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genomic instability

Sunday 13 July 2003

genetic instability; genome instability

Definition: Genomic instability is considered as a significant factor in the pathogenesis of cancer.

There are several patterns of genomic instability, which are reflections of different functional defects in the cancer cells.

Genomic instability can be divided into 2 categories: Retour ligne manuel
- chromosomal instability (CIN) Retour ligne manuel
- microsatellite instability (MSI).

Genetic alterations can affect the structure of chromosomes, their number, or their nucleotide sequence.

An example of the last pattern is microsatellite instability (MSI) in hereditary nonpolyposis colorectal cancer (HNPCC), in which defects in the mismatch repair machinery (MMR) result in changes of nucleotide sequence.

However, numerical or structural chromosomal aberrations are typically lacking in this cancer. This is in strong contrast to other solid cancers, which virtually all show chromosomal aberrations.

Aberrations that only affect chromosome number (numerical chromosomal anomalies) are thought to be because of defects of the mitotic chromosome segregation apparatus, whereas intra- and interchromosomal aberrations (structural chromosomal anomalies) seem to be related to the generation or the repair of DNA breaks.

Data from mutator mutants in yeast have shown that genes involved in S-phase checkpoint functions, recombination, and telomere addition at double-strand breaks are essential for control of chromosomal integrity.

Defects that permit numerical chromosomal aberrations could result in a less malignant phenotype, as compared those that promote structural aberrations, because whole chromosomes are likely to harbor some genes that provide a growth advantage along with others that provide a disadvantage for growth.

In contrast, cancers bearing only the fragment carrying the advantageous genes are freed from the normally present growth-inhibiting genes on the same chromosome and would be likely to grow faster and acquire a malignant phenotype.

The degree of genomic instability would increase the plasticity of the genome and permit a rapid evolution of the hallmarks of cancer.

Tumors with a more rigid genome, such as those whose defect only permits a change in chromosome numbers, would undergo a slower progression or may not be able to acquire all features of malignancy before they undergo replicative senescence and halt progression.

Types of genomic instability

Genomic instability can be divided into 2 categories:
- chromosomal instability (CIN)

  • CIN has been linked to aneuploidy and chromosomal aberrations, and high-level loss of heterozygosity (LOH-H) has been suggested to be an indicator of CIN.
  • The most common form of genomic instability observed in colorectal cancer is chromosomal instability (CIN), whose molecular bases remain to be determined.

- microsatellite instability (MSI).

  • High-level MSI (MSI-H), which results from nonfunctional mismatch repair, has previously been suggested to be mutually exclusive with CIN.

RECQLs and genomic instability

The three genetic disorders associated with RECQLs mutations (Bloom syndrome, Werner syndrome, Rothmund-Thomson syndrome) are associated with a inherent genomic instability.

In the case of Bloom syndrome cells, this instability is manifested as a 10-fold elevated frequency of homologous recombination events, including reciprocal exchanges between sister-chromatids and homologous chromosomes. Werner syndrome cells do not show elevated SCE frequencies, but they do display increased illegitimate recombination and a high frequency of large chromosomal deletions.

The genomic instability of RTS cells has not been analysed in detail, but there are reports of an increased frequency of chromosome aberrations.

p53 and genomic stability

Mutations in TP53, encoding p53, which has been dubbed the ‘guardian of the genome’, are seen in >50% of all sporadic cancers in humans. p53 functions in a highly dynamic and controlled manner; induction of p53 leads to cell cycle arrest in G1 and/or G2, allowing time for DNA repair to take place, but may additionally lead to apoptotic cell death. Moreover, the loss of p53 results in genomic instability.

Genomic instability diseases

- DExH-containing DNA helicases

  • XPD
  • XPB
  • WRN
  • BLM

See also

- genetic instability syndromes with progeroid features

References

- Oberdoerffer P, Sinclair DA. The role of nuclear architecture in genomic instability and ageing. Nat Rev Mol Cell Biol. 2007 Sep;8(9):692-702. PMID: #17700626#

- Lai LA, Paulson TG, Li X, Sanchez CA, Maley C, Odze RD, Reid BJ, Rabinovitch PS. Increasing genomic instability during premalignant neoplastic progression revealed through high resolution array-CGH. Genes Chromosomes Cancer. 2007 Jun;46(6):532-42. PMID: #17330261#

- Charames GS, Bapat B. Genomic instability and cancer. Curr Mol Med. 2003 Nov;3(7):589-96. PMID: #14601634#

- Chin K, De Solorzano CO, Knowles D, Jones A, Chou W, Rodriguez EG, Kuo WL, Ljung BM, Chew K, Myambo K, Miranda M, Krig S, Garbe J, Stampfer M, Yaswen P, Gray JW, Lockett SJ. In situ analyses of genome instability in breast cancer. Nat Genet. 2004 Aug 8 PMID: #15300252#

- Charames GS, Bapat B. Genomic instability and cancer. Curr Mol Med. 2003 Nov;3(7):589-96. PMID: #14601634#

- De la Torre C, Pincheira J, Lopez-Saez JF. Human syndromes with genomic instability and multiprotein machines that repair DNA double-strand breaks. Histol Histopathol. 2003 Jan;18(1):225-43. PMID: #12507302#

- Sieber OM, Heinimann K, Tomlinson IP. Genomic instability—the engine of tumorigenesis? Nat Rev Cancer. 2003 Sep;3(9):701-8. PMID: #12951589#

- Rajagopalan H, Nowak MA, Vogelstein B, Lengauer C. The significance of unstable chromosomes in colorectal cancer. Nat Rev Cancer. 2003 Sep;3(9):695-701. PMID: #12951588#

- Feldser DM, Hackett JA, Greider CW. Telomere dysfunction and the initiation of genome instability. Nat Rev Cancer. 2003 Aug;3(8):623-7. PMID: #12894250#

- Matzke MA, Mette MF, Kanno T, Matzke AJ. Does the intrinsic instability of aneuploid genomes have a causal role in cancer? Trends Genet. 2003 May;19(5):253-6. PMID: #12711216#

- Bohr VA: Human premature aging syndromes and genomic instability. Mech Ageing Dev 123:987, 2002.