Carcinogenesis Advance Access originally published online on January 27, 2005
Carcinogenesis 2005 26(5):923-930; doi:10.1093/carcin/bgi032
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Carcinogenesis vol.26 no.5 © Oxford University Press 2005; all rights reserved.
Evidence that both genetic instability and selection contribute to the accumulation of chromosome alterations in cancer
Cancer Genomics Program, 1 Departments of Oncology and 2 Pathology, Hutchison/MRC Research Centre, University of Cambridge, Cambridge CB2 2XZ, UK and 3 Cancer Research UK Human Cancer Genetics Research Group, Strangeways Research Laboratories, Worts Causeway, Cambridge, UK
Present addresses: 4 Comparative Genomics Centre, James Cook University, Townsville, QLD 4811, Australia, 5 Cambridge Cytogenetics Laboratory, Addenbrooke's NHS Trust, Kefford House, Cambridge CB2 2FF, UK and 6 IPATIMUP, Rua Dr Roberto Frias, s/n 4200-465 Porto, Portugal
* To whom correspondence should be addressed Email: kylie.gorringe{at}jcu.edu.au; cc234{at}cam.ac.uk
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 an inactivation of mismatch repair. Average ploidy by centromeric fluorescence in situ hybridization (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 chromosomal 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 six-colour chromosome painting. The variation in chromosome number was different among 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 chromosomal losses. The six-colour FISH data showed that SUM159 had more stable structural chromosomal alterations (e.g. chromosomal translocations) compared with MT-3 and MT-1, but had 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 CIN may contribute to aneuploidy, but that selection plays an important role, particularly for the accumulation of structural chromosomal changes.
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