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Carcinogenesis Advance Access published online on January 27, 2005
Carcinogenesis, doi:10.1093/carcin/bgi032
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Oxford University Press
Received November 2, 2004
Revised January 5, 2005
Accepted January 18, 2005

CANCER BIOLOGY

Evidence that both genetic instability and selection contribute to the accumulation of chromosome alterations in cancer

Kylie L. Gorringe 1*, Suet-Feung Chin 1, Paul Pharoah 2, Joanne M. Staines 3, Carla Oliveira 1, Paul A. W. Edwards 3, and Carlos Caldas 1

1 Cancer Genomics Program, Department of Oncology, Hutchison/MRC Research Centre, University of Cambridge, Cambridge CB2 2XZ, United Kingdom
2 Cancer Research UK Human Cancer Genetics Research Group, Strangeways Research Laboratories, Worts Causeway, Cambridge, United Kingdom
3 Cancer Genomics Program, Department of Pathology, Hutchison/MRC Research Centre, University of Cambridge, Cambridge CB2 2XZ, United Kingdom

* To whom correspondence should be addressed.
Kylie L. Gorringe, E-mail: kylie.gorringe{at}jcu.edu.au


  Abstract

Cancer cells contain many genetic alterations, and genetic instability may be important in tumourigenesis. We evaluated 58 breast and ovarian cancer cell lines for microsatellite instability (MSI) and chromosomal instability (CIN). MSI was identified in 3/33 breast and 5/25 ovarian cell lines, and 7/8 MSI lines showed inactivation of mismatch repair. Average ploidy by centromeric FISH of MSI (n: 8, average ploidy = 2.65) and microsatellite stable (MSS; n: 7, average ploidy = 3.01) cell lines was not different, due to the presence of three aneuploid MSI lines, and two near-diploid MSS lines. However, the variability of the centromeric FISH data was different between MSI and MSS (p=0.049). The complexity of structural chromosome rearrangements was not different between MSI and MSS. Thus, MSI and numerical CIN are not mutually exclusive, and structural CIN occurs independently of MSI or numerical CIN. Dynamic genetic instability was evaluated in three cell lines - MSI diploid (MT-3), MSS diploid (SUM159), and MSS aneuploid (MT-1). Ten clones of each of these cell lines were analysed by centromeric FISH and 6-colour chromosome painting. The variation in chromosome number was different between all three cell lines (p < 0.001). MT-3 appeared numerically constant (94% of centromeric FISH signals matched the mode). SUM159 was 88% constant, however 7% of cells had duplicated chromosomes. MT-1 was 82% constant; most changes were chromosome losses. The 6-colour FISH data showed that SUM159 had increased stable structural chromosomal alterations (e.g. chromosome translocations) compared with MT-3 and MT-1, but no increase in unstable changes (e.g. chromatid breaks) when compared with MT-3. MT-1 had fewer unstable changes than both MT-3 and SUM159. These data suggest that numerical chromosome instability may contribute to aneuploidy, but that selection plays an important role, particularly for accumulation of structural chromosome changes.

Keywords: mismatch repair; cancer; chromosome instability.
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