Chromothripsis

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Chromothripsis is the name for a mutation process in which a cell , triggered by a single event, leads to a large number of rearrangements of chromosome segments. It was discovered in 2011 in cell lines from patients with various cancers .

description

The mutation process of chromothripsis was first described in 2011 in a publication in the journal Cell by scientists from the Wellcome Trust Sanger Institute in Cambridge , who discovered it in a patient with chronic lymphocytic leukemia and coined the corresponding term. The affected cells from this patient had 42 rearrangements in localized clusters on the long arm of chromosome 4 . In the cells of other examined patients with other cancers , other chromosome areas, complete chromosomes or several chromosomes were also affected at the same time. The type and distribution of the changes on the chromosomes suggest that these did not arise as part of a progressive process, but rather are all the result of the same event that the authors call a “catastrophic” or “cellular crisis”, which is too multiple Chromosome breaks are coming. Based on their results, the authors estimated that such an event played a role in two to three percent of all cancers, with an accumulation of up to a quarter of all bone tumor cases . An analysis of over 8,000 cancer genomes later published by researchers at Harvard University confirmed this estimate.

Contrary to what would be expected with such massive destruction of the chromosome structure, not all of the affected cells probably die from apoptosis . Rather, the mechanisms of DNA repair in some cells seem to succeed in partially reassembling the chromosomes, whereby the cell may survive. This leads to a large number of deletions , duplications , inversions and, as a result of translocations, merging of previously non-adjacent chromosome segments. The consequence of these changes, which are passed on through cell division , is a loss of the function of tumor suppressor genes . In the opinion of the first description, this phenomenon is likely to occur when the chromosomes are in condensed form during mitosis . As possible triggers, they suspect, among other things, ionizing radiation or a connection with the stretching and compression of the chromosomes during the shortening of the telomeres at the chromosome ends during cell division.

In 2012, Heidelberg scientists described in the journal Cell that in medulloblastoma , a malignant tumor of the cerebellum in early childhood , chromothripsis occurs in connection with hereditary mutations of the TP53 gene ( Li-Fraumeni syndrome ). The associated loss of the p53 protein, which is also referred to as the “guardian of the genome”, is a possible explanation for why, despite massive destruction of the chromosome structure, the cells do not die due to apoptosis or the cell cycle is terminated as a result of chromothripsis comes. For the tumor suppressor gene RB1 , the loss of which leads to the development of retinoblastomas , chromothripsis was proven to be a possible inactivation mechanism in 2014. In addition to cancer, a form of chromosome destruction comparable to chromothripsis has also been described for congenital diseases. In an article published in the specialist journal Cell in March 2013 , several criteria are described that can be used to detect chromothripsis in genomic data.

In 2015, several research groups presented experimental evidence that the chromothripsis mutation process is actually caused by a single catastrophic event. With the help of a combination of microscopy and single-cell genome sequencing of manually isolated cells, it was shown that the formation of small nuclei can produce a large number of genomic rearrangements, some of which recapitulate the well-known characteristics of chromothripsis. In addition, two research studies showed that cell clones generated by telomere shortening can directly recapitulate the chromosomal catastrophe model of chromothripsis.

literature

  • Mathew JK Jones, Prasad V. Jallepalli: Chromothripsis : Chromosomes in Crisis. In: Developmental Cell. 23 (5) / 2012. Cell Press, pp. 908-917, ISSN  1534-5807
  • Josep V. Forment, Abderrahmane Kaidi & Stephen P. Jackson: Chromothripsis and Cancer: Causes and Consequences of Chromosome Shattering. In: Nature Reviews Cancer. 12 (10) / 2012. Nature Publishing Group, pp. 663-670, ISSN  1474-175X
  • Karin Hollricher: Keyword of the month: Chromothripsis. In: Laborjournal. 3/2011. LJ-Verlag Merzhausen, p. 46, ISSN  1612-8354

Web links

Nadja Podbregar: Chromosome "explosion" as a cancer trigger. In: scinexx.de. June 9, 2020, accessed June 10, 2020 .

Individual evidence

  1. ^ Philip J. Stephens et al .: Massive Genomic Rearrangement Acquired in a Single Catastrophic Event during Cancer Development. In: Cell. 144 (1) / 2011. Elsevier, pp. 27-40, ISSN  0092-8674
  2. ↑ Tae-Min Kim et al .: Functional Genomic Analysis of Chromosomal Aberrations in a Compendium of 8000 Cancer Genomes. In: Genome Research. 23 (2) / 2013. Cold Spring Harbor Laboratory Press, pp. 217-227, ISSN  1088-9051
  3. ↑ Tobias Rausch et al .: Genome Sequencing of Pediatric Medulloblastoma Links Catastrophic DNA Rearrangements with TP53 Mutations. In: Cell. 148 (1) / 2012. Elsevier, pp. 59-71, ISSN  0092-8674
  4. ^ Justina McEvoy et al .: RB1 gene inactivation by chromothripsis in human retinoblastoma. In: Oncotarget. 5 (2) / 2014. Impact Journals, pp. 438-450, ISSN  1949-2553
  5. ^ Wigard P. Kloosterman & Edwin Cuppen: Chromothripsis in Congenital Disorders and Cancer: Similarities and Differences. In: Current Opinion in Cell Biology. 25 (3) / 2013. Elsevier, pp. 341-348, ISSN  0955-0674
  6. ^ Jan Korbel & Peter Campbell: Criteria for Inference of Chromothripsis in Cancer Genomes. In: Cell. 152 (6) / 2013. Elsevier, pp. 1226-1236, ISSN  0092-8674
  7. ^ Zhang et al .: Chromothripsis from DNA damage in micronuclei. In: Nature. 522 (7555) / 2015. Nature Publishing Group, pp. 179-84
  8. ↑ Balca Mardin et al .: A cell-based model system left chromothripsis with hyperploidy. In: Mol Syst Biol. 11 (9) / 2015. EMBO Press, p. 828
  9. ^ Maciejowski et al .: Chromothripsis and kataegis induced by telomere crisis. In: Cell. 163 (7) / 2015. Cell Press, pp. 1641-54