cancer chromosomal instability

Definition: Cancer chromosomal instability (CIN) results in an increased rate of change of chromosome number and structure and generates intratumour heterogeneity. CIN is observed in most solid tumours and is associated with both poor prognosis and drug resistance.

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

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.

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

For example, the most common form of genomic instability observed in colorectal cancer is chromosomal instability (CIN), whose molecular bases remain to be determined.

Cancer cells frequently exhibit gross chromosomal alterations such as translocations, deletions, or gene amplifications an important source of chromosomal instability in malignant cells.

Chromosomal instabilities are related to abnormalities of DNA metabolism, DNA repair, cell-cycle governance, or control of apoptosis.

Anaphase bridges-chromosomes

One of the better-documented mechanism of chromosomal instability is the formation of anaphase bridges-chromosomes pulled in opposite directions by the spindle apparatus. Anaphase bridges are associated with DNA double strand breaks (DSBs).

While the majority of DSBs are repaired correctly, to restore the original chromosome structure, incorrect fusion events also occur leading to bridging.

Chromosomal instability syndromes

 ataxia telangiectasia
 Fanconi anaemia
 Bloom syndrome
 Nijmegen breakage syndrome
 ataxia telangiectasia-like disorder

Chromosomal segregation

Inactivation in human cells of several components of the Pes1-Bop1 complex (BOP1, GRWD1, PES1, ORC6L, and RPL3), involved in ribosome biogenesis, altered chromosome segregation. (16804918)

Cancer

Chromosome instability, which is equated to mitotic defects and consequential chromosome segregation errors, provides a formidable basis for the acquisition of further malignant phenotypes during tumour progression.

Centrosomes have a crucial role in the formation of bipolar mitotic spindles, which are essential for accurate chromosome segregation.

Mutations of certain oncogenic and tumour-suppressor proteins directly induce chromosome instability by disrupting the normal function and numeral integrity of centrosomes.

Open references

 Cancer chromosomal instability: therapeutic and diagnostic challenges. McGranahan N, Burrell RA, Endesfelder D, Novelli MR, Swanton C. EMBO Rep. 2012 Jun 1;13(6):528-38. doi : 10.1038/embor.2012.61 PMID: 22595889 [Free]

 Relationship of extreme chromosomal instability with long-term survival in a retrospective analysis of primary breast cancer. Roylance R, Endesfelder D, Gorman P, Burrell RA, Sander J, Tomlinson I, Hanby AM, Speirs V, Richardson AL, Birkbak NJ, Eklund AC, Downward J, Kschischo M, Szallasi Z, Swanton C. Cancer Epidemiol Biomarkers Prev. 2011 Oct;20(10):2183-94. doi : 10.1158/1055-9965.EPI-11-0343 PMID: 21784954 [Free]

 Chromosomal instability confers intrinsic multidrug resistance. Lee AJ, Endesfelder D, Rowan AJ, Walther A, Birkbak NJ, Futreal PA, Downward J, Szallasi Z, Tomlinson IP, Howell M, Kschischo M, Swanton C. Cancer Res. 2011 Mar 1;71(5):1858-70. doi : 10.1158/0008-5472.CAN-10-3604 PMID: 21363922 (Free)

Reviews

 Duesberg P. Chromosomal chaos and cancer. Sci Am. 2007 May;296(5):52-9. PMID: 17500414

 Duesberg P, Li R, Fabarius A, Hehlmann R. Aneuploidy and cancer: from correlation to causation. Contrib Microbiol. 2006;13:16-44. PMID: 16627957

 Warren WD, Gorringe KL. A molecular model for sporadic human aneuploidy. Trends Genet. 2006 Apr;22(4):218-24. PMID: 16497408

 Duesberg P, Li R, Fabarius A, Hehlmann R. The chromosomal basis of cancer. Cell Oncol. 2005;27(5-6):293-318. PMID: 16373963

 Cimini D, Degrassi F. Aneuploidy: a matter of bad connections. Trends Cell Biol. 2005 Aug;15(8):442-51. PMID: 16023855

 Kops GJ, Weaver BA, Cleveland DW. On the road to cancer: aneuploidy and the mitotic checkpoint. Nat Rev Cancer. 2005 Oct;5(10):773-85. PMID: 16195750

 Duesberg P. Does aneuploidy or mutation start cancer? Science. 2005 Jan 7;307(5706):41. PMID : 15637254

 Rajagopalan H, Lengauer C.Aneuploidy and cancer.Nature. 2004 Nov 18;432(7015):338-41. PMID: 15549096

 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

 Fukasawa K. Oncogenes and tumour suppressors take on centrosomes. Nat Rev Cancer. 2007 Dec;7(12):911-24. PMID: 18004399

 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

 Acilan C, Potter DM, Saunders WS. DNA repair pathways involved in anaphase bridge formation. Genes Chromosomes Cancer. 2007 Jun;46(6):522-31. PMID: 17366618

 Carter SL, Eklund AC, Kohane IS, Harris LN, Szallasi Z. A signature of chromosomal instability inferred from gene expression profiles predicts clinical outcome in multiple human cancers. Nat Genet. 2006 Sep;38(9):1043-8. PMID: 16921376

 Michor F, Iwasa Y, Vogelstein B, Lengauer C, Nowak MA. Can chromosomal instability initiate tumorigenesis? Semin Cancer Biol. 2005 Feb;15(1):43-9. PMID: 15613287

 Lengauer C. Aneuploidy and genetic instability in cancer. Semin Cancer Biol. 2005 Feb;15(1):1. PMID: 15613282

 Mathieu N, Pirzio L, Freulet-Marriere MA, Desmaze C, Sabatier L. Telomeres and chromosomal instability. Cell Mol Life Sci. 2004 Mar;61(6):641-56. PMID: 15052408

 Kapoor TM. Chromosome segregation: correcting improper attachment. Curr Biol. 2004 Dec 14;14(23):R1011-3. PMID: 15589138

 Rajagopalan H, Lengauer C. Aneuploidy and cancer. Nature. 2004 Nov 18;432(7015):338-41. PMID: 15549096

 Draviam VM, Xie S, Sorger PK. Chromosome segregation and genomic stability. Curr Opin Genet Dev. 2004 Apr;14(2):120-5. PMID: 15196457

 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

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

 Richards RI. Fragile and unstable chromosomes in cancer: causes and consequences. Trends Genet. 2001 Jun;17(6):339-45. PMID: 11377796

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

References

 Replication stress links structural and numerical cancer chromosomal instability. Rebecca A. Burrell et al. , Ian P. Tomlinson & Charles Swanton. Nature 494, 492–496 (28 February 2013). doi : 10 1038/nature11935

 Maser RS, Choudhury B, Campbell PJ, Feng B, Wong KK, Protopopov A, O’Neil J, Gutierrez A, Ivanova E, Perna I, Lin E, Mani V, Jiang S, McNamara K, Zaghlul S, Edkins S, Stevens C, Brennan C, Martin ES, Wiedemeyer R, Kabbarah O, Nogueira C, Histen G, Aster J, Mansour M, Duke V, Foroni L, Fielding AK, Goldstone AH, Rowe JM, Wang YA, Look AT, Stratton MR, Chin L, Futreal PA, DePinho RA. Chromosomally unstable mouse tumours have genomic alterations similar to diverse human cancers. Nature. 2007 Jun 21;447(7147):966-71. PMID: 17515920

 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

 Gao C, Furge K, Koeman J, Dykema K, Su Y, Cutler ML, Werts A, Haak P, Vande Woude GF. Chromosome instability, chromosome transcriptome, and clonal evolution of tumor cell populations. Proc Natl Acad Sci U S A. 2007 May 22;104(21):8995-9000. PMID: 17517657