Cancer cells preferentially lose small chromosomes

Duijf, Pascal H. G., Schultz, Nikolaus and Benezra, Robert (2013) Cancer cells preferentially lose small chromosomes. International Journal of Cancer, 132 10: 2316-2326. doi:10.1002/ijc.27924


Author Duijf, Pascal H. G.
Schultz, Nikolaus
Benezra, Robert
Title Cancer cells preferentially lose small chromosomes
Journal name International Journal of Cancer   Check publisher's open access policy
ISSN 0020-7136
1097-0215
Publication date 2013-05-01
Year available 2012
Sub-type Article (original research)
DOI 10.1002/ijc.27924
Volume 132
Issue 10
Start page 2316
End page 2326
Total pages 11
Place of publication Hoboken, NJ, United States
Publisher John Wiley & Sons
Language eng
Abstract Genetic and genomic aberrations are the primary cause of cancer. Chromosome missegregation leads to aneuploidy and provides cancer cells with a mechanism to lose tumor suppressor loci and gain extra copies of oncogenes. Using cytogenetic and array-based comparative genomic hybridization data, we analyzed numerical chromosome aneuploidy in 43,205 human tumors and found that 68% of solid tumors are aneuploid. In solid tumors, almost all chromosomes are more frequently lost than gained with chromosomes 7, 12 and 20 being the only exceptions with more frequent gains. Strikingly, small chromosomes are lost more readily than large ones, but no such inverse size correlation is observed with chromosome gains. Because of increasing levels of proteotoxic stress, chromosome gains have been shown to slow cell proliferation in a manner proportional to the number of extra gene copies gained. However, we find that the extra chromosome in trisomic tumors does not preferentially have a low gene copy number, suggesting that a proteotoxicity-mediated proliferation barrier is not sustained during tumor progression. Paradoxically, despite a bias toward chromosome loss, gains of chromosomes are a poor prognostic marker in ovarian adenocarcinomas. In addition, we find that solid and non-solid cancers have markedly distinct whole-chromosome aneuploidy signatures, which may underlie their fundamentally different etiologies. Finally, preferential chromosome loss is observed in both early and late stages of astrocytoma. Our results open up new avenues of enquiry into the role and nature of whole-chromosome aneuploidy in human tumors and will redirect modeling and genetic targeting efforts in patients. What's new? Aneuploidy - an abnormal number of chromosomes resulting from missegregation during cell division - is a hallmark of most cancers and is strongly associated with poor prognosis. However, a systematic study of the nature of whole-chromosome aneuploidy is lacking. Looking at a large tumor dataset, here the authors find that nearly all chromosomes, particularly small ones, are preferentially lost rather than gained. They also find that, despite the strong bias towards chromosome loss, chromosome gains constitute a poorer prognostic marker in ovarian carcinoma patients. These results could facilitate more accurate genetic cancer modeling and the development of more effective treatment strategies.
Keyword Genomic instability
Chromosome instability
Aneuploidy
Cancer
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Article first published online: 26 November 2012.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
UQ Diamantina Institute Publications
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 24 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 32 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Sun, 07 Apr 2013, 10:05:23 EST by System User on behalf of UQ Diamantina Institute