Genomic and Chromosomal Instability

Abstract

The multiplicity of mutations found in human cancers reflects the consequences of breakdown in genome maintenance and helps to provide insight into the origins of malignancy.

Keywords: genetic instability; DNA damage; DNA repair; mutation; cancer

Figure 1.

Cancer cells show a multitude of genetic changes. (a) Karyotype of chromosomes from a normal cell; note the normal arrangement of 44 autosomes and 2 sex chromosomes. (b) Karyotype of leukemic cell chromosomes from a patient with acute myelogenous leukemia. Many chromosomes are missing. There are multiple translocations, deletions and amplifications. In fact, each chromosome pair exhibits one or more aberrations. (This karyotype was generously provided by Dr Christine Diesteche, University of Washington, Seattle.)

Figure 2.

Human tumors manifest a mutator phenotype. Random mutations in genes involved in genome maintenance can lead to loss of genome stability functions and can predispose the cell to accumulate additional mutations. ‘Hits’ on oncogenes and tumor suppressors can lead to increased cell division, invasion and metastasis of malignant cells.

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References

Armitage P and Doll R (1954) The age distribution of cancer and a multi‐stage theory of carcinogenesis. British Journal of Cancer 8: 1–12.

Barrett MT, Sanchez CA, Prevo LJ, et al. (1999) Evolution of neoplastic cell lineages in Barrett oesophagus. Nature Genetics 22(1): 106–109.

Cui H, Horon IL, Ohlsson R, Hamilton SR and Feinberg AP (1998) Loss of imprinting in normal tissue of colorectal cancer patients with microsatellite instability. Nature Medicine 4(11): 1276–1280.

Cunningham JM, Christensen ER, Tester DJ, et al. (1998) Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability. Cancer Research 58(15): 3455–3460.

Druker BJ (2002) Perspectives on the development of a molecularly targeted agent. Cancer Cell 1(1): 31–36.

Esteller M, Toyota M, Sanchez‐Cespedes M, et al. (2000) Inactivation of the DNA repair gene O6‐methylguanine‐DNA methyltransferase by promoter hypermethylation is associated with G to A mutations in K‐ras in colorectal tumorigenesis. Cancer Research 60(9): 2368–2371.

Greenblatt MS, Bennett WP, Hollstein M and Harris CC (1994) Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Research 54(18): 4855–4878.

Hanahan D and Weinberg RA (2000) The hallmarks of cancer. Cell 100(1): 57–70.

Hoeijmakers JH (2001) Genome maintenance mechanisms for preventing cancer. Nature 411(6835): 366–374.

Knudson Jr AG (1971) Mutation and cancer: statistical study of retinoblastoma. Proceedings of the National Academy of Sciences of the United States of America 68: 820–823.

Loeb LA (2001) A mutator phenotype in cancer. Cancer Research 61(8): 3230–3239.

Loeb LA, Springgate CF and Battula N (1974) Errors in DNA replication as a basis of malignant change. Cancer Research 34: 2311–2321.

Modrich P (1995) Mismatch repair, genetic stability, and tumor avoidance. Philosophical Transactions of the Royal Society of London Series B: Biological Sciences 347: 89–95.

North S and Hainaut P (2000) p53 and cell‐cycle control: a finger in every pie. Pathologie Biologie 48(3): 255–270.

Robles AI and Harris CC (2001) p53‐mediated apoptosis and genomic instability diseases. Acta Oncologica 40(6): 696–701.

Slamon DJ, Leyland‐Jones B, Shak S, et al. (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. New England Journal of Medicine 344(11): 783–792.

Solomon E, Voss R, Hall V, et al. (1987) Chromosome 5 allele loss in human colorectal carcinomas. Nature 328(6131): 616–619.

Stoler DL, Chen N, Basik M, et al. (1999) The onset and extent of genomic instability in sporadic colorectal tumor progression. Proceedings of the National Academy of Sciences of the United States of America 96(26): 15121–15126.

Tlsty TD, Margolin B and Lum K (1989) Differences in the rates of gene amplification in nontumorigenic and tumorigenic cell lines as measured by Luria–Delbruck fluctuation analysis. Proceedings of the National Academy of Sciences of the United States of America 86(23): 9441–9445.

Wang TL, Rago C, Silliman N, et al. (2002) Prevalence of somatic alterations in the colorectal cancer cell genome. Proceedings of the National Academy of Sciences of the United States of America 99(5): 3076–3080.

Williams C, Ponten F, Ahmadian A, et al. (1998) Clones of normal keratinocytes and a variety of simultaneously present epidermal neoplastic lesions contain a multitude of p53 gene mutations in a xeroderma pigmentosum patient. Cancer Research 58(11): 2449–2455.

Wood RD, Mitchell M, Sgouros J and Lindahl T (2001) Human DNA repair genes. Science 291(5507): 1284–1289.

Web Links

Breakpoint cluster region (BCR); Locus ID: 613. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=613

Tumor protein p53 (Li‐Fraumeni syndrome) (TP53); Locus ID: 7157. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=7157

v‐abl Abelson murine leukemia viral oncogene homolog 1 (ABL1); Locus ID:25. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=25

v‐erb‐b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian) (ERBB2); Locus ID: 2064. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=2064

v‐myc myelocytomatosis viral related oncogene, neuroblastoma derived (avian) (MYCN); Locus ID: 4613. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=4613

Breakpoint cluster region (BCR); MIM number: 151410. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?151410

Tumor protein p53 (Li‐Fraumeni syndrome) (TP53); MIM number: 191170. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?191170

v‐abl Abelson murine leukemia viral oncogene homolog 1 (ABL1); MIM number: 189980. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?189980

v‐erb‐b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian) (ERBB2); MIM number: 164870. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?164870

v‐myc myelocytomatosis viral related oncogene, neuroblastoma derived (avian) (MYCN); MIM number: 164840. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?164840

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Guo, Haiwei H, Davidson, John F, and Loeb, Lawrence A(Jan 2006) Genomic and Chromosomal Instability. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1038/npg.els.0005499]