Genetic instability in colorectal cancers (original) (raw)
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- Published: 10 April 1997
Nature volume 386, pages 623–627 (1997)Cite this article
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Abstract
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.
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References
- Loeb, L. Mutator phenotype may be required for multistage carcinogenesis. Cancer Res. 51, 3075–3079 (1991).
CAS PubMed Google Scholar - Hartwell, L. Defects in a cell cycle checkpoint may be responsible for the genomic instability of cancer cells. Cell 71, 543–546 (1992).
Article CAS Google Scholar - Heim, S. & Mitelman, F. Cancer Cytogenetics (Liss, New York, 1987).
Google Scholar - Marra, G. & Boland, C. R. Hereditary nonpolyposis colorectal cancer: the syndrome, the genes, and historical perspectives. J. Natl Cancer Inst. 87, 1114–1125 (1995).
Article CAS Google Scholar - 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).
Article Google Scholar - 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).
Google Scholar - 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).
CAS Google Scholar - 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).
CAS Google Scholar - 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).
Article CAS Google Scholar - Mayer, V. W. & Aguilera, A. High levels of chromosome instability in polyploids of Saccharomyces cerevisiae. Mut. Res. 231, 177–186 (1990).
Article CAS Google Scholar - Shackney, S. et al. Model for the genetic evolution of human solid tumors. Cancer Res. 49, 3344–3354 (1989).
CAS PubMed Google Scholar - 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).
Article ADS CAS Google Scholar - 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).
Article CAS Google Scholar - Rodrigues, N. R. et al. p53 mutations in colorectal cancer. Proc. Natl Acad. Sci. USA 87, 7555–7559 (1990).
Article ADS CAS Google Scholar - 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).
Article CAS Google Scholar - Huang, J. et al. APC mutations in colorectal tumors with mismatch repair deficiency. Proc. Natl Acad. Sci. USA 93, 9049–9054 (1996).
Article ADS CAS Google Scholar - Aaltonen, L. A. et al. Clues to the pathogenesis of familial colorectal cancer. Science 260, 812–816 (1993).
Article ADS CAS Google Scholar - Bocker, M. et al. Genomic instability in colorectal carcinomas: comparison of different evaluation methods and their biological significance. J. Path. 179, 15–19 (1996).
Article CAS Google Scholar - Livingston, L. R. et al. Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53. Cell 70, 923–935 (1992).
Article Google Scholar - 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).
Article CAS Google Scholar - Cottu, P. H. et al. Inverse correlation between RER+ status and p53 mutation in colorectal cancer cell lines. Oncogene 13, 2727–2730 (1996).
CAS PubMed Google Scholar - Papadopoulos, N. et al. Mutation of the mutL homolog in hereditary colon cancer. Science 263, 1625–1629 (1994).
Article ADS CAS Google Scholar - Papadopoulos, N. et al. Mutations of GTBP in genetically unstable cells. Science 268, 1915–1917 (1995).
Article ADS CAS Google Scholar - 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).
CAS PubMed Google Scholar - Hollstein, M. et al. Database of p53 gene somatic mutations in human tumors and cell lines. Nucleic Acids Res. 22, 3551–3555 (1994).
CAS PubMed PubMed Central Google Scholar - 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).
Article CAS Google Scholar - Lichter, P. & Cremer, T. in Human Cytogenetics: A Practical Approach (eds Rooney, D. E. & Czepulkowski, B. H.) 157–192 (IRL, Oxford, 1992).
Google Scholar - 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).
CAS Google Scholar - 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).
Article ADS CAS Google Scholar
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Authors and Affiliations
- Howard Hughes Medical Institute and The Johns Hopkins Oncology Center, Baltimore, Maryland, 21231, USA
C. Lengauer, K. W. Kinzler & B. Vogelstein
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- C. Lengauer
You can also search for this author inPubMed Google Scholar - K. W. Kinzler
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Lengauer, C., Kinzler, K. & Vogelstein, B. Genetic instability in colorectal cancers.Nature 386, 623–627 (1997). https://doi.org/10.1038/386623a0
- Received: 28 November 1996
- Accepted: 11 February 1997
- Issue Date: 10 April 1997
- DOI: https://doi.org/10.1038/386623a0