and research is ongoing to discover new clastogens. Some known clastogens only exhibit clastogenic activity in certain cell types, such as caffeine which exhibits clastogenic activity in plant cells. Researchers are interested in clastogens for researching cancer, as well as for other human health concerns such as the inheritability of clastogen effected paternal germ cells that lead to fetus developmental defects.

<span class="mw-page-title-main">Ataxia telangiectasia and Rad3 related</span> Protein kinase that detects DNA damage and halts cell division

Serine/threonine-protein kinase ATR, also known as ataxia telangiectasia and Rad3-related protein (ATR) or FRAP-related protein 1 (FRP1), is an enzyme that, in humans, is encoded by the ATR gene. It is a large kinase of about 301.66 kDa. ATR belongs to the phosphatidylinositol 3-kinase-related kinase protein family. ATR is activated in response to single strand breaks, and works with ATM to ensure genome integrity.

Caretaker genes encode products that stabilize the genome. Fundamentally, mutations in caretaker genes lead to genomic instability. Tumor cells arise from two distinct classes of genomic instability: mutational instability arising from changes in the nucleotide sequence of DNA and chromosomal instability arising from improper rearrangement of chromosomes.

<span class="mw-page-title-main">Demecolcine</span> Chemical compound

Demecolcine is a drug used in chemotherapy. It is closely related to the natural alkaloid colchicine with the replacement of the acetyl group on the amino moiety with methyl, but it is less toxic. It depolymerises microtubules and limits microtubule formation, thus arresting cells in metaphase and allowing cell harvest and karyotyping to be performed.

Telomere-binding proteins function to bind telomeric DNA in various species. In particular, telomere-binding protein refers to TTAGGG repeat binding factor-1 (TERF1) and TTAGGG repeat binding factor-2 (TERF2). Telomere sequences in humans are composed of TTAGGG sequences which provide protection and replication of chromosome ends to prevent degradation. Telomere-binding proteins can generate a T-loop to protect chromosome ends. TRFs are double-stranded proteins which are known to induce bending, looping, and pairing of DNA which aids in the formation of T-loops. They directly bind to TTAGGG repeat sequence in the DNA. There are also subtelomeric regions present for regulation. However, in humans, there are six subunits forming a complex known as shelterin.

Genome instability refers to a high frequency of mutations within the genome of a cellular lineage. These mutations can include changes in nucleic acid sequences, chromosomal rearrangements or aneuploidy. Genome instability does occur in bacteria. In multicellular organisms genome instability is central to carcinogenesis, and in humans it is also a factor in some neurodegenerative diseases such as amyotrophic lateral sclerosis or the neuromuscular disease myotonic dystrophy.

<span class="mw-page-title-main">Cancerous micronuclei</span>

Cancerous micronuclei is a type of micronucleus that is associated with cancerous cells.

<span class="mw-page-title-main">Breakage-fusion-bridge cycle</span>

Breakage-fusion-bridge (BFB) cycle is a mechanism of chromosomal instability, discovered by Barbara McClintock in the late 1930s.

Antineoplastic resistance, often used interchangeably with chemotherapy resistance, is the resistance of neoplastic (cancerous) cells, or the ability of cancer cells to survive and grow despite anti-cancer therapies. In some cases, cancers can evolve resistance to multiple drugs, called multiple drug resistance.

Chromosomal instability (CIN) is a type of genomic instability in which chromosomes are unstable, such that either whole chromosomes or parts of chromosomes are duplicated or deleted. More specifically, CIN refers to the increase in rate of addition or loss of entire chromosomes or sections of them. The unequal distribution of DNA to daughter cells upon mitosis results in a failure to maintain euploidy leading to aneuploidy. In other words, the daughter cells do not have the same number of chromosomes as the cell they originated from. Chromosomal instability is the most common form of genetic instability and cause of aneuploidy.

Chromoplexy refers to a class of complex DNA rearrangement observed in the genomes of cancer cells. This phenomenon was first identified in prostate cancer by whole genome sequencing of prostate tumors. Chromoplexy causes genetic material from one or more chromosomes to become scrambled as multiple strands of DNA are broken and ligated to each other in a new configuration. In prostate cancer, chromoplexy may cause multiple oncogenic events within a single cell cycle, providing a proliferative advantage to a (pre-)cancerous cell. Several oncogenic mutations in prostate cancer occur through chromoplexy, such as disruption of the tumor suppressor gene PTEN or creation of the TMPRSS2-ERG fusion gene.

Mutational signatures are characteristic combinations of mutation types arising from specific mutagenesis processes such as DNA replication infidelity, exogenous and endogenous genotoxin exposures, defective DNA repair pathways, and DNA enzymatic editing.

References

  1. 1 2 3 4 5 6 7 8 Maher CA, Wilson RK (2012). "Chromothripsis and Human Disease: Piecing Together the Shattering Process". Cell . 148 (1–2): 29–32. doi:10.1016/j.cell.2012.01.006. PMC   3658123 . PMID   22265399.
  2. 1 2 3 4 5 6 Stephens PJ, Greenman CD, Fu B, et al. (2011). "Massive Genomic Rearrangement Acquired in a Single Catastrophic Event during Cancer Development". Cell . 144 (1): 27–40. doi:10.1016/j.cell.2010.11.055. PMC   3065307 . PMID   21215367.
  3. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Forment JV, Kaidi A, Jackson SP (2012). "Chromothripsis and cancer: causes and consequences of chromosome shattering". Nature Reviews Cancer . 12 (10): 663–670. doi:10.1038/nrc3352. PMID   22972457. S2CID   28146930.
  4. ↑ David H. McDermott; Ji-Liang Gao; Qian Liu; Marie Siwicki; Craig Martens; Paejonette Jacobs; Daniel Velez; Erin Yim; Christine R. Bryke; Nancy Hsu; Zunyan Dai; Martha M. Marquesen; Elina Stregevsky; Nana Kwatemaa; Narda Theobald; Debra A. Long Priel; Stefania Pittaluga; Mark A. Raffeld; Katherine R. Calvo; Irina Maric; Ronan Desmond; Kevin L. Holmes; Douglas B. Kuhns; Karl Balabanian; Françoise Bachelerie; Stephen F. Porcella; Harry L. Malech; Philip M. Murphy (2015). "Chromothriptic Cure of WHIM Syndrome". Cell . 160 (4): 686–699. doi:10.1016/j.cell.2015.01.014. PMC   4329071 . PMID   25662009.
  5. 1 2 Kloosterman WP, Hoogstraat M, Paling O, et al. (2011). "Chromothripsis is a common mechanism driving genomic reaarangements in primary and metastatic colorectal cancer". Genome Biology . 12 (10): R103. doi: 10.1186/gb-2011-12-10-r103 . PMC   3333773 . PMID   22014273.
  6. ↑ Parker M, Mohankumar KM, Punchihewa C, Weinlich R, Dalton JD, Li Y, Lee R, Tatevossian RG, Phoenix TN, Thiruvenkatam R, White E (2014). "C11orf95–RELA fusions drive oncogenic NF-κB signalling in ependymoma". Nature. 506 (7489): 451–5. Bibcode:2014Natur.506..451P. doi:10.1038/nature13109. PMC   4050669 . PMID   24553141.
  7. ↑ Anderson ND, de Borja R, Young MD, Fuligni F, Rosic A, Roberts ND, Hajjar S, Layeghifard M, Novokmet A, Kowalski PE, Anaka M (August 2018). "Rearrangement bursts generate canonical gene fusions in bone and soft tissue tumors". Science. 361 (6405): eaam8419. doi:10.1126/science.aam8419. PMC   6176908 . PMID   30166462.
  8. 1 2 3 4 5 Korbel JO, Campbell PJ (2013). "Criteria for inference of chromothripsis in cancer genomes". Cell . 152 (6): 1226–36. doi: 10.1016/j.cell.2013.02.023 . PMID   23498933.
  9. 1 2 Liu P, Erez A, Nagamani SC, et al. (2011). "Chromosome Catastrophes Involve Replication Mechanisms Generating Complex Genomic Rearrangements". Cell . 146 (6): 889–903. doi:10.1016/j.cell.2011.07.042. PMC   3242451 . PMID   21925314.
  10. 1 2 3 Crasta K, Ganem NJ, Dagher R, et al. (2012). "DNA breaks and chromosome pulverization from errors in mitosis". Nature . 482 (7383): 53–58. Bibcode:2012Natur.482...53C. doi:10.1038/nature10802. PMC   3271137 . PMID   22258507.
  11. ↑ Giunta S, Belotserkovskaya R, Jackson SP (2010). "DNA damage signalling in response to double-strand breaks during mitosis". The Journal of Cell Biology . 190 (2): 197–207. doi:10.1083/jcb.200911156. PMC   2930281 . PMID   20660628.
  12. ↑ Rao PN, Johnson RT (1972). "Premature Chromosome Condensation: A mechanism for the elimination of chromosomes in virus-fused cells". Journal of Cell Science . 10 (2): 495–513. doi:10.1242/jcs.10.2.495. PMID   4336114.
  13. 1 2 Tubio JM, Estavill X (2011). "Cancer: When catastrophe strikes a cell". Nature . 470 (7335): 476–477. Bibcode:2011Natur.470..476T. doi:10.1038/470476a. PMID   21350479. S2CID   4429121.
  14. ↑ Rausch T, Jones DT, Zaptka M, et al. (2012). "Genome Sequencing of Pediatric Medulloblastoma Links Catastrophic DNA rearrangements with TP53 Mutations". Cell . 148 (1–2): 59–71. doi:10.1016/j.cell.2011.12.013. PMC   3332216 . PMID   22265402.
  15. ↑ Waszak SM, Northcott PA, et al. (2018). "Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort". The Lancet Oncology . 19 (6): 785–798. doi:10.1016/S1470-2045(18)30242-0. PMC   5984248 . PMID   29753700.
  16. ↑ Janssen A, Van der Burg M, Szuhai K, et al. (2011). "Chromosome Segregation Errors as a cause of DNA Damage and Structural Chromosome Aberrations". Science . 333 (6051): 1895–1898. Bibcode:2011Sci...333.1895J. doi:10.1126/science.1210214. PMID   21960636. S2CID   23488879.
  17. ↑ Thompson SL, Compton DA (2011). "Proliferation of aneuploid human cells is limited by a p53-dependent mechanism". The Journal of Cell Biology. 188 (3): 369–381. doi:10.1083/jcb.200905057. PMC   2819684 . PMID   20123995.
  18. ↑ Li M, Fang X, Baker DJ, et al. (2011). "The ATM-P53 pathway suppresses aneuploidy-induced tumorigenesis". Proceedings of the National Academy of Sciences . 107 (32): 14188–14193. doi: 10.1073/pnas.1005960107 . PMC   2922543 . PMID   20663956.
  19. ↑ Rosin MP, German J (1985). "Evidence for chromosome instability in vivo in bloom syndrome: Increased numbers of micronuclei in exfoliated cells". Human Genetics . 71 (3): 187–191. doi:10.1007/BF00284570. PMID   4065890. S2CID   22597999.
  20. ↑ Tischkowitz MD, Hodgson SV (2003). "Fanconi anaemia". Journal of Medical Genetics . 40 (1): 1–10. doi:10.1136/jmg.40.1.1. PMC   1735271 . PMID   12525534.
  21. ↑ Heddle JA, Lue CB, Sauders EF, Benz RD (1978). "Sensitivity to five mutagens in Fanconi's Anemia as measured by the micronucleus method". Cancer Research . 38 (9): 2983–29881. PMID   679206.
  22. ↑ Molenaar JJ, Koster J, Zwijenburg DA, et al. (2012). "Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes". Nature . 483 (7391): 589–593. Bibcode:2012Natur.483..589M. doi: 10.1038/nature10910 . hdl: 1765/57581 . PMID   22367537.
  23. ↑ Righolt C, Mai S (November 2012). "Shattered and stitched chromosomes—chromothripsis and chromoanasynthesis—manifestations of a new chromosome crisis?". Genes, Chromosomes and Cancer . 51 (11): 975–981. doi:10.1002/gcc.21981. PMID   22811041. S2CID   26090401.
  24. ↑ Sorzano CO, Pascual-Montano A, Sánchez de Diego A, Martínez-A C, van Wely KH (July 2013). "Chromothripsis: Breakage-fusion-bridge over and over again". Cell Cycle . 12 (13): 2016–2023. doi:10.4161/cc.25266. PMC   3737304 . PMID   23759584. Archived from the original on 19 August 2013.
  25. ↑ Zhang CZ, Spektor A, Cornils H, Francis JM, Jackson EK, Liu S, Meyerson M, Pellman D (2015). "Chromothripsis from DNA damage in micronuclei". Nature . 522 (7555): 179–84. Bibcode:2015Natur.522..179Z. doi:10.1038/nature14493. PMC   4742237 . PMID   26017310.
  26. ↑ Mardin BR, Drainas AP, Waszak SM, Weischenfeldt J, Isokane M, Stütz AM, Raeder B, Efthymiopoulos T, Buccitelli C, Segura-Wang M, Northcott P, Pfister SM, Lichter P, Ellenberg J, Korbel JO (2015). "A cell-based model system links chromothripsis with hyperploidy". Mol Syst Biol . 11 (9): 828. doi: 10.15252/msb.20156505 . PMC   4592670 . PMID   26415501.
  27. ↑ Maciejowski J, Li Y, Bosco N, Campbell PJ, de Lange T (2015). "Chromothripsis and kataegis induced by telomere crisis". Cell . 163 (7): 1641–54. doi: 10.1016/j.cell.2015.11.054 . PMC   4687025 . PMID   26687355.

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.