Gastroenterology
Volume 135, Issue 4 , Pages 1079-1099 , October 2008

Genomic and Epigenetic Instability in Colorectal Cancer Pathogenesis

  • William M. Grady

      Affiliations

    • Department of Medicine, University of Washington Medical School, Seattle, Washington
    • Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
    • VA Puget Sound Healthcare System, Seattle, Washington
    • ,
  • John M. Carethers

      Affiliations

    • Department of Medicine, University of California, San Diego, San Diego, California
    • Rebecca and John Moores Comprehensive Cancer Center, University of California, San Diego, San Diego, California
    • VA San Diego Healthcare System, San Diego, California
    • Corresponding Author InformationAddress requests for reprints to: John M. Carethers, MD, Division of Gastroenterology, University of California, San Diego, UC303, MC 0063, 9500 Gilman Drive, La Jolla, California 92093-0063. fax: (858) 534-3337

Received 1 April 2008 ,Accepted 28 July 2008.

References 

  1. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70
  2. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61:759–767
  3. Lengauer C, Kinzler K, Vogelstein B. Genetic instabilities in human cancers. Nature. 1998;396:643–649
  4. Grady WM. Genomic instability and colon cancer. Cancer Metastasis Rev. 2004;23:11–27
  5. Gollin SM. Mechanisms leading to chromosomal instability. Semin Cancer Biol. 2005;15:33–42
  6. Boland CR, Koi M, Chang DK, et al. The biochemical basis of microsatellite instability and abnormal immunohistochemistry and clinical behavior in Lynch Syndrome: from bench to bedside. Familial Cancer. 2008;7:41–52
  7. Sieber OM, Lipton L, Crabtree M, et al. Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH. N Engl J Med. 2003;348:791–799
  8. Sampson JR, Dolwani S, Jones S, et al. Autosomal recessive colorectal adenomatous polyposis due to inherited mutations of MYH. Lancet. 2003;362:39–41
  9. Sieber OM, Heinimann K, Tomlinson IP. Genomic instability—the engine of tumorigenesis?. Nat Rev Cancer. 2003;3:701–708
  10. Cheadle JP, Sampson JR. Exposing the MYtH about base excision repair and human inherited disease. Hum Mol Genet. 2003;12:R159–R165
  11. De Jong AE, Morreau H, Van Puijenbroek M, et al. The role of mismatch repair gene defects in the development of adenomas in patients with HNPCC. Gastroenterology. 2004;126:42–48
  12. Kirchhoff T, Satagopan JM, Kauff ND, et al. Frequency of BRCA1 and BRCA2 mutations in unselected Ashkenazi Jewish patients with colorectal cancer. J Natl Cancer Inst. 2004;96:68–70
  13. Gruber SB, Ellis NA, Scott KK, et al. BLM heterozygosity and the risk of colorectal cancer. Science. 2002;297:2013
  14. Herrmann JL, Rastelli L, Burgess CE, et al. Implications of oncogenomics for cancer research and clinical oncology. Cancer J. 2001;7:40–51
  15. Cahill DP, Lengauer C, Yu J, et al. Mutations of mitotic checkpoint genes in human cancers. Nature. 1998;392:300–303
  16. Wang Z, Cummins JM, Shen D, et al. Three classes of genes mutated in colorectal cancers with chromosomal instability. Cancer Res. 2004;64:2998–3001
  17. Storchová Z, Breneman A, Cande J, et al. Genome-wide genetic analysis of polyploidy in yeast. Nature. 2006;443:541–547
  18. Grady WM, Markowitz SD. Genetic and epigenetic alterations in colon cancer. Annu Rev Genomics Hum Genet. 2002;3:101–128
  19. Carethers JM. The cellular and molecular pathogenesis of colorectal cancer. Gastroenterol Clin North Am. 1996;25:737–754
  20. Michor F, Iwasa Y, Lengauer C, et al. Dynamics of colorectal cancer. Semin Cancer Biol. 2005;15:484–493
  21. Rajagopalan H, Nowak MA, Vogelstein B, et al. The significance of unstable chromosomes in colorectal cancer. Nat Rev Cancer. 2003;3:695–701
  22. Muhua L, Adames NR, Murphy MD, et al. A cytokinesis checkpoint requiring the yeast homologue of an APC-binding protein. Nature. 1998;393:487–491
  23. Fodde R, Kuipers J, Rosenberg C, et al. Mutations in the APC tumour suppressor gene cause chromosomal instability. Nat Cell Biol. 2001;3:433–438
  24. Jallepalli PV, Lengauer C. Chromosome segregation and cancer: cutting through the mystery. Nat Rev Cancer. 2001;1:109–117
  25. Aaltonen LA, Peltomäki P, Mecklin JP, et al. Replication errors in benign and malignant tumors from hereditary nonpolyposis colorectal cancer patients. Cancer Res. 1994;54:1645–1648
  26. Grady WM, Rajput A, Myeroff L, et al. Mutation of the type II transforming growth factor-b receptor is coincident with the transformation of human colon adenomas to malignant carcinomas. Cancer Res. 1998;58:3101–3104
  27. Shih IM, Zhou W, Goodman SN, et al. Evidence that genetic instability occurs at an early stage of colorectal tumorigenesis. Cancer Res. 2001;61:818–822
  28. Stoler DL, Chen N, Basik M, et al. The onset and extent of genomic instability in sporadic colorectal tumor progression. Proc Natl Acad Sci U S A. 1999;96:15121–15126
  29. Nowak MA, Komarova NL, Sengupta A, et al. The role of chromosomal instability in tumor initiation. Proc Natl Acad Sci U S A. 2002;99:16226–16231
  30. Michor F, Iwasa Y, Nowak MA. Dynamics of cancer progression. Nat Rev Cancer. 2004;4:197–205
  31. Michor F, Iwasa Y, Vogelstein B, et al. Can chromosomal instability initiate tumorigenesis?. Semin Cancer Biol. 2005;15:43–49
  32. Bartkova J, Horejsí Z, Koed K, et al. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature. 2005;434:864–870
  33. Boland CR, Thibodeau SN, Hamilton SR, et al. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res. 1998;58:5248–5257
  34. Aaltonen LA, Peltomaki P, Leach FS, et al. Clues to the pathogenesis of familial colorectal cancer. Science. 1993;260:812–816
  35. Tsao JL, Yatabe Y, Salovaara R, et al. Genetic reconstruction of individual colorectal tumor histories. Proc Natl Acad Sci U S A. 2000;97:1236–1241
  36. Markowitz S, Wang J, Myeroff L, et al. Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science. 1995;268:1336–1338
  37. Jung B, Doctolero RT, Tajima A, et al. Loss of activin receptor type 2 protein expression in microsatellite unstable colon cancers. Gastroenterology. 2004;126:654–659
  38. Marra G, Boland CR. DNA repair and colorectal cancer. Gastroenterol Clin North Am. 1996;25:755–772
  39. Fishel R. Mismatch repair, molecular switches, and signal transduction. Genes Dev. 1998;12:2096–2101
  40. Hare JT, Taylor JH. One role for DNA methylation in vertebrate cells is strand discrimination in mismatch repair. Proc Natl Acad Sci U S A. 1985;82:7350–7354
  41. Thomas DC, Roberts JD, Kunkel TA. Heteroduplex repair in extracts of human HeLa cells. J Biol Chem. 1990;266:3744–3751
  42. Fishel R, Ewel A, Lescoe MK. Purified human MSH2 protein binds to DNA containing mismatched nucleotides. Cancer Res. 1994;54:5539–5542
  43. Leach FS, Nicolaides NC, Papadopoulos N, et al. Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell. 1993;75:1215–1225
  44. Fishel R, Lescoe MK, Rao MRS, et al. The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell. 1993;75:1027–1038
  45. Papadopoulos N, Nicolaides NC, Wei Y-F, et al. Mutation of a mutL homolog in hereditary colon cancer. Science. 1994;263:1625–1629
  46. Bronner CE, Baker SM, Morrison PT, et al. Mutation in the DNA mismatch repair homologue hMLH1 is associated with hereditary non-polyposis colon cancer. Nature. 1994;368:258–261
  47. Akiyama Y, Sato H, Yamada T, et al. Germ-line mutation of the hMSH6/GTBP gene in an atypical hereditary nonpolyposis colorectal cancer kindred. Cancer Res. 1997;57:3920–3923
  48. Wijnen J, de Leeuw W, Vasen H, et al. Familial endometrial cancer in female carriers of MSH6 germline mutations. Nat Genet. 1999;23:142–144
  49. Kolodner RD, Tytell JD, Schmeits J, et al. Germline msh6 mutations in colorectal cancer families. Cancer Res. 1999;59:5068–5074
  50. Nicolaides NC, Papadopoulos N, Liu B, et al. Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. Nature. 1994;371:75–80
  51. Chang DK, Ricciardiello L, Goel A, et al. Steady-state regulation of the human DNA mismatch repair system. J Biol Chem. 2000;275:18424–18431
  52. Kane MF, Loda M, Gaida GM, et al. 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. 1997;57:808–811
  53. Herman JG, Umar A, Polyak K. Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci U S A. 1998;95:6870–6875
  54. Veigl ML, Kasturi L, Olechnowicz J, et al. Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers. Proc Natl Acad Sci U S A. 1998;95:8698–8702
  55. Hemminki A, Peltomaki P, Mecklin J-K. Loss of the wild type MLH1 gene is a feature of hereditary nonpolyposis colorectal cancer. Nat Genet. 1994;8:405–410
  56. Drummond JT, Li G-M, Longley MJ, et al. Isolation of an hMSH2-p160 heterodimer that restores DNA mismatch repair to tumor cells. Science. 1995;268:1909
  57. Palombo F, Gallinari P, Iaccarino I, et al. GTBP, a 160-kilodalton protein essential for mismatch-binding activity in human cells. Science. 1995;268:1912–1914
  58. Papadopoulos N, Nicolaides NC, Liu B, et al. Mutations ofGTBP in genetically unstable cells. Science. 1995;268:1915–1917
  59. Fishel R, Ewel A, Lescoe MK. Purified human MSH2 protein binds to DNA containing mismatched nucleotides. Cancer Res. 1994;54:5539–5542
  60. Palombo F, Iaccarino I, Nakajima E, et al. hMutSbeta, a heterodimer of hMSH2 and hMSH3, binds to insertion/deletion loops in DNA. Curr Biol. 1996;6:1181–1184
  61. Genschel J, Littman SJ, Drummond JT, et al. Isolation of MutSb from human cells and comparison of the mismatch repair specificities of MutSb and MutSa. J Biol Chem. 1998;273:19895–19901
  62. McCulloch SD, Gu L, Li GM. Bi-directional processing of DNA loops by mismatch repair-dependent and -independent pathways in human cells. J Biol Chem. 2003;278:3891–3896
  63. Littman SJ, Fang WH, Modrich P. Repair of large insertion/deletion heterologies in human nuclear extracts is directed by a 5' single-strand break and is independent of the mismatch repair system. J Biol Chem. 1999;274:7474–7481
  64. Gradia S, Subramanian D, Wilson T, et al. hMSH2-hMSH6 forms a hydrolysis-independent sliding clamp on mismatched DNA. Mol Cell. 1999;3:255–261
  65. Gradia S, Acharya S, Fishel R. The human mismatch recognition complex hMSH2-hMSH6 functions as a novel molecular switch. Cell. 1997;91:995–1005
  66. Kunkel TA, Erie DA. DNA mismatch repair. Annu Rev Biochem. 2005;74:681–710
  67. Modrich P, Lahue R. Mismatch repair in replication fidelity, genetic recombination, and cancer biology. Annu Rev Biochem. 1996;65:101–133
  68. Schmutte C, Marinescu RC, Sadoff MM, et al. Human exonuclease I interacts with the mismatch repair protein hMSH2. Cancer Res. 1998;58:4537–4542
  69. Genschel J, Modrich P. Mechanism of 5'-directed excision in human mismatch repair. Mol Cell. 2003;12:1077–1086
  70. Dzantiev L, Constantin N, Genschel J, et al. A defined huamn system that supports bidirectional mismatch-provoked excision. Mol Cell. 2004;15:31–41
  71. Longley MJ, Pierce AJ, Modrich P. DNA polymerase delta is required for human mismatch repair in vitro. J Biol Chem. 1997;272:10917–10921
  72. Umar A, Buermeyer AB, Simon JA, et al. Requirement for PCNA in DNA mismatch repair at a step preceding DNA resynthesis. Cell. 1996;87:65–73
  73. Zhang Y, Yuan F, Presnell SR, et al. Reconstitution of 5'-directed human mismatch repair in a purified system. Cell. 2005;122:693–705
  74. Clark AB, Valle F, Drotschmann K, et al. Functional interaction of proliferating cell nuclar antigen with MSH2-MSH6 and MSH2-MSH3 complexes. J Biol Chem. 2000;275:36498–36501
  75. Flores-Rozas H, Clark D, Kolodner RD. Proliferating cell nuclear antigen and Msh2p-Msh6p interact to form an active mispair recognition complex. Nat Genet. 2000;26:375–378
  76. Kleezkowska HE, Marra G, Lettieri T, et al. hMSH3 and hMSH6 interact with PCNA and colocalize with it to replication foci. Genes Dev. 2001;15:724–736
  77. Kadyrov FA, Dzantiev L, Constantin N, et al. Endonucleolic function of MutLalpha in human mismatch repair. Cell. 2006;126:297–308
  78. Ramilo C, Gu L, Guo S, et al. Partial reconstitution of human DNA mismatch repair in vitro: characterization of the role of human replication protein A. Mol Cell Biol. 2002;22:2037–2046
  79. Guo S, Zhang Y, Yuan F, et al. Regulation of replication protein A functions in mismatch repair by phosphorylation. J Biol Chem. 2006;281:21607–21616
  80. Yan F, Gu L, Guo S, Wang C, et al. Evidence for involvement of HMGB1 protein in human DNA mismatch repair. J Biol Chem. 2004;279:20935–20940
  81. Parsons R, Myeroff LL, Liu B, et al. Microsatellite instability and mutations of the transforming growth factor beta type II receptor gene in colorectal cancer. Cancer Res. 1995;55:5548–5550
  82. Souza RF, Appel R, Yin J, et al. Microsatellite instability in the insulin-like growth factor II receptor gene in gastrointestinal tumours. Nat Genet. 1996;14:255–257
  83. Rampino N, Yamamoto H, Ionov Y, et al. Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype. Science. 1997;275:967–969
  84. Yamamoto H, Sawai H, Perucho M. Frameshift somatic mutations in gastrointestinal cancer of the microsatellite mutator phenotype. Cancer Res. 1997;57:4420–4426
  85. Yagi OK, Yoshimitsu A, Nomizu T, et al. Proapoptotic gene BAX is frequently mutated in hereditary nonpolyposis colorectal cancers but not in adenomas. Gastroenterology. 1998;114:268–274
  86. Watanabe T, Wu TT, Catalano PJ, et al. Molecular predictors of survival after adjuvant chemotherapy for colon cancer. N Engl J Med. 2001;344:1196–1206
  87. Malkhosyan S, Rampino N, Yamamoto H, et al. Frameshift mutator mutations. Nature. 1996;382:499–500
  88. Mori Y, Yin J, Rashid A, et al. Instabilotyping: comprehensive identification of frameshift mutations caused by coding region microsatellite instability. Cancer Res. 2001;61:6046–6049
  89. Jung B, Smith EJ, Doctolero RT, et al. Influence of target gene mutations on survival, stage and histology in sporadic microsatellite unstable colon cancers. Int J Cancer. 2006;118:2509–2513
  90. Jung BH, Beck SE, Cabral J, et al. Activin type 2 receptor restoration in MSI-H colon cancer suppresses growth and enhances migration with activin. Gastroenterology. 2007;132:633–644
  91. Deng G, Bell I, Crawley S, et al. BRAF mutation is frequently present in sporadic colorectal cancer with methylated hMLH1, but not in hereditary nonpolyposis colorectal cancer. Clin Cancer Res. 2004;10:191–195
  92. Ionov Y, Peinado MA, Malkhosyan S, et al. Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature. 1993;363:558–561
  93. Thibodeau SN, Bren G, Schaid D. Microsatellite instability in cancer of the proximal colon. Science. 1993;260:816–819
  94. Popat S, Hubner R, Houlston RS. Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol. 2005;23:609–618
  95. Schwitalle Y, Kloor M, Eiermann S, et al. Immune response against frameshift-induced neopeptides in HNPCC patients and healthy HNPCC mutation carriers. Gastroenterology. 2008;134:988–997
  96. Gryfe R, Kim H, Hsieh ET, et al. Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med. 2000;342:69–77
  97. Walther A, Houlston R, Tomlinson I. Association between chromosomal instability and prognosis in colorectal cancer: a meta-analysis. Gut. 2008;57:941–950
  98. Carethers JM, Hawn MT, Chauhan DP, et al. Competency in mismatch repair prohibits clonal expansion of cancer cells treated with N-methyl-N'-nitro-N-nitrosoguanidine. J Clin Invest. 1996;98:199–206
  99. Hawn MT, Umar A, Carethers JM, et al. Evidence for a connection between the mismatch repair system and the G2 cell cycle checkpoint. Cancer Res. 1995;55:3721–3725
  100. Fink D, Nebel S, Aebi S, et al. The role of DNA mismatch repair in platinum drug resistance. Cancer Res. 1996;56:4881–4886
  101. Papouli E, Cejka P, Jiricny J. Dependence of the cytotoxicity of DNA-damaging agents on the mismatch repair status of human cells. Cancer Res. 2004;64:3391–3394
  102. Carethers JM, Chauhan DP, Fink D, et al. Mismatch repair proficiency and in vitro response to 5-fluorouracil. Gastroenterology. 1999;117:123–131
  103. Tajima A, Hess MT, Cabrera BL, et al. The mismatch repair complex hMutSa recognizes 5-fluoruracil-modified DNA: implications for chemosensitivity and resistance. Gastroenterology. 2004;127:1678–1684
  104. Major PP, Egan E, Herrick D, et al. 5-Fluorouracil incorporation in DNA of human breast carcinoma cells. Cancer Res. 1982;42:3005–3009
  105. Arnold CN, Goel A, Boland CR. Role of hMLH1 promoter hypermethylation in drug resistance to 5-fluoruracil in colorectal cancer cell lines. Int J Cancer. 2003;106:66–73
  106. Meyers M, Wagner MW, Mazurek A, et al. DNA mismatch repair-dependent response to fluoropyrimidine-generated damage. J Biol Chem. 2005;280:5516–5526
  107. Carethers JM, Smith EJ, Behling CA, et al. Use of 5-fluorouracil and survival in patients with microsatellite unstable colorectal cancer. Gastroenterology. 2004;126:394–401
  108. Ribic CM, Sargent DJ, Moore MJ, et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med. 2003;349:247–257
  109. Jover R, Zapater P, Castells A, et al. Mismatch repair status in the prediction of benefit from adjuvant fluorouracil chemotherapy in colorectal cancer. Gut. 2006;55:848–855
  110. de Vos tot Nedervee Cappel WH, Neulenbeld HJ, Keibeuker JH, et al. Survival after adjuvant 5-FU treatment for stage III coon cancer in hereditary nonpolyposis colorectal cancer. In J Cancer. 2004;109:468–471
  111. Duckett DR, Bronstein SM, Taya Y, et al. hMutSa- and hMutLa-dependent phosphorylation of p53 in response to DNA methylator damage. Proc Natl Acad Sci U S A. 1999;96:12384–12388
  112. Stojic L, Mojas N, Cejka P, et al. Mismatch repair-dependent G2 checkpoint induced by low doses of SN1 type methylating agents requires the ATR kinase. Genes Dev. 2004;19:1331–1344
  113. Tibbetts RS, Brumbaugh KM, Williams JM, et al. A role for ATR in the DNA damage-induced phosphorylation of p53. Genes Dev. 1999;13:152–157
  114. Mailand N, Podtelejnikov AV, Groth A, et al. Regulation of G2/M events by Cdc25A through phosphorylation-dependent modulation of its stability. EMBO J. 2002;21:5911–5920
  115. Hickman MJ, Samson LD. Apoptotic signaling in response to a single type of DNA lesion, O6-methylguanine. Mol Cell. 2004;14:105–116
  116. Aguilera A, Gómez-González B. Genome instability: a mechanistic view of its causes and consequences. Nat Rev Genet. 2008;9:204–217
  117. Bardi G, Sukhikh T, Pandis N, et al. Karyotypic characterization of colorectal adenocarcinomas. Genes Chromosomes Cancer. 1995;12:97–109
  118. Tomlins SA, Laxman B, Dhanasekaran SM, et al. Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer. Nature. 2007;448:595–599
  119. Saha S, Bardelli A, Buckhaults P, et al. A phosphatase associated with metastasis of colorectal cancer. Science. 2001;294:1343–1346
  120. Bardelli A, Saha S, Sager JA, et al. PRL-3 expression in metastatic cancers. Clin Cancer Res. 2003;9:5607–5615
  121. Shin HJ, Baek KH, Jeon AH, et al. Dual roles of human BubR1, a mitotic checkpoint kinase, in the monitoring of chromosomal instability. Cancer Cell. 2003;4:483–497
  122. Lengauer C, Kinzler K, Vogelstein B. Genetic instability in colorectal cancers. Nature. 1997;386:623–627
  123. Weaver BA, Silk AD, Montagna C, et al. Aneuploidy acts both oncogenically and as a tumor suppressor. Cancer Cell. 2007;11:25–36
  124. Liu G, Parant JM, Lang G, et al. Chromosome stability, in the absence of apoptosis, is critical for suppression of tumorigenesis in Trp53 mutant mice. Nat Genet. 2004;36:63–68
  125. Yuen KW, Warren CD, Chen O, et al. Systematic genome instability screens in yeast and their potential relevance to cancer. Proc Natl Acad Sci U S A. 2007;104:3925–3930
  126. Sato N, Mizumoto K, Nakamura M, et al. Correlation between centrosome abnormalities and chromosomal instability in human pancreatic cancer cells. Cancer Genet Cytogenet. 2001;126:13–19
  127. Saunders WS, Shuster M, Huang X, et al. Chromosomal instability and cytoskeletal defects in oral cancer cells. Proc Natl Acad Sci U S A. 2000;97:303–308
  128. Wood LD, Parsons DW, Jones S, et al. The genomic landscapes of human breast and colorectal cancers. Science. 2007;318:1108–1113
  129. Chittenden TW, Howe EA, Culhane AC, et al. Functional classification analysis of somatically mutated genes in human breast and colorectal cancers. Genomics. 2008;91:508–511
  130. Eshleman JR, Casey G, Kochera ME, et al. Chromosome number and structure both are markedly stable in RER colorectal cancers and are not destabilized by mutation of p53. Oncogene. 1998;17:719–725
  131. Rajagopalan H, Lengauer C. Aneuploidy and cancer. Nature. 2004;432:338–341
  132. Sieber OM, Heinimann K, Gorman P, et al. Analysis of chromosomal instability in human colorectal adenomas with two mutational hits at APC. Proc Natl Acad Sci U S A. 2002;99:16910–16915
  133. Chow E, Thirlwell C, Macrae F, et al. Colorectal cancer and inherited mutations in base-excision repair. Lancet Oncol. 2004;5:600–606
  134. Al-Tassan N, Chmiel NH, Maynard J, et al. Inherited variants of MYH associated with somatic G:C → T:A mutations in colorectal tumors. Nat Genet. 2002;30:227–232
  135. Sieber OM, Lipton L, Crabtree M, et al. Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH. N Engl J Med. 2003;348:791–799
  136. Olinski R, Zastawny T, Budzbon J, et al. DNA base modifications in chromatin of human cancerous tissues. FEBS Lett. 1992;309:193–198
  137. Halford SE, Rowan AJ, Lipton L, et al. Germline mutations but not somatic changes at the MYH locus contribute to the pathogenesis of unselected colorectal cancers. Am J Pathol. 2003;162:1545–1548
  138. Cardoso J, Molenaar L, de Menezes RX, et al. Chromosomal instability in MYH- and APC-mutant adenomatous polyps. Cancer Res. 2006;66:2514–2519
  139. Amon A. The spindle checkpoint. Curr Opin Genet Dev. 1999;9:69–75
  140. Tang Z, Bharadwaj R, Li B, et al. Mad2-Independent inhibition of APCCdc20 by the mitotic checkpoint protein BubR1. Dev Cell. 2001;1:227–237
  141. Jallepalli PV, Waizenegger IC, Bunz F, et al. Securin is required for chromosomal stability in human cells. Cell. 2001;105:445–457
  142. Li Y, Benezra R. Identification of a human mitotic checkpoint gene: hsMAD2. Science. 1996;274:246–248
  143. Jin D, Spencer F, Jeang K. Human T cell leukemia virus type 1 oncoprotein Tax targets the human mitotic checkpoint protein MAD1. Cell. 1998;93:81–91
  144. Domínguez A, Ramos-Morales F, Romero F, et al. hpttg, a human homologue of rat pttg, is overexpressed in hematopoietic neoplasms (Evidence for a transcriptional activation function of hPTTG). Oncogene. 1998;17:2187–2193
  145. Sáez C, Japón MA, Ramos-Morales F, et al. hpttg is over-expressed in pituitary adenomas and other primary epithelial neoplasias. Oncogene. 1999;18:5473–5476
  146. Heaney AP, Singson R, McCabe CJ, et al. Expression of pituitary-tumour transforming gene in colorectal tumours. Lancet. 2000;355:716–719
  147. Michel LS, Liberal V, Chatterjee A, et al. MAD2 haplo-insufficiency causes premature anaphase and chromosome instability in mammalian cells. Nature. 2001;409:355–359
  148. Wang X, Cheung HW, Chun AC, et al. Mitotic checkpoint defects in human cancers and their implications to chemotherapy. Front Biosci. 2008;13:2103–2114
  149. Tomonaga T, Matsushita K, Yamaguchi S, et al. Overexpression and mistargeting of centromere protein-A in human primary colorectal cancer. Cancer Res. 2003;63:3511–3516
  150. Tomonaga T, Matsushita K, Ishibashi M, et al. Centromere protein H is up-regulated in primary human colorectal cancer and its overexpression induces aneuploidy. Cancer Res. 2005;65:4683–4689
  151. Tatsuka M, Katayama H, Ota T, et al. Multinuclearity and increased ploidy caused by overexpression of the aurora- and Ipl1-like midbody-associated protein mitotic kinase in human cancer cells. Cancer Res. 1998;58:4811–4816
  152. Adams RR, Eckley DM, Vagnarelli P, et al. Human INCENP colocalizes with the Aurora-B/AIRK2 kinase on chromosomes and is overexpressed in tumour cells. Chromosoma. 2001;110:65–74
  153. Doxsey S. The centrosome-a tiny organelle with big potential. Nat Genet. 1998;20:104–106
  154. Oikawa T, Okuda M, Ma Z, et al. Transcriptional control of BubR1 by p53 and suppression of centrosome amplification by BubR1. Mol Cell Biol. 2005;25:4046–4061
  155. D'Assoro AB, Lingle WL, Salisbury JL. Centrosome amplification and the development of cancer. Oncogene. 2002;21:6146–6153
  156. Brinkley BR. Managing the centrosome numbers game: from chaos to stability in cancer cell division. Trends Cell Biol. 2001;11:18–21
  157. Fukasawa K. Oncogenes and tumour suppressors take on centrosomes. Nat Rev Cancer. 2007;7:911–924
  158. Pihan GA, Purohit A, Wallace J, et al. Centrosome defects can account for cellular and genetic changes that characterize prostate cancer progression. Cancer Res. 2001;61:2212–2219
  159. Lingle WL, Barrett SL, Negron VC, et al. Centrosome amplification drives chromosomal instability in breast tumor development. Proc Natl Acad Sci U S A. 2002;99:1978–1983
  160. Zhou M, Sheldon S, Akel N, et al. Chromosomal aneuploidy in leukemic blast crisis: a potential source of error in interpretation of bone marrow engraftment analysis by VNTR amplification. Mol Diagn. 1999;4:153–157
  161. Zhou H, Kuang J, Zhong L, et al. Tumour amplified kinase STK15/BTAK induces centrosome amplification, aneuploidy and transformation. Nat Genet. 1998;20:189–193
  162. Sen S, Zhou H, White RA. A putative serine/threonine kinase encoding gene BTAK on chromosome 20q13 is amplified and overexpressed in human breast cancer cell lines. Oncogene. 1997;14:2195–2200
  163. Bischoff JR, Anderson L, Zhu Y, et al. A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers. EMBO J. 1998;17:3052–3065
  164. Glover DM, Leibowitz MH, McLean DA, et al. Mutations in aurora prevent centrosome separation leading to the formation of monopolar spindles. Cell. 1995;81:95–105
  165. Francisco L, Wang W, Chan CS. Type 1 protein phosphatase acts in opposition to IpL1 protein kinase in regulating yeast chromosome segregation. Mol Cell Biol. 1994;14:4731–4740
  166. Macmillan JC, Hudson JW, Bull S, et al. Comparative expression of the mitotic regulators SAK and PLK in colorectal cancer. Ann Surg Oncol. 2001;8:729–740
  167. Grisendi S, Mecucci C, Falini B, et al. Nucleophosmin and cancer. Nat Rev Cancer. 2006;6:493–505
  168. Czarnecka AM, Campanella C, Zummo G, et al. Mitochondrial chaperones in cancer: from molecular biology to clinical diagnostics. Cancer Biol Ther. 2006;5:714–720
  169. Ortega S, Malumbres M, Barbacid M. Cyclin D-dependent kinases, INK4 inhibitors and cancer. Biochim Biophys Acta. 2002;1602:73–87
  170. Myung K, Chen C, Kolodner RD. Multiple pathways cooperate in the suppression of genome instability in Saccharomyces cerevisiae. Nature. 2001;411:1073–1076
  171. Nyberg KA, Michelson RJ, Putnam CW, et al. Toward maintaining the genome: DNA Damage and Replication Checkpoints. Annu Rev Genet. 2002;36:617–656
  172. Kennedy RD, D'Andrea AD. DNA repair pathways in clinical practice: lessons from pediatric cancer susceptibility syndromes. J Clin Oncol. 2006;24:3799–3808
  173. Bao S, Chang M-S, Auclair D, et al. HRad17, a human homologue of the Schizosaccharomyces pombe checkpoint gene rad17, is overexpressed in colon carcinoma. Cancer Res. 1999;59:2023–2028
  174. Rotman G, Shiloh Y. ATM: from gene to function. Hum Mol Genet. 1998;7:1555–1563
  175. Smith L. Duplication of ATR inhibits MyoD, induces aneuploidy and eliminates radiation-induced G1 arrest. Nat Genet. 1998;19:39–46
  176. Zhang H, Tombline G, Weber B. BRCA1, BRCA2, and DNA damage response: collision or collusion. Cell. 1998;92:433–436
  177. Lane D. Awakening angels. Nature. 1998;394:616–617
  178. Rouse J, Jackson SP. Interfaces between the detection, signaling, and repair of DNA damage. Science. 2002;297:547–551
  179. Kolodner RD, Putnam CD, Myung K. Maintenance of genome stability in Saccharomyces cerevisiae. Science. 2002;297:552–557
  180. Rajagopalan H, Jallepalli PV, Rago C, et al. Inactivation of hCDC4 can cause chromosomal instability. Nature. 2004;428:77–81
  181. van der Heijden MS, Brody JR, Elghalbzouri-Maghrani E, et al. Does tumorigenesis select for or against mutations of the DNA repair-associated genes BRCA2 and MRE11?: considerations from somatic mutations in microsatellite unstable (MSI) gastrointestinal cancers. BMC Genet. 2006;7:3
  182. Loeb KR, Kostner H, Firpo E, et al. A mouse model for cyclin E-dependent genetic instability and tumorigenesis. Cancer Cell. 2005;8:35–47
  183. Perez-Losada J, Mao JH, Balmain A. Control of genomic instability and epithelial tumor development by the p53-Fbxw7/Cdc4 pathway. Cancer Res. 2005;65:6488–6492
  184. Yoon HS, Ghaleb AM, Nandan MO, et al. Krüppel-like factor 4 prevents centrosome amplification following gamma-irradiation-induced DNA damage. Oncogene. 2005;24:4017–4025
  185. Blasco MA. Telomeres and human disease: ageing, cancer and beyond. Nat Rev Genet. 2005;6:611–622
  186. Maser RS, DePinho RA. Connecting chromosomes, crisis, and cancer. Science. 2002;297:565–569
  187. Kim NW, Piatyszek MA, Prowse KR, et al. Specific association of human telomerase activity with immortal cells and cancer. Science. 1994;266:2011–2015
  188. Rudolph KL, Millard M, Bosenberg MW, et al. Telomere dysfunction and evolution of intestinal carcinoma in mice and humans. Nat Genet. 2001;28:155–159
  189. O'Hagan RC, Chang S, Maser RS, et al. Telomere dysfunction provokes regional amplification and deletion in cancer genomes. Cancer Cell. 2002;2:149–155
  190. Artandi SE, Chang S, Lee SL, et al. Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice. Nature. 2000;406:641–645
  191. Glick AB, Weinberg WC, Wu IH, et al. Transforming growth factor beta 1 suppresses genomic instability independent of a G1 arrest, p53, and Rb. Cancer Res. 1996;56:3645–3650
  192. Shadan FF, Cunningham C, Boland CR. JC virus: a biomarker for colorectal cancer?. Med Hypotheses. 2002;59:667–669
  193. Felsher DW, Bishop JM. Transient excess of MYC activity can elicit genomic instability and tumorigenesis. Proc Natl Acad Sci U S A. 1999;96:3940–3944
  194. Kondo Y, Issa JP. Epigenetic changes in colorectal cancer. Cancer Metastasis Rev. 2004;23:29–39
  195. Baylin SB, Herman JG. DNA hypermethylation in tumorigenesis: epigenetics joins genetics. Trends Genet. 2000;16:168–174
  196. Jones P, Laird P. Cancer epigenetics comes of age. Nat Genet. 1999;21:163–167
  197. Jubb AM, Bell SM, Quirke P. Methylation and colorectal cancer. J Pathol. 2001;195:111–134
  198. Baylin SB, Bestor TH. Altered methylation patterns in cancer cell genomes: cause or consequence. Cancer Cell. 2002;1:299–305
  199. Esteller M, Fraga MF, Guo M, et al. DNA methylation patterns in hereditary human cancers mimic sporadic tumorigenesis. Hum Mol Genet. 2001;10:3001–3007
  200. Chen WY, Zeng X, Carter MG, et al. Heterozygous disruption of Hic1 predisposes mice to a gender-dependent spectrum of malignant tumors. Nat Genet. 2003;33:197–202
  201. Herman JG, Merlo A, Mao L, et al. Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers. Cancer Res. 1995;55:4525–4530
  202. Toyota M, Ho C, Ahuja N, et al. Identification of differentially methylated sequences in colorectal cancer by methylated CpG island amplification. Cancer Res. 1999;59:2307–2312
  203. Toyota M, Ahuja N, Ohe-Toyota M, et al. CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci U S A. 1999;96:8681–8686
  204. Rashid A, Shen L, Morris JS, et al. CpG island methylation in colorectal adenomas. Am J Pathol. 2001;159:1129–1135
  205. Petko Z, Ghiassi M, Shuber A, et al. Aberrantly methylated CDKN2A, MGMT, and MLH1 in colon polyps and in fecal DNA from patients with colorectal polyps. Clin Cancer Res. 2005;11:1203–1209
  206. Li H, Myeroff L, Smiraglia D, et al. SLC5A8, a sodium transporter, is a tumor suppressor gene silenced by methylation in human colon aberrant crypt foci and cancers. Proc Natl Acad Sci U S A. 2003;100:8412–8417
  207. Chan AO, Broaddus RR, Houlihan PS, et al. CpG island methylation in aberrant crypt foci of the colorectum. Am J Pathol. 2002;160:1823–1830
  208. Moinova HR, Chen WD, Shen L, et al. HLTF gene silencing in human colon cancer. Proc Natl Acad Sci U S A. 2002;99:4562–4567
  209. Yamashita K, Dai T, Dai Y, et al. Genetics supersedes epigenetics in colon cancer phenotype. Cancer Cell. 2003;4:121–131
  210. Weisenberger DJ, Siegmund KD, Campan M, et al. CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet. 2006;38:787–793
  211. Shen L, Toyota M, Kondo Y, et al. Integrated genetic and epigenetic analysis identifies three different subclasses of colon cancer. Proc Natl Acad Sci U S A. 2007;104:18654–18659
  212. Samowitz WS, Albertsen H, Herrick J, et al. Evaluation of a large, population-based sample supports a CpG island methylator phenotype in colon cancer. Gastroenterology. 2005;129:837–845
  213. Ogino S, Kawasaki T, Kirkner GJ, et al. Molecular correlates with MGMT promoter methylation and silencing support CpG island methylator phenotype-low (CIMP-low) in colorectal cancer. Gut. 2007;56:1564–1571
  214. Deng G, Chen A, Pong E, et al. Methylation in hMLH1 promoter interferes with its binding to transcription factor CBF and inhibits gene expression. Oncogene. 2001;20:7120–7127
  215. Jenuwein T, Allis CD. Translating the histone code. Science. 2001;293:1074–1080
  216. Seligson DB, Horvath S, Shi T, et al. Global histone modification patterns predict risk of prostate cancer recurrence. Nature. 2005;435:1262–1266
  217. Fraga MF, Esteller M. Towards the human cancer epigenome: a first draft of histone modifications. Cell Cycle. 2005;4:1377–1381

 Supported by the US Public Health Service (CA11518 to W.M.G. and DK067287 and DK080506 to J.M.C.) and the VA Research Service (W.M.G. and J.M.C.).

PII: S0016-5085(08)01451-0

doi: 10.1053/j.gastro.2008.07.076

Gastroenterology
Volume 135, Issue 4 , Pages 1079-1099 , October 2008

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