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. 2001 Feb 27;98(5):2538-43.
doi: 10.1073/pnas.041603298. Epub 2001 Feb 20.

Spectral karyotyping suggests additional subsets of colorectal cancers characterized by pattern of chromosome rearrangement

W M Abdel-Rahman  1 , K Katsura, W Rens, P A Gorman, D Sheer, D Bicknell, W F Bodmer, M J Arends, A H Wyllie, P A Edwards
Affiliations

Spectral karyotyping suggests additional subsets of colorectal cancers characterized by pattern of chromosome rearrangement

W M Abdel-Rahman et al. Proc Natl Acad Sci U S A. .

Abstract

The abundant chromosome abnormalities in most carcinomas are probably a reflection of genomic instability present in the tumor, so the pattern and variability of chromosome abnormalities will reflect the mechanism of instability combined with the effects of selection. Chromosome rearrangement was investigated in 17 colorectal carcinoma-derived cell lines. Comparative genomic hybridization showed that the chromosome changes were representative of those found in primary tumors. Spectral karyotyping (SKY) showed that translocations were very varied and mostly unbalanced, with no translocation occurring in more than three lines. At least three karyotype patterns could be distinguished. Some lines had few chromosome abnormalities: they all showed microsatellite instability, the replication error (RER)+ phenotype. Most lines had many chromosome abnormalities: at least seven showed a surprisingly consistent pattern, characterized by multiple unbalanced translocations and intermetaphase variation, with chromosome numbers around triploid, 6-16 structural aberrations, and similarities in gains and losses. Almost all of these were RER-, but one, LS411, was RER+. The line HCA7 showed a novel pattern, suggesting a third kind of genomic instability: multiple reciprocal translocations, with little numerical change or variability. This line was also RER+. The coexistence in one tumor of two kinds of genomic instability is to be expected if the underlying defects are selected for in tumor evolution.

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Figures

Figure 1
Figure 1
Copy numbers of chromosome segments estimated by CGH, using ploidy information from the karyotype. Each colored bar represents the copy number of a chromosome in a particular cell line, different colors representing different copy numbers according to the key shown. For example, for chromosome 1, the bar nearest the ideogram represents DLD1 and shows that in DLD1 there are two copies (yellow) of most of chromosome 1, but three copies of distal 1p (green). Cell lines from left to right are: first group (RER+) DLD1 (nearest to chromosome ideogram), GP2d, HCT116, LoVo, LS174T, VACO5, HCA7, LS411; second group (RER−) C70, HT29, LIM1863, SW1417, SW403, SW480, SW620, SW837, VACO4A (furthest from chromosome ideogram).
Figure 2
Figure 2
Comparison of CGH data between cell lines and surgical material (Left), xenografts (Right). CGH data are expressed as percentage of tumors, xenografts, or lines showing the change, and each point represents the gain or loss of an individual chromosome arm. (Left) Pooled data from primary tumors, unselected for RER status (–32), compared with data from this study, combining the RER+ and RER− cell lines in the ratio 2:8 to mimic unselected surgical material. Linear regression analysis gave slope 1.4, r = 0.7. (Right) Data from RER−, first-pass xenografts, obtained in one of our laboratories (6, 33), compared with the RER− cell lines. Slope = 1.0, r = 0.7.
Figure 3
Figure 3
Examples of karyotypes of the cell lines given by SKY analysis and their relation to CGH data. Lines not illustrated here are in Fig. 4 or have no abnormal chromosomes: Vaco5 and LS174T. (A–F) Images of complete metaphases. (A) C70. (B) SW837. (C) SW403. (D) VACO4A. (E) HCA7. (F) LS411. These are typical metaphases that may not show all of the chromosomes described in Results. The HCA7 metaphase is of the most complex clone. The metaphases for C70 and SW837 show rearranged chromosomes unique to that metaphase, respectively a reciprocal t(1;2) and a der(5)t(2;5). The chromosomes are shown in classification colors, i.e., each pixel is assigned a color representing the chromosome that the software has identified from the fluorescence at that position. Satellites at chromosomes 13, 14, 15, 21, and 22 as well as pericentromeric heterochromatin, e.g., of chromosome 1, hybridize nonspecifically so they are often miscolored. Some of the classifications are incorrect in detail, because of overlap of adjacent fluorescence colors, and their correct composition, determined by conventional fluorescence in situ hybridization with single dyes, is shown in Results. (G–J) Partial metaphases from near-diploid lines showing only the chromosomes with structural abnormalities and their normal counterparts for comparison. (G) HCT116. (H) GP2d. (I) DLD1. (J) LoVo. Underneath G and H the copy numbers of the corresponding chromosomes from CGH are shown as in Fig. 1.
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