Abstract
Intensive research efforts during the last several decades have increased our understanding of carcinogenesis, and have identified a genetic basis for the multi-step process of cancer development. Tumors grow through a process of clonal expansion driven by mutation. Several forms of molecular alteration have been described in human cancers, and these can be generally classified as chromosomal abnormalities and nucleotide sequence abnormalities. Most cancer cells display a phenotype characterized by genomic hypermutability, suggesting that genomic instability may precede the acquisition of transforming mutations in critical target genes. Reduced to its essence, cancer is a disease of abnormal gene expression, and these genetic abnormalities contribute to cancer pathogenesis through inactivation of negative mediators of cell proliferation (including tumor suppressor genes) and activation of positive mediators of cell proliferation (including proto-oncogenes). In several human tumor systems, specific genetic alterations have been shown to correlate with well-defined histopathological stages of tumor development and progression. Although the significance of mutations to the etiological mechanisms of tumor development has been debated, a causal role for such genetic lesions is now commonly accepted for most human cancers. Thus, genetic lesions represent an integral part of the processes of neoplastic transformation, tumorigenesis, and tumor progression, and as such represent potentially valuable markers for cancer detection and staging.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Bishop JM (1991) Molecular themes in oncogenesis. Cell 64: 235–248
Lengauer C, Kinzler KW, Vogelstein B (1998) Genetic instabilities in human cancers. Nature 396: 643–649
Mao L, Sidransky D (1994) Cancer screening based on genetic alterations in human tumors. Cancer Res 54: 1939s–1940s
Sidransky D (1995) Molecular markers in cancer: can we make better predictions? Int J Cancer 64: 1–2
Renan MJ (1993) How many mutations are required for tumorigenesis? Implications from human cancer data. Mol Carcinog 7: 139–146
Loeb KR, Loeb LA (2000) Significance of multiple mutations in cancer. Carcinogenesis 21: 379–385
Cohen AM, Minsky BD, Schilsky RL. (1997) Cancer of the colon. In: VT De Vita, S Hellman, SA Rosenberg (eds): Cancer: Principles and Practice of Oncology, 5th ed. Lippincott-Raven, Philadelphia, 1144–1197
Kinzler KW, Vogelstein B (2001) Colorectal tumors. In: CR Scriver, AL Beaudet, WS Sly, D Valle (eds): The Metabolic and Molecular Bases of Inherited Disease, 8th ed. McGraw-Hill, New York 1033–1062
Crow JF (1997) The high spontaneous mutation rate: is it a health risk? Proc Natl Acad Sci USA 94: 8380–8386
Cairns J (1998) Mutation and cancer: the antecedents to our studies of adaptive mutation. Genetics 148: 1433–1440
Ruddon RW (1995) Cancer Biology, 3rd ed. Oxford University Press, New York
Albertson DG, Collins C, McCormick F, Gray JW (2003) Chromosome aberrations in solid tumors. Nat Genet 34: 369–376
Hussain SP, Harris CC (1998) Molecular epidemiology of human cancer: contribution of mutation spectra studies of tumor suppressor genes. Cancer Res 58: 4023–4037
Hedenfalk I, Ringner M, Ben-Dor A, Yakhini Z, Chen Y, Chebil G, Ach R, Loman N, Olsson H, Meltzer P et al. (2003) Molecular classification of familial non-BRCA1/BRCA2 breast cancer. Proc Natl Acad Sci USA 100: 2532–2537
Chung CH, Parker JS, Karaca G, Wu J, Funkhouser WK, Moore D, Butterfoss D, Xiang D, Zanation A, Yin X et al. (2004) Molecular classification of head and neck squamous cell carcinomas using patterns of gene expression. Cancer Cell 5: 489–500
Meyerson M, Franklin WA, Kelley MJ (2004) Molecular classification and molecular genetics of human lung cancers. Semin Oncol 31: 4–19
Hoang CD, D’Cunha J, Tawfic SH, Gruessner AC, Kratzke RA, Maddaus MA (2004) Expression profiling of non-small cell lung carcinoma identifies metastatic genotypes based on lymph node tumor burden. J Thorac Cardiovasc Surg 127: 1332–1341; discussion 1342
Warner GC, Reis PP, Jurisica I, Sultan M, Arora S, Macmillan C, Makitie AA, Grenman R, Reid N, Sukhai M et al. (2004) Molecular classification of oral cancer by cDNA microarrays identifies overexpressed genes correlated with nodal metastasis. Int J Cancer 110: 857–868
Cleator S, Ashworth A (2004) Molecular profiling of breast cancer: clinical implications. Br J Cancer 90: 1120–1124
Troester MA, Hoadley KA, Sorlie T, Herbert BS, Borresen-Dale AL, Lonning PE, Shay JW, Kaufmann WK, Perou CM (2004) Cell-type-specific responses to chemotherapeutics in breast cancer. Cancer Res 64: 4218–4226
Armitage P, Doll R (1957) A two-stage theory of carcinogenesis in relation to the age distribution of human cancer. Br J Cancer 11: 161–169
Knudson AG Jr, (1971) Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 68: 820–823
Baylin SB (2002) Mechanisms underlying epigenetically mediated gene silencing in cancer. Semin Cancer Biol 12: 331–337
Herman JG, Baylin SB (2003) Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med 349: 2042–2054
Fazzari MJ, Greally JM (2004) Epigenomics: beyond CpG islands. Nat Rev Genet 5: 446–455
Fearon ER, Vogelstein B (1990) A genetic model for colorectal tumorigenesis. Cell 61: 759–767
Jackson AL, Loeb LA (1998) The mutation rate and cancer. Genetics 148: 1483–1490
Loeb LA (2001) A mutator phenotype in cancer. Cancer Res 61: 3230–3239
Loeb LA, Christians FC (1996) Multiple mutations in human cancers. Mutat Res 350: 279–286
Perucho M (1996) Cancer of the microsatellite mutator phenotype. Biol Chem 377: 675–684
Orr-Weaver TL, Weinberg RA (1998) A checkpoint on the road to cancer. Nature 392: 223–224
Goyette MC, Cho K, Fasching CL, Levy DB, Kinzler KW, Paraskeva C, Vogelstein B, Stanbridge EJ (1992) Progression of colorectal cancer is associated with multiple tumor suppressor gene defects but inhibition of tumorigenicity is accomplished by correction of any single defect via chromosome transfer. Mol Cell Biol 12: 1387–1395
Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, Nakamura Y, White R, Smits AM, Bos JL (1988) Genetic alterations during colorectal-tumor development. N Engl J Med 319: 525–532
Duesberg P, Rausch C, Rasnick D, Hehlmann R (1998) Genetic instability of cancer cells is proportional to their degree of aneuploidy. Proc Natl Acad Sci USA 95: 13692–13697
Strauss BS (1998) Hypermutability in carcinogenesis. Genetics 148: 1619–1626
Sieber OM, Heinimann K, Tomlinson IP (2003) Genomic instability—the engine of tumorigenesis? Nat Rev Cancer 3: 701–708
Hollstein M, Shomer B, Greenblatt M, Soussi T, Hovig E, Montesano R, Harris CC (1996) Somatic point mutations in the p53 gene of human tumors and cell lines: updated compilation. Nucleic Acids Res 24: 141–146
Moolgavkar SH, Luebeck EG (2003) Multistage carcinogenesis and the incidence of human cancer. Genes Chromosomes Cancer 38: 302–306
Boesen JJ, Niericker MJ, Dieteren N, Simons JW (1994) How variable is a spontaneous mutation rate in cultured mammalian cells? Mutat Res 307: 121–129
Eldridge SR, Gould MN (1992) Comparison of spontaneous mutagenesis in early-passage human mammary cells from normal and malignant tissues. Int J Cancer 50: 321–324
Wittenkeller JL, Storer B, Bittner G, Schiller JH (1997) Comparison of spontaneous and induced mutation rates in an immortalized human bronchial epithelial cell line and its tumorigenic derivative. Oncology 54: 335–341
Loeb LA (1991) Mutator phenotype may be required for multistage carcinogenesis. Cancer Res 51: 3075–3079
Loeb LA (1997) Transient expression of a mutator phenotype in cancer cells. Science277: 1449–1450
Richards B, Zhang H, Phear G, Meuth M (1997) Conditional mutator phenotypes in hMSH2-deficient tumor cell lines. Science 277: 1523–1526
Bhattacharyya NP, Skandalis A, Ganesh A, Groden J, Meuth M (1994) Mutator phenotypes in human colorectal carcinoma cell lines. Proc Natl Acad Sci USA 91: 6319–6323
Eshleman JR, Lang EZ, Bowerfind GK, Parsons R, Vogelstein B, Willson JK, Veigl ML, Sedwick WD, Markowitz SD (1995) Increased mutation rate at the hprt locus accompanies microsatellite instability in colon cancer. Oncogene 10: 33–37
Glaab WE, Tindall KR (1997) Mutation rate at the hprt locus in human cancer cell lines with specific mismatch repair-gene defects. Carcinogenesis 18: 1–8
Tlsty TD, Margolin BH, Lum K (1989) Differences in the rates of gene amplification in nontumorigenic and tumorigenic cell lines as measured by Luria-Delbruck fluctuation analysis. Proc Natl Acad Sci USA 86: 9441–9445
Cairns J (1975) Mutation selection and the natural history of cancer. Nature 255: 197–200
Foulds L (1958) The natural history of cancer. J Chronic Dis 8: 2–37
Nowell PC (1976) The clonal evolution of tumor cell populations. Science 194: 23–28
Eshleman JR, Markowitz SD (1996) Mismatch repair defects in human carcinogenesis. Hum Mol Genet 5 Spec No: 1489–1494
Lengauer C, Kinzler KW, Vogelstein B (1997) Genetic instability in colorectal cancers. Nature 386: 623–627
Cahill DP, Lengauer C, Yu J, Riggins GJ, Willson JK, Markowitz SD, Kinzler KW, Vogelstein B (1998) Mutations of mitotic checkpoint genes in human cancers. Nature 392: 300–303
Greenblatt MS, Bennett WP, Hollstein M, Harris CC (1994) Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res 54: 4855–4878
Baker SJ, Fearon ER, Nigro JM, Hamilton SR, Preisinger AC, Jessup JM, van Tuinen P, Ledbetter DH, Barker DF, Nakamura Y et al. (1989) Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science 244: 217–221
Bos JL (1989) ras oncogenes in human cancer: a review. Cancer Res 49: 4682–4689
Dalla-Favera R, Martinotti S, Gallo RC, Erikson J, Croce CM (1983) Translocation and rearrangements of the c-myc oncogene locus in human undifferentiated B-cell lymphomas. Science 219: 963–967
Coleman WB, Tsongalis GJ (2002) The role of genomic instability in the development of human cancer. In: WB Coleman, GJ Tsongalis (eds): The Molecular Basis of Human Cancer. Humana Press, Totowa, 115–142
Rosenberg SM, Thulin C, Harris RS (1998) Transient and heritable mutators in adaptive evolution in the lab and in nature. Genetics 148: 1559–1566
Aaltonen LA, Peltomaki P, Leach FS, Sistonen P, Pylkkanen L, Mecklin JP, Jarvinen H, Powell SM, Jen J, Hamilton SR et al. (1993) Clues to the pathogenesis of familial colorectal cancer. Science 260: 812–816
Aaltonen LA, Peltomaki P, Mecklin JP, Jarvinen H, Jass JR, Green JS, Lynch HT, Watson P, Tallqvist G, Juhola M et al. (1994) Replication errors in benign and malignant tumors from hereditary nonpolyposis colorectal cancer patients. Cancer Res 54: 1645–1648
Feig DI, Reid TM, Loeb LA (1994) Reactive oxygen species in tumorigenesis. Cancer Res 54: 1890s–1894s
Jackson AL, Chen R, Loeb LA (1998) Induction of microsatellite instability by oxidative DNA damage. Proc Natl Acad Sci USA 95: 12468–12473
Baba S (1997) Recent advances in molecular genetics of colorectal cancer. World J Surg 21: 678–687
Yamada NA, Parker JM, Farber RA (2003) Mutation frequency analysis of mononucleotide and dinucleotide repeats after oxidative stress. Environ Mol Mutagen 42: 75–84
Mitelman F (1994) Catalog of Chromosome Aberrations in Cancer, 5th ed. Wiley-Liss Publishers, New York
Meltzer PS, Kallioniemi A, Trent JM (2001) Chromosome alterations in human solid tumors. In: CR Scriver, AL Beaudet, WS Sly, D Valle (eds): The Metabolic and Molecular Bases of Inhierited Disease, 8th ed. McGraw-Hill, New York, 575–596
Cahill DP, Lengauer C (2001) Tumor genome instabilities. In: CR Scriver, AL Beaudet, WS Sly, D Valle (eds): The Metabolic and Molecular Bases of Inherited Disease, 8th ed. McGraw-Hill, New York 611–612
Wang Z, Cummins JM, Shen D, Cahill DP, Jallepalli PV, Wang TL, Parsons DW, Traverso G, Awad M, Silliman N et al. (2004) Three classes of genes mutated in colorectal cancers with chromosomal instability. Cancer Res 64: 2998–3001
Vogelstein B, Fearon ER, Kern SE, Hamilton SR, Preisinger AC, Nakamura Y, White R (1989) Allelotype of colorectal carcinomas. Science 244: 207–211
Tsuchiya E, Nakamura Y, Weng SY, Nakagawa K, Tsuchiya S, Sugano H, Kitagawa T (1992) Allelotype of non-small cell lung carcinoma—comparison between loss of heterozygosity in squamous cell carcinoma and adenocarcinoma. Cancer Res 52: 2478–2481
Seymour AB, Hruban RH, Redston M, Caldas C, Powell SM, Kinzler KW, Yeo CJ, Kern SE (1994) Allelotype of pancreatic adenocarcinoma. Cancer Res 54: 2761–2764
Roncalli M, Borzio M, Bianchi P, Laghi L (2000) Comprehensive allelotype study of hepatocellular carcinoma. Hepatology 32: 876
Miller BJ, Wang D, Krahe R, Wright FA (2003) Pooled analysis of loss of heterozygosity in breast cancer: a genome scan provides comparative evidence for multiple tumor suppressors and identifies novel candidate regions. Am J Hum Genet 73: 748–767
Thiagalingam S, Laken S, Willson JK, Markowitz SD, Kinzler KW, Vogelstein B, Lengauer C (2001) Mechanisms underlying losses of heterozygosity in human colorectal cancers. Proc Natl Acad Sci USA 98: 2698–2702
El-Naggar AK, Vielh P (2004) Solid tumor DNA content analysis. Methods Mol Biol 263: 355–370
Kallioniemi OP, Kallioniemi A, Piper J, Isola J, Waldman FM, Gray JW, Pinkel D (1994) Optimizing comparative genomic hybridization for analysis of DNA sequence copy number changes in solid tumors. Genes Chromosomes Cancer 10: 231–243
Kallioniemi OP, Kallioniemi A, Sudar D, Rutovitz D, Gray JW, Waldman F, Pinkel D (1993) Comparative genomic hybridization: a rapid new method for detecting and mapping DNA amplification in tumors. Semin Cancer Biol 4: 41–46
Bayani JM, Squire JA (2002) Applications of SKY in cancer cytogenetics. Cancer Invest 20: 373–386
Patel AS, Hawkins AL, Griffin CA (2000) Cytogenetics and cancer. Curr Opin Oncol 12: 62–67
Radford DM, Fair KL, Phillips NJ, Ritter JH, Steinbrueck T, Holt MS, Donis-Keller H (1995) Allelotyping of ductal carcinoma in situ of the breast: deletion of loci on 8p, 13q, 16q, 17p and 17q. Cancer Res 55: 3399–3405
Boige V, Laurent-Puig P, Fouchet P, Flejou JF, Monges G, Bedossa P, Bioulac-Sage P, Capron F, Schmitz A, Olschwang S, Thomas G (1997) Concerted nonsyntenic allelic losses in hyperploid hepatocellular carcinoma as determined by a high-resolution allelotype. Cancer Res 57: 1986–1990
Nowak MA, Komarova NL, Sengupta A, Jallepalli PV, Shih Ie M, Vogelstein B, Lengauer C (2002) The role of chromosomal instability in tumor initiation. Proc Natl Acad Sci USA 99: 16226–16231
Rajagopalan H, Nowak MA, Vogelstein B, Lengauer C (2003) The significance of unstable chromosomes in colorectal cancer. Nat Rev Cancer 3: 695–701
Ghadimi BM, Sackett DL, Difilippantonio MJ, Schrock E, Neumann T, Jauho A, Auer G, Ried T (2000) Centrosome amplification and instability occurs exclusively in aneuploid, but not in diploid colorectal cancer cell lines, and correlates with numerical chromosomal aberrations. Genes Chromosomes Cancer 27: 183–190
Harwood J, Tachibana A, Davis R, Bhattacharyya NP, Meuth M (1993) High rate of multilocus deletion in a human tumor cell line. Hum Mol Genet 2: 165–171
Phear G, Bhattacharyya NP, Meuth M (1996) Loss of heterozygosity and base substitution at the APRT locus in mismatch-repair-proficient and-deficient colorectal carcinoma cell lines. Mol Cell Biol 16: 6516–6523
Le Beau MM (1997) Molecular biology of cancer: Cytogenetics. In: VT De Vita, S Hellman, SA Rosenberg (eds): Cancer: Principles and Practice of Oncology, 5th ed. Lippincott-Raven, Philadelphia 103–119
Gollin SM (2004) Chromosomal instability. Curr Opin Oncol 16: 25–31
Kastan MB, Kuerbitz SJ (1993) Control of G1 arrest after DNA damage. Environ Health Perspect 101,Suppl 5: 55–58
Kastan MB, Onyekwere O, Sidransky D, Vogelstein B, Craig RW (1991) Participation of p53 protein in the cellular response to DNA damage. Cancer Res 51: 6304–6311
Solomon E, Borrow J, Goddard AD (1991) Chromosome aberrations and cancer. Science 254: 1153–1160
Jong YJ, Li LH, Tsou MH, Chen YJ, Cheng SH, Wang-Wuu S, Tsai SF, Chen CM, Huang AT, Hsu MT, Lin CH (2004) Chromosomal comparative genomic hybridization abnormalities in early-and late-onset human breast cancers: correlation with disease progression and TP53 mutations. Cancer Genet Cytogenet 148: 55–65
Sugai T, Takahashi H, Habano W, Nakamura S, Sato K, Orii S, Suzuki K (2003) Analysis of genetic alterations, classified according to their DNA ploidy pattern, in the progression of colorectal adenomas and early colorectal carcinomas. J Pathol 200: 168–176
Filatov L, Golubovskaya V, Hurt JC, Byrd LL, Phillips JM, Kaufmann WK (1998) Chromosomal instability is correlated with telomere erosion and inactivation of G2 checkpoint function in human fibroblasts expressing human papillomavirus type 16 E6 oncoprotein. Oncogene 16: 1825–1838
Honma M, Momose M, Tanabe H, Sakamoto H, Yu Y, Little JB, Sofuni T, Hayashi M (2000) Requirement of wild-type p53 protein for maintenance of chromosomal integrity. Mol Carcinog 28: 203–214
Tarapore P, Fukasawa K (2000) p53 mutation and mitotic infidelity. Cancer Invest 18: 148–155
Shih IM, Zhou W, Goodman SN, Lengauer C, Kinzler KW, Vogelstein B (2001) Evidence that genetic instability occurs at an early stage of colorectal tumorigenesis. Cancer Res 61: 818–822
Baker SJ, Preisinger AC, Jessup JM, Paraskeva C, Markowitz S, Willson JK, Hamilton S, Vogelstein B (1990) p53 gene mutations occur in combination with 17p allelic deletions as late events in colorectal tumorigenesis. Cancer Res 50: 7717–7722
Eshleman JR, Casey G, Kochera ME, Sedwick WD, Swinler SE, Veigl ML, Willson JK, Schwartz S, Markowitz SD (1998) Chromosome number and structure both are markedly stable in RER colorectal cancers and are not destabilized by mutation of p53. Oncogene 17: 719–725
Kramer A, Neben K, Ho AD (2002) Centrosome replication, genomic instability and cancer. Leukemia 16: 767–775
Lingle WL, Barrett SL, Negron VC, D’Assoro AB, Boeneman K, Liu W, Whitehead CM, Reynolds C, Salisbury JL (2002) Centrosome amplification drives chromosomal instability in breast tumor development. Proc Natl Acad Sci USA 99: 1978–1983
Bischoff JR, Anderson L, Zhu Y, Mossie K, Ng L, Souza B, Schryver B, Flanagan P, Clairvoyant F, Ginther C et al. (1998) A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers. Embo J 17: 3052–3065
Zhou H, Kuang J, Zhong L, Kuo WL, Gray JW, Sahin A, Brinkley BR, Sen S (1998) Tumour amplified kinase STK15/BTAK induces centrosome amplification, aneuploidy and transformation. Nat Genet 20: 189–193
Wolf G, Elez R, Doermer A, Holtrich U, Ackermann H, Stutte HJ, Altmannsberger HM, Rubsamen-Waigmann H, Strebhardt K (1997) Prognostic significance of polo-like kinase (PLK) expression in non-small cell lung cancer. Oncogene 14: 543–549
Tanaka T, Kimura M, Matsunaga K, Fukada D, Mori H, Okano Y (1999) Centrosomal kinase AIK1 is overexpressed in invasive ductal carcinoma of the breast. Cancer Res 59: 2041–2044
Carroll PE, Okuda M, Horn HF, Biddinger P, Stambrook PJ, Gleich LL, Li YQ, Tarapore P, Fukasawa K (1999) Centrosome hyperamplification in human cancer: chromosome instability induced by p53 mutation and/or Mdm2 overexpression. Oncogene 18: 1935–1944
Tarapore P, Fukasawa K (2002) Loss of p53 and centrosome hyperamplification. Oncogene 21: 6234–6240
Tutt A, Gabriel A, Bertwistle D, Connor F, Paterson H, Peacock J, Ross G, Ashworth A (1999) Absence of Brca2 causes genome instability by chromosome breakage and loss associated with centrosome amplification. Curr Biol 9: 1107–1110
Deng CX (2002) Roles of BRCA1 in centrosome duplication. Oncogene 21: 6222–6227
Bharadwaj R, Yu H (2004) The spindle checkpoint, aneuploidy, and cancer. Oncogene 23: 2016–2027
Hartwell LH, Kastan MB (1994) Cell cycle control and cancer. Science 266: 1821–1828
Cahill DP, da Costa LT, Carson-Walter EB, Kinzler KW, Vogelstein B, Lengauer C (1999) Characterization of MAD2B and other mitotic spindle checkpoint genes. Genomics 58: 181–187
Li Y, Benezra R (1996) Identification of a human mitotic checkpoint gene: hsMAD2. Science 274: 246–248
Jaffrey RG, Pritchard SC, Clark C, Murray GI, Cassidy J, Kerr KM, Nicolson MC, McLeod HL (2000) Genomic instability at the BUB1 locus in colorectal cancer, but not in non-small cell lung cancer. Cancer Res 60: 4349–4352
Myrie KA, Percy MJ, Azim JN, Neeley CK, Petty EM (2000) Mutation and expression analysis of human BUB1 and BUB1B in aneuploid breast cancer cell lines. Cancer Lett 152: 193–199
Sato M, Sekido Y, Horio Y, Takahashi M, Saito H, Minna JD, Shimokata K, Hasegawa Y (2000) Infrequent mutation of the hBUB1 and hBUBR1 genes in human lung cancer. Jpn J Cancer Res 91: 504–509
Yamaguchi K, Okami K, Hibi K, Wehage SL, Jen J, Sidransky D (1999) Mutation analysis of hBUB1 in aneuploid HNSCC and lung cancer cell lines. Cancer Lett 139: 183–187
Imai Y, Shiratori Y, Kato N, Inoue T, Omata M (1999) Mutational inactivation of mitotic checkpoint genes, hsMAD2 and hBUB1, is rare in sporadic digestive tract cancers. Jpn J Cancer Res 90: 837–840
Gualberto A, Aldape K, Kozakiewicz K, Tlsty TD (1998) An oncogenic form of p53 confers a dominant, gain-of-function phenotype that disrupts spindle checkpoint control. Proc Natl Acad Sci USA 95: 5166–5171
Shigeta T, Takagi M, Delia D, Chessa L, Iwata S, Kanke Y, Asada M, Eguchi M, Mizutani S (1999) Defective control of apoptosis and mitotic spindle checkpoint in heterozygous carriers of ATM mutations. Cancer Res 59: 2602–2607
Canman CE, Lim DS (1998) The role of ATM in DNA damage responses and cancer. Oncogene 17: 3301–3308
Zhang H, Tombline G, Weber BL (1998) BRCA1, BRCA2, and DNA damage response: collision or collusion? Cell 92: 433–436
Tlsty TD, Briot A, Gualberto A, Hall I, Hess S, Hixon M, Kuppuswamy D, Romanov S, Sage M, White A (1995) Genomic instability and cancer. Mutat Res 337: 1–7
Hogarty MD, Brodeur GM (2001) Gene amplification in human cancers: Biological and clinical significance. In: CR Scriver, AL Beaudet, WS Sly, D Valle (eds): The Metabolic and Molecular Bases of Inherited Disease, 8th ed. McGraw-Hill, New York, 597–610
Livingstone LR, White A, Sprouse J, Livanos E, Jacks T, Tlsty TD (1992) Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53. Cell 70: 923–935
Yin Y, Tainsky MA, Bischoff FZ, Strong LC, Wahl GM (1992) Wild-type p53 restores cell cycle control and inhibits gene amplification in cells with mutant p53 alleles. Cell 70: 937–948
Oren M (1994) Relationship of p53 to the control of apoptotic cell death. Semin Cancer Biol 5: 221–227
Nowell PC, Hungerford DA (1960) Chromosome studies on normal and leukemic human leukocytes. J Natl Cancer Inst 25: 85–109
Dubeau L. (2001) Ovarian cancer. In: CR Scriver, AL Beaudet, WS Sly, D Valle (eds): The Metabolic and Molecular Bases of Inherited Disease, 8th ed. McGraw-Hill, New York, 1091–1096
Hruban RH, Wilentz RE, Kern SE (2000) Genetic progression in the pancreatic ducts. Am J Pathol 156: 1821–1825
Croce CM (1986) Chromosome translocations and human cancer. Cancer Res 46:6019–6023
Kinzler KW, Nilbert MC, Su LK, Vogelstein B, Bryan TM, Levy DB, Smith KJ, Preisinger AC, Hedge P, McKechnie D et al. (1991) Identification of FAP locus genes from chromosome 5q21. Science 253: 661–665
Fearon ER, Cho KR, Nigro JM, Kern SE, Simons JW, Ruppert JM, Hamilton SR, Preisinger AC, Thomas G, Kinzler KW et al. (1990) Identification of a chromosome 18q gene that is altered in colorectal cancers. Science 247: 49–56
Peinado MA, Malkhosyan S, Velazquez A, Perucho M (1992) Isolation and characterization of allelic losses and gains in colorectal tumors by arbitrarily primed polymerase chain reaction. Proc Natl Acad Sci USA 89: 10065–10069
Ionov Y, Peinado MA, Malkhosyan S, Shibata D, Perucho M (1993) Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 363: 558–561
Thibodeau SN, Bren G, Schaid D (1993) Microsatellite instability in cancer of the proximal colon. Science 260: 816–819
Zhang L, Yu J, Willson JK, Markowitz SD, Kinzler KW, Vogelstein B (2001) Short mononucleotide repeat sequence variability in mismatch repair-deficient cancers. Cancer Res 61: 3801–3805
Yamada NA, Castro A, Farber RA (2003) Variation in the extent of microsatellite instability in human cell lines with defects in different mismatch repair genes. Mutagenesis 18: 277–282
Honchel R, Halling KC, Thibodeau SN (1995) Genomic instability in neoplasia. Semin Cell Biol 6: 45–52
Thibodeau SN, French AJ, Cunningham JM, Tester D, Burgart LJ, Roche PC, McDonnell SK, Schaid DJ, Vockley CW, Michels VV et al. (1998) Microsatellite instability in colorectal cancer: different mutator phenotypes and the principal involvement of hMLH1. Cancer Res 58: 1713–1718
Hoang JM, Cottu PH, Thuille B, Salmon RJ, Thomas G, Hamelin R (1997) BAT-26, an indicator of the replication error phenotype in colorectal cancers and cell lines. Cancer Res 57: 300–303
Zhou XP, Hoang JM, Li YJ, Seruca R, Carneiro F, Sobrinho-Simoes M, Lothe RA, Gleeson CM, Russell SE, Muzeau F et al. (1998) Determination of the replication error phenotype in human tumors without the requirement for matching normal DNA by analysis of mononucleotide repeat microsatellites. Genes Chromosomes Cancer 21: 101–107
Dietmaier W, Wallinger S, Bocker T, Kullmann F, Fishel R, Ruschoff J (1997) Diagnostic microsatellite instability: definition and correlation with mismatch repair protein expression. Cancer Res 57: 4749–4756
Parsons R, Myeroff LL, Liu B, Willson JK, Markowitz SD, Kinzler KW, Vogelstein B (1995) Microsatellite instability and mutations of the transforming growth factor beta type II receptor gene in colorectal cancer. Cancer Res 55: 5548–5550
Eichler EE, Holden JJ, Popovich BW, Reiss AL, Snow K, Thibodeau SN, Richards CS, Ward PA, Nelson DL (1994) Length of uninterrupted CGG repeats determines instability in the FMR1 gene. Nat Genet 8: 88–94
Mao L, Lee DJ, Tockman MS, Erozan YS, Askin F, Sidransky D (1994) Microsatellite alterations as clonal markers for the detection of human cancer. Proc Natl Acad Sci USA 91: 9871–9875
Risinger JI, Umar A, Barrett JC, Kunkel TA (1995) A hPMS2 mutant cell line is defective in strand-specific mismatch repair. J Biol Chem 270: 18183–18186
Risinger JI, Umar A, Boyd J, Berchuck A, Kunkel TA, Barrett JC (1996) Mutation of MSH3 in endometrial cancer and evidence for its functional role in heteroduplex repair. Nat Genet 14: 102–105
Oki E, Oda S, Maehara Y, Sugimachi K (1999) Mutated gene-specific phenotypes of dinucleotide repeat instability in human colorectal carcinoma cell lines deficient in DNA mismatch repair. Oncogene 18: 2143–2147
Baranovskaya S, Soto JL, Perucho M, Malkhosyan SR (2001) Functional significance of concomitant inactivation of hMLH1 and hMSH6 in tumor cells of the microsatellite mutator phenotype. Proc Natl Acad Sci USA 98: 15107–15112
Horii A, Han HJ, Shimada M, Yanagisawa A, Kato Y, Ohta H, Yasui W, Tahara E, Nakamura Y (1994) Frequent replication errors at microsatellite loci in tumors of patients with multiple primary cancers. Cancer Res 54: 3373–3375
Akiyama Y, Nakasaki H, Nihei Z, Iwama T, Nomizu T, Utsunomiya J, Yuasa Y (1996) Frequent microsatellite instabilities and analyses of the related genes in familial gastric cancers. Jpn J Cancer Res 87: 595–601
Nakashima H, Honda M, Inoue H, Shibuta K, Arinaga S, Era S, Ueo H, Mori M, Akiyoshi T (1995) Microsatellite instability in multiple gastric cancers. Int J Cancer 64: 239–242
Jiricny J, Nystrom-Lahti M (2000) Mismatch repair defects in cancer. Curr Opin Genet Dev 10: 157–161
Fishel R, Lescoe MK, Rao MR, Copeland NG, Jenkins NA, Garber J, Kane M, Kolodner R (1993) The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 75: 1027–1038
Leach FS, Nicolaides NC, Papadopoulos N, Liu B, Jen J, Parsons R, Peltomaki P, Sistonen P, Aaltonen LA, Nystrom-Lahti M et al. (1993) Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 75: 1215–1225
Umar A, Risinger JI, Glaab WE, Tindall KR, Barrett JC, Kunkel TA (1998) Functional overlap in mismatch repair by human MSH3 and MSH6. Genetics 148: 1637–1646
Palombo F, Gallinari P, Iaccarino I, Lettieri T, Hughes M, D’Arrigo A, Truong O, Hsuan JJ, Jiricny J (1995) GTBP, a 160-kilodalton protein essential for mismatch-binding activity in human cells. Science 268: 1912–1914
Papadopoulos N, Nicolaides NC, Liu B, Parsons R, Lengauer C, Palombo F, D’Arrigo A, Markowitz S, Willson JK, Kinzler KW et al. (1995) Mutations of GTBP in genetically unstable cells. Science 268: 1915–1917
Bronner CE, Baker SM, Morrison PT, Warren G, Smith LG, Lescoe MK, Kane M, Earabino C, Lipford J, Lindblom A et al. (1994) Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer. Nature 368: 258–261
Papadopoulos N, Nicolaides NC, Wei YF, Ruben SM, Carter KC, Rosen CA, Haseltine WA, Fleischmann RD, Fraser CM, Adams MD et al. (1994) Mutation of a mutL homolog in hereditary colon cancer. Science 263: 1625–1629
Nicolaides NC, Papadopoulos N, Liu B, Wei YF, Carter KC, Ruben SM, Rosen CA, Haseltine WA, Fleischmann RD, Fraser CM et al. (1994) Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. Nature 371: 75–80
Lipkin SM, Wang V, Jacoby R, Banerjee-Basu S, Baxevanis AD, Lynch HT, Elliott RM, Collins FS (2000) MLH3: a DNA mismatch repair gene associated with mammalian microsatellite instability. Nat Genet 24: 27–35
Muller A, Fishel R (2002) Mismatch repair and the hereditary non-polyposis colorectal cancer syndrome (HNPCC). Cancer Invest 20: 102–109
Liu B, Nicolaides NC, Markowitz S, Willson JK, Parsons RE, Jen J, Papadopolous N, Peltomaki P, de la Chapelle A, Hamilton SR et al. (1995) Mismatch repair gene defects in sporadic colorectal cancers with microsatellite instability. Nat Genet 9: 48–55
Schmutte C, Fishel R (1999) Genomic instability: first step to carcinogenesis. Anticancer Res 19: 4665–4696
Arzimanoglou II, Gilbert F, Barber HR (1998) Microsatellite instability in human solid tumors. Cancer 82: 1808–1820
Lothe RA (1997) Microsatellite instability in human solid tumors. Mol Med Today 3: 61–68
Schlotterer C, Tautz D (1992) Slippage synthesis of simple sequence DNA. Nucleic Acids Res 20: 211–215
Thomas DC, Umar A, Kunkel TA (1996) Microsatellite instability and mismatch repair defects in cancer. Mutat Res 350: 201–205
Boyer JC, Farber RA (1998) Mutation rate of a microsatellite sequence in normal human fibroblasts. Cancer Res 58: 3946–3949
Hanford MG, Rushton BC, Gowen LC, Farber RA (1998) Microsatellite mutation rates in cancer cell lines deficient or proficient in mismatch repair. Oncogene 16: 2389–2393
Umar A, Koi M, Risinger JI, Glaab WE, Tindall KR, Kolodner RD, Boland CR, Barrett JC, Kunkel TA (1997) Correction of hypermutability, methyl-N’-nitro-N-nitrosoguanidine resistance, and defective DNA mismatch repair by introducing chromosome 2 into human tumor cells with mutations in MSH2 and MSH6. Cancer Res 57: 3949–3955
da Costa LT, Liu B, el-Deiry W, Hamilton SR, Kinzler KW, Vogelstein B, Markowitz S, Willson JK, de la Chapelle A, Downey KM et al. (1995) Polymerase delta variants in RER colorectal tumours. Nat Genet 9: 10–11
Parc YR, Halling KC, Wang L, Christensen ER, Cunningham JM, French AJ, Burgart LJ, Price-Troska TL, Roche PC, Thibodeau SN (2000) HMSH6 alterations in patients with microsatellite instability-low colorectal cancer. Cancer Res 60: 2225–2231
Koi M, Umar A, Chauhan DP, Cherian SP, Carethers JM, Kunkel TA, Boland CR (1994) Human chromosome 3 corrects mismatch repair deficiency and microsatellite instability and reduces N-methyl-N’-nitro-N-nitrosoguanidine tolerance in colon tumor cells with homozygous hMLH1 mutation. Cancer Res 54: 4308–4312
Risinger JI, Umar A, Glaab WE, Tindall KR, Kunkel TA, Barrett JC (1998) Single gene complementation of the hPMS2 defect in HEC-1-A endometrial carcinoma cells. Cancer Res 58: 2978–2981
Lettieri T, Marra G, Aquilina G, Bignami M, Crompton NE, Palombo F, Jiricny J (1999) Effect of hMSH6 cDNA expression on the phenotype of mismatch repair-deficient colon cancer cell line HCT15. Carcinogenesis 20: 373–382
Lengauer C, Kinzler KW, Vogelstein B (1997) DNA methylation and genetic instability in colorectal cancer cells. Proc Natl Acad Sci USA 94: 2545–2550
Cunningham JM, Christensen ER, Tester DJ, Kim CY, Roche PC, Burgart LJ, Thibodeau SN (1998) Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability. Cancer Res 58: 3455–3460
Herman JG, Umar A, Polyak K, Graff JR, Ahuja N, Issa JP, Markowitz S, Willson JK, Hamilton SR, Kinzler KW et al. (1998) Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci USA 95: 6870–6875
Kane MF, Loda M, Gaida GM, Lipman J, Mishra R, Goldman H, Jessup JM, Kolodner R (1997) Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res 57: 808–811
Bevilacqua RA, Simpson AJ (2000) Methylation of the hMLH1 promoter but no hMLH1 mutations in sporadic gastric carcinomas with high-level microsatellite instability. Int J Cancer 87: 200–203
Endoh Y, Tamura G, Ajioka Y, Watanabe H, Motoyama T (2000) Frequent hypermethylation of the hMLH1 gene promoter in differentiated-type tumors of the stomach with the gastric foveolar phenotype. Am J Pathol 157: 717–722
Simpkins SB, Bocker T, Swisher EM, Mutch DG, Gersell DJ, Kovatich AJ, Palazzo JP, Fishel R, Goodfellow PJ (1999) MLH1 promoter methylation and gene silencing is the primary cause of microsatellite instability in sporadic endometrial cancers. Hum Mol Genet 8: 661–666
Glaab WE, Hill RB, Skopek TR (2001) Suppression of spontaneous and hydrogen peroxideinduced mutagenesis by the antioxidant ascorbate in mismatch repair-deficient human colon cancer cells. Carcinogenesis 22: 1709–1713
Ekbom A, Helmick C, Zack M, Adami HO (1990) Ulcerative colitis and colorectal cancer. A population-based study. N Engl J Med 323: 1228–1233
Willenbucher RF, Aust DE, Chang CG, Zelman SJ, Ferrell LD, Moore DH, 2nd, Waldman FM (1999) Genomic instability is an early event during the progression pathway of ulcerative-colitisrelated neoplasia. Am J Pathol 154: 1825–1830
Loeb KR, Loeb LA (1999) Genetic instability and the mutator phenotype. Studies in ulcerative colitis. Am J Pathol 154: 1621–1626
Fleisher AS, Esteller M, Tamura G, Rashid A, Stine OC, Yin J, Zou TT, Abraham JM, Kong D, Nishizuka S et al. (2001) Hypermethylation of the hMLH1 gene promoter is associated with microsatellite instability in early human gastric neoplasia. Oncogene 20: 329–335
Chang CL, Marra G, Chauhan DP, Ha HT, Chang DK, Ricciardiello L, Randolph A, Carethers JM, Boland CR (2002) Oxidative stress inactivates the human DNA mismatch repair system. Am J Physiol Cell Physiol 283: C148–154
Brentnall TA, Crispin DA, Bronner MP, Cherian SP, Hueffed M, Rabinovitch PS, Rubin CE, Haggitt RC, Boland CR (1996) Microsatellite instability in nonneoplastic mucosa from patients with chronic ulcerative colitis. Cancer Res 56: 1237–1240
Iwaya T, Maesawa C, Nishizuka S, Suzuki Y, Sakata K, Sato N, Ikeda K, Koeda K, Ogasawara S, Otsuka K et al. (1998) Infrequent frameshift mutations of polynucleotide repeats in multiple primary cancers affecting the esophagus and other organs. Genes Chromosomes Cancer 23: 317–322
Suzuki H, Harpaz N, Tarmin L, Yin J, Jiang HY, Bell JD, Hontanosas M, Groisman GM, Abraham JM, Meltzer SJ (1994) Microsatellite instability in ulcerative colitis-associated colorectal dysplasias and cancers. Cancer Res 54: 4841–4844
Perucho M (2003) Tumors with microsatellite instability: many mutations, targets and paradoxes. Oncogene 22: 2223–2225
Duval A, Hamelin R (2002) Genetic instability in human mismatch repair deficient cancers. Ann Genet 45: 71–75
Lin HY, Wang XF, Ng-Eaton E, Weinberg RA, Lodish HF (1992) Expression cloning of the TGF-beta type II receptor, a functional transmembrane serine/threonine kinase. Cell 68: 775–785
Markowitz S, Wang J, Myeroff L, Parsons R, Sun L, Lutterbaugh J, Fan RS, Zborowska E, Kinzler KW, Vogelstein B et al. (1995) Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science 268: 1336–1338
Tomita S, Miyazato H, Tamai O, Muto Y, Toda T (1999) Analyses of microsatellite instability and the transforming growth factor-beta receptor type II gene mutation in sporadic human gastrointestinal cancer. Cancer Genet Cytogenet 115: 23–27
Leung SY, Chan TL, Chung LP, Chan AS, Fan YW, Hung KN, Kwong WK, Ho JW, Yuen ST (1998) Microsatellite instability and mutation of DNA mismatch repair genes in gliomas. Am J Pathol 153: 1181–1188
Woerner SM, Benner A, Sutter C, Schiller M, Yuan YP, Keller G, Bork P, Doeberitz MK, Gebert JF (2003) Pathogenesis of DNA repair-deficient cancers: a statistical meta-analysis of putative Real Common Target genes. Oncogene 22: 2226–2235
Duval A, Hamelin R (2002) Mutations at coding repeat sequences in mismatch repair-deficient human cancers: toward a new concept of target genes for instability. Cancer Res 62: 2447–2454
Malkhosyan S, Rampino N, Yamamoto H, Perucho M (1996) Frameshift mutator mutations. Nature 382: 499–500
Author information
Authors and Affiliations
Rights and permissions
Copyright information
© 2006 Birkhäuser Verlag/Switzerland
About this chapter
Cite this chapter
Coleman, W.B., Tsongalis, G.J. (2006). Molecular mechanisms of human carcinogenesis. In: Cancer: Cell Structures, Carcinogens and Genomic Instability. Experientia Supplementum, vol 96. Birkhäuser Basel. https://doi.org/10.1007/3-7643-7378-4_14
Download citation
DOI: https://doi.org/10.1007/3-7643-7378-4_14
Publisher Name: Birkhäuser Basel
Print ISBN: 978-3-7643-7156-2
Online ISBN: 978-3-7643-7378-8
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)