It has long been considered that genetic instability is an integral component of human neoplasia1–3. In a small fraction of tumours, mismatch repair deficiency leads to a microsatellite instability at the nucleotide sequence level4,5. In other tumours, an abnormal chromosome number (aneuploidy) has suggested an instability, but the nature and magnitude of the postulated instability is a matter of conjecture. We show here that colorectal tumours without microsatellite instability exhibit a striking defect in chromosome segregation, resulting in gains or losses in excess of 10 –2 per chromosome per generation. This form of chromosomal instability reflected a continuing cellular defect that persisted throughout the lifetime of the tumour cell and was not simply related to chromosome number. While microsatellite instability is a recessive trait6,7, chromosomal instability appeared to be dominant. These data indicate that persistent genetic instability may be critical for the development of all colorectal cancers, and that such instability can arise through two distinct pathways.
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Loeb, L. Mutator phenotype may be required for multistage carcinogenesis. Cancer Res. 51, 3075–3079 (1991).
Hartwell, L. Defects in a cell cycle checkpoint may be responsible for the genomic instability of cancer cells. Cell 71, 543–546 (1992).
Heim, S. & Mitelman, F. Cancer Cytogenetics (Liss, New York, 1987).
Marra, G. & Boland, C. R. Hereditary nonpolyposis colorectal cancer: the syndrome, the genes, and historical perspectives. J. Natl Cancer Inst. 87, 1114–1125 (1995).
Bhattacharyya, N. P., Skandalis, A., Ganesh, A., Groden, J. & Meuth, M. Mutator phenotypes in human colorectal carcinoma cell lines. Proc. Natl Acad. Sci. USA 87, 7555–7559 (1990).
Koi, M. et al. Human chromosome 3 corrects mismatch repair deficiency and microsatellite instability and reduces N-methyl-N’-N-nitrosoguanidine tolerance in colon tumor cells with homozygous hMLHl mutation. Cancer Res. 54, 4302–4312 (1994).
Casares, S., lonov, Y., Ge, H.-Y., Standbridge, E. & Perucho, M. The microsatellite mutator phenotype of colon cancer cells is often recessive. Oncogene 11, 2303–2310 (1995).
Lichter, P., Boyle, A. L., Cremer, T. & Ward, D. Analysis of genes and chromosomes by nonisotopic in situ hybridization. Gen. Anal. Tech. Appl. 8, 24–35 (1991).
Hartwell, L., Weinert, T., Kadyk, L. & Garvik, B. Cell cycle checkpoints, genomic integrity, and cancer. Cold Spring Harb. Symp. Quant. Biol. 59, 259–263 (1994).
Mayer, V. W. & Aguilera, A. High levels of chromosome instability in polyploids of Saccharomyces cerevisiae. Mut. Res. 231, 177–186 (1990).
Shackney, S. et al. Model for the genetic evolution of human solid tumors. Cancer Res. 49, 3344–3354 (1989).
Tanaka, K. et al. Suppression of tumorigenicity in human colon carcinoma cells by introduction of normal chromosome 5 or 18. Nature 349, 340–342 (1991).
Goyette, M. C. et al. Progression of colorectal cancer is associated with multiple tumor suppressor gene defects but inhibition of tumorigeneity is accomplished by correction of any single defect via chromosome transfer. Mol. Cell. Biol. 12, 1387–1395 (1992).
Rodrigues, N. R. et al. p53 mutations in colorectal cancer. Proc. Natl Acad. Sci. USA 87, 7555–7559 (1990).
Shibata, D., Peinado, M. A., lonov, Y., Malkhosyan, S. & Perucho, M. Genomic instability in repeated sequences is an early somatic event in colorectal tumorigenesis that persists after transformation. Nature Genet. 6, 273–281 (1994).
Huang, J. et al. APC mutations in colorectal tumors with mismatch repair deficiency. Proc. Natl Acad. Sci. USA 93, 9049–9054 (1996).
Aaltonen, L. A. et al. Clues to the pathogenesis of familial colorectal cancer. Science 260, 812–816 (1993).
Bocker, M. et al. Genomic instability in colorectal carcinomas: comparison of different evaluation methods and their biological significance. J. Path. 179, 15–19 (1996).
Livingston, L. R. et al. Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53. Cell 70, 923–935 (1992).
Yin, Y., Tainsky, M. A., Bischoff, F. Z., Strong, L. C. & Wahl, G. M. Wild-type p53 restores cell cycle control and inhibits gene amplification in cells with mutant p53 alleles. Cell 70, 937–948 (1992).
Cottu, P. H. et al. Inverse correlation between RER+ status and p53 mutation in colorectal cancer cell lines. Oncogene 13, 2727–2730 (1996).
Papadopoulos, N. et al. Mutation of the mutL homolog in hereditary colon cancer. Science 263, 1625–1629 (1994).
Papadopoulos, N. et al. Mutations of GTBP in genetically unstable cells. Science 268, 1915–1917 (1995).
Umar, A. et al. Defective mismatch repair in extracts of colorectal and endometrial cancer lines exhibiting microsatellite instability. J. Biol. Chem. 269, 14367–14370 (1994).
Hollstein, M. et al. Database of p53 gene somatic mutations in human tumors and cell lines. Nucleic Acids Res. 22, 3551–3555 (1994).
Ried, T. et al. Specific metaphase and interphase detection of the breakpoint region in 8q24 of Burkitt lymphoma cells by triple-color fluorescence in situ hybridization. Genes Chrom. Cancer 4, 69–74 (1992).
Lichter, P. & Cremer, T. in Human Cytogenetics: A Practical Approach (eds Rooney, D. E. & Czepulkowski, B. H.) 157–192 (IRL, Oxford, 1992).
Lengauer, C. et al. Large-scale isolation of human Ip36-specific PI clones and their use for fluorescence in situ hybridization. Gen. Anal Tech. Appl. 11, 140–147 (1994).
Ried, T., Baldini, A., Rand, T. C. & Ward, D. C. Simultaneous visualization of seven different DNA probes by in situ hybridization using combinatorial fluorescence and digital imaging microscopy. Proc. NatlAcad. Sci. USA 89, 1388–1392 (1992).
About this article
Cite this article
Lengauer, C., Kinzler, K. & Vogelstein, B. Genetic instability in colorectal cancers. Nature 386, 623–627 (1997). https://doi.org/10.1038/386623a0
Radiology Case Reports (2021)
Reduced SKP1 and CUL1 expression underlies increases in Cyclin E1 and chromosome instability in cellular precursors of high-grade serous ovarian cancer
British Journal of Cancer (2021)
Journal of Cell Biology (2021)
A genome‐wide study of the relationship between chromosomal abnormalities and gene expression in colorectal tumors
Genes, Chromosomes and Cancer (2021)
Journal of Biological Chemistry (2021)