The molecular genetics of colonic cancer

  • Leonard H. Augenlicht
Chapter
Part of the Cancer Treatment and Research book series (CTAR, volume 98)

Abstract

The molecular genetics of tumor initiation and progression is understood better for colonic cancer than for any other human solid tumor. While much remains to be learned regarding the mechanisms that contribute to the altered growth and metastatic properties of colonic epithelial cells, and in particular, how multiple alterations in gene structure and function interact in affecting cell and tissue homeostasis, the advances thus far are being moved into translational research and direct clinical application for diagnosis and prognosis of colon cancer, and new treatment modalities will certainly develop from these areas of investigation. Moreover, the approaches — both conceptual and methodological — that have driven the research in this disease now serve as models for understanding the fundamental process of tumorigenesis in other organs. Thus, the work in colon cancer has established a new paradigm regarding the causes and clinical progression of human cancer, and has already formulated new approaches to clinical management of populations at risk for disease development and of patients with established tumors. Therefore, an understanding of the molecular genetics of colonic tumorigenesis is essential for the practicing oncologist.

Keywords

Familial Adenomatous Polyposis Adenomatous Polyposis Coli Colonic Epithelial Cell Adenomatous Polyposis Coli Gene Adenomatous Polyposis Coli Protein 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
This is a preview of subscription content, log in to check access.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Murray MJ, Shilo B-Z, Shih C, Cowing D, Hsu HW, Weinberg RA. 1981. Three different human tumor cell lines contain different oncogenes. Cell 25:355–361.PubMedGoogle Scholar
  2. 2.
    Shih C, Padhy LC, Murray M, Weinberg 1981. Transforming genes of carcinomas and neuroblastomas introduced into mouse fibroblasts. Nature 290:261–264.PubMedGoogle Scholar
  3. 3.
    Vogelstein B, Fearon ER, Kern SE, Hamilton SR, Preisinger AC, Nakamura Y, White R. 1989. Allelotype of colorectal carcinomas. Science 244:207–211.PubMedGoogle Scholar
  4. 4.
    Pathek S, Kakati S. 1989. Cytogenetics of colorectal cancer. In Augenlicht LH (ed), Cell and Molecular Biology of Colon Cancer. CRC Press: Boca Raton, pp 139–163.Google Scholar
  5. 5.
    Sager R. 1986. Genetic suppression of tumor formation: a new frontier in cancer research. Cancer Res 46:1573–1580.PubMedGoogle Scholar
  6. 6.
    Knudson AG. 1985. Hereditary cancer, oncogenes and antioncogenes. Cancer Res 45:1437–1443.PubMedGoogle Scholar
  7. 7.
    Cavenee WK, Dryja TP, Phillips RA, Benedict WF, Godbout R, Gallie BL, Murphree AL, Strong LC, White RL. 1983. Expression of recessive alleles by chromosomal mechanisms in retinoblastoma. Nature 305:779–784.PubMedGoogle Scholar
  8. 8.
    Nowell PC. 1986. Mechanisms of tumor progression. Cancer Res 46:2203–2207.PubMedGoogle Scholar
  9. 9.
    Fearon ER, Vogelstein B. 1990. A genetic model for colorectal tumorigenesis. Cell 61:759–767.PubMedGoogle Scholar
  10. 10.
    Kern SE, Fearon ER, Tersmette KWF, Enterline JP, Leppert M, Nakamura Y, White R, Vogelstein B, Hamilton SR. 1989. Allelic loss in colorectal carcinoma. JAMA 261:3099–3103.PubMedGoogle Scholar
  11. 11.
    Augenlicht LH, Wahrman MZ, Halsey H, Anderson L, Taylor J, Lipkin M. 1987. Expression of cloned sequences in biopsies of human colonic tissue and in colonic carcinoma cells induced to differentiate in vitro. Cancer Res 47:6017–6021.PubMedGoogle Scholar
  12. 12.
    Augenlicht LH, Wadler S, Corner G, Richards C, Ryan L, Multani AS, Pathak S, Benson A, Haller D, Heerdt BG. Submitted. Low-level c-myc amplification in human colonic carcinoma cell lines and tumors: a frequent, p53 independent, mutation associated with improved outcome in a randomized multi-institutional trial.Google Scholar
  13. 13.
    Bussey HJR. 1975. Familial Polyposis Coli. Johns Hopkins University Press: Baltimore.Google Scholar
  14. 14.
    Bodmer WF, Bailey CJ, Bodmer J, Bussey HJR, Ellis A, Gorman P, Lucibello FC, Murday VA, Rider SH, Scambler P, Sheer D, Solomon E, Spurr NK. 1987. Localization of the gene for familial adenomatous polyposis on chromosome 5. Nature 328:614–616.PubMedGoogle Scholar
  15. 15.
    Leppert M, Dobbs M, Scambler P, O’Connell P, Nakamura Y, Stauffer D, Woodward S, Burt R, Hughes J, Gardner E, Lathrop M, Wasmuth J, Lalouel J-M, White R. 1987. The gene for familial polyposis coli maps to the long arm of chromosome 5. Science 238:1411–1413.PubMedGoogle Scholar
  16. 16.
    Joslyn G, Carlson M, Thliveris A, Albertsen H, Gelbert L, Samowitz W, Groden J, Stevens J, Spirio L, Robertson M, Sargeant L, Krapcho K, Wolff E, Burt R, Hughes JP, Warrington J, McPherson J, Wasmuth J, Le Paslier D, Abderrahim H, Cohen D, Leppert M, and White R. 1991. Identification of deletion mutations and three new genes at the familial polyposis locus. Cell 66:601–613.PubMedGoogle Scholar
  17. 17.
    Kinzler KW, Nilbert MC, Su L-K, Vogelstein B, Bryan TM, Levy DB, Smith KJ, Preisinger AC, Hedge P, McKechnie D, Finniear R, Markham A, Groffen J, Boguski MS, Altschul SF, Horii A, Ando H, Miyoshi Y, Miki Y, Nishisho I, Nakamura Y. 1991. Identification of FAP locus genes from chromosome 5q21. Science 253:661–665.PubMedGoogle Scholar
  18. 18.
    Groden J, Thilveris A, Samowitz W, Carlson M, Gelbert L, Albertson H, Joslyn G, Stevens J, Spiro L, Robertson M, Sargeant L, Krapcho K, Wolff E, Burt R, Hughes JP, Warrington J, McPherson J, Wasmuth J, Le Paslier D, Abderrahim H, Cohen D, Leppert M, White R. 1991. Identification and characterization of the familial adenomatous polyposis coli gene. Cell 66:589–600.PubMedGoogle Scholar
  19. 19.
    Nishisho I, Nakamura Y, Miyoshi Y, Miki Y, Ando H, Horii A, Koyama K, Utsunomiya J, Baba S, Hedge P, Markham A, Krush AJ, Petersen G, Hamilton SR, Nilbert MC, Levy DB, Bryan TM, Preisinger AC, Smith KJ, Su L-K, Kinzler KW, Vogelstein B. 1991. Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 253:665–669.PubMedGoogle Scholar
  20. 20.
    Powell SM, Zilz N, Beazer-Barclay Y, Bryan TM, Hamilton SR, Thibodeau SN, Vogelstein B, Kinzler K. 1992. APC mutations occur early during colorectal tumorigenesis. Nature 359:235–237.PubMedGoogle Scholar
  21. 21.
    Moser AR, Pitot HC, Dove WF. 1990. A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. Science 247:322–324.PubMedGoogle Scholar
  22. 22.
    Su L-K, Kinzler KW, Vogelstein B, Preisinger AC, Moser AP, Luongo C, Gould KA, Dove WF. 1992. Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science 256:668–670.PubMedGoogle Scholar
  23. 23.
    Fodde R, Edelmann W, Yang K, van Leeuwen C, Carlson C, Renault B, Breukel C, Alt E, Lipkin M, Khan PM, Kucherlapati R. 1994. A targeted chain-termination mutation in the mouse Apc gene results in multiple intestinal tumors. Proc Nat Acad Sci USA 91:8969–8973.PubMedGoogle Scholar
  24. 24.
    Miyoshi Y, Ando H, Nagase H, Nishisho I, Horii A, Miki Y, Mori T, Utsunomiya J, Baba S, Petersen G, Hamilton SR, Kinzler KW, Vogelstein B, Nakamura Y. 1992. Germ-line mutations of APC gene in 53 familial adenomatous polyposis patients. Proc Nat Acad Sci USA 89:4452–4456.PubMedGoogle Scholar
  25. 25.
    Powell SM, Petersen GM, Krush AJ, Booker S, Jen J, Giardiello FM, Hamilton SR, Vogelstein B, Kinzler K. 1993. Molecular diagnosis of familial adenomatous polyposis. N Engl J Med 329:1982–1987.PubMedGoogle Scholar
  26. 26.
    Miyaki M, Konishi M, Kikuchi-Yanoshita R, Enomoto M, Igari T, Tanaka K, Muraoka M, Takahashi H, Amada Y, Fukayama M, Maeda Y, Iwama T, Mishima Y, Mori T, Koike M. 1994. Characteristics of somatic mutation of the adenomatous polyposis coli gene in colorectal tumors. Cancer Res 54:3011–3020.PubMedGoogle Scholar
  27. 27.
    Okamoto M, Sasaki M, Sugio K, Sato C, Iwama T, Ikeuchi T, Tonomura A, Sasazuki T, Miyaki M. 1988. Loss of constitutional heterozygosity in colon carcinoma patients with familial polyposis coli. Nature 331:273–277.PubMedGoogle Scholar
  28. 28.
    Solomon E, Voss R, Hall V, Bodmer WF, Jass JR, Jeffreys AJ, Lucibello FC, Patel I, Rider SH. 1987. Chromosome 5 allele loss in human colorectal carcinomas. Nature 328:616–619.PubMedGoogle Scholar
  29. 29.
    Levy DB, Smith KJ, Beazer-Barclay Y, Hamilton SR, Vogelstein B, Kinzler KW. 1994. Inactivation of both APC alleles in human and mouse tumors. Cancer Res 54:5953–5958.PubMedGoogle Scholar
  30. 30.
    Luongo C, Moser AR, Geldhill S, Dove WF. 1994. Loss of Apc+ in intestinal adenomas from Min mice. Cancer Res 54:5947–5952.PubMedGoogle Scholar
  31. 31.
    Oshima M, Oshima H, Kobayashi M, Tsutsumi M, Taketo MM. 1995. Evidence against dominant negative mechanisms of intestinal polyp formation by Apc gene mutations. Cancer Res 55:2719–2722.PubMedGoogle Scholar
  32. 32.
    Spiro L, Otterud B, Stauffer D, Lynch H, Lynch P, Watson P, Lanspa S, Smyrk T, Cavalieri J, Howard L, Burt R, White R, Leppert M. 1993. Linkage of a variant or attenuated form of adenomatous polyposis coli to the adenomatous polyposis coli (APC) locus. Am J Hum Genet 51:92–100.Google Scholar
  33. 33.
    Spiro L, Olschwang S, Groden J, Robertson M, Samowitz W, Joslyn G, Gelbart L, Thliveris A, Carlson M, Otterud B, Lynch H, Watson P, Lynch P, Laurent-Puig P, Burt R, Hughes JP, Thomas G, Leppert M, White R. 1993. Alleles of the APC gene: an attenuated form of familial polyposis. Cell 75:951–957.Google Scholar
  34. 34.
    Smith KJ, Johnson KA, Bryan TM, Hill DE, Markowitz S, Willson JKV, Paraskeva C, Petersen GM, Hamilton SR, Vogelstein B, Kinzler KW. 1993. The APC gene product in normal and tumor cells. Proc Nat Acad Sci USA 90:2846–2850.PubMedGoogle Scholar
  35. 35.
    Rubinfeld B, Souza B, Albert I, Muller O, Chamberlain SH, Masiarz FR, Munemitsu S, Polakis P. 1993. Association of the APC gene product with bcatenin. Science 262:1731–1734.PubMedGoogle Scholar
  36. 36.
    Su L-K, Vogelstein B, Kinzler K. 1993. Association of the APC tumor suppressor protein with catenins. Science 262: 1734–1737.PubMedGoogle Scholar
  37. 37.
    Takeichi M. 1991. Cadherin cell adhesion receptors as a morphogenetic regulator. Science 251:1451–1455.PubMedGoogle Scholar
  38. 38.
    Smith KJ, Levy DB, Maupin P, Pollard TD, Vogelstein B, Kinzler KW. 1994. Wild-type but not mutant APC associates with the microtubule cytoskeleton. Cancer Res 54:3672–3675.PubMedGoogle Scholar
  39. 39.
    Munemitsu S, Souza B, Muller O, Albert I, Rubinfeld B, Polakis P. 1994. The APC gene product associates with microtubules in vivo and promotes their assemby in vitro. Cancer Res 54:3676–3681.PubMedGoogle Scholar
  40. 40.
    Moser AR, Dove WF, Roth KA, Gordon JI. 1992. The Min (multiple intestinal neoplasia) mutation: its effect on gut epithelial cell differentiation and interaction with a modifier system. J Cell Biol 116:1517–1526.PubMedGoogle Scholar
  41. 41.
    Dietrich WF, Lander ES, Smith JS, Moser AR, Gould KA, Luongo C, Borenstein N, Dove W. 1993. Genetic identification of Mom-1, a major modifier locus affecting Min-induced intestinal neoplasia in the mouse. Cell 75:631–639.PubMedGoogle Scholar
  42. 42.
    MacPhee M, Chepenik KP, Liddell RA, Nelson KK, Siracusa LD, Buchberg AM. 1995. The secretory phospholipase A2 gene is a candidate for the Mom 1 locus, a major modifier of Apc-min induced intestinal neoplasia. Cell 81:957–966.PubMedGoogle Scholar
  43. 43.
    Spirio LN, Kutchera W, Winstead MV, Pearson B, Kaplan C, Robertson M, Lawrence E, Burt RW, Tischfield JA, Leppert MF, Prescott SM, White R. 1996. Three secretory phospholipase A2 genes that map to human chromosome 1p35-36 are not mutated in individuals with attenuated adenomatous polyposis coli. Cancer Res 56:955–958.PubMedGoogle Scholar
  44. 44.
    Lipkin M, Yang K, Fan K, Newmark H, Edelmann W, Fodde R, Leung D, Kucherlapati R. 1995. Modulation of colonic lesions induced in Apc 1638 mice by a western-style diet. Proc Am Assoc Cancer Res 36:596.Google Scholar
  45. 45.
    Boolbol SK, Dannenberg AJ, Chadburn A, Martucci C, Guo XJ, Ramonetti JT, Abreu-Goris M, Newmark HL, Lipkin M, DeCosse JJ, Bertagnolli MM. 1996. Cyclooxygenase-2 overexpression and tumor formation are blocked by sulindac in a murine model of familial adenomatous polyposis. Cancer Res 56:2556–2560.PubMedGoogle Scholar
  46. 46.
    Kennedy AR, Beazer-Barclay Y, Kinzler KW, Newberne PM. 1996. Suppression of carcinogenesis in the intestines of Min mice by the soybean-derived Bowman-Birk inhibitor. Cancer Res 56:679–682.PubMedGoogle Scholar
  47. 47.
    Jacoby RF, Marshall DJ, Newton MA, Navakovic K, Tutsch K, Cole CE, Lubet RA, Kelloff GJ, Verman A, Moser AR, Dove WF. 1996. Chemoprevention of spontaneous intestinal adenomas in the Apc Min mouse model by the nonsteroidal anti-inflammatory drug Piroxicam. Cancer Res 56:710–714.PubMedGoogle Scholar
  48. 48.
    Labayle D, Fischer D, Vielh P, Drouhin F, Pariente A, Bories C, Duhamel O, Trousset M, Attali P. 1991. Sulindac causes regression of rectal polyps infamilial adenomatous polyposis. Gastroenterology 101:635–639.PubMedGoogle Scholar
  49. 49.
    Kinzler KW, Nilbert MC, Vogelstein B, Bryan TM, Levy DB, Smith KJ, Preisinger AC, Hamilton SR, Hedge P, Markham A, Carlson M, Joslyn G, Groden J, White R, Miki Y, Miyoshi Y, Nishisho I, Nakamura Y. 1991. Identification of a gene located at chromosome 5q21 that is mutated in colorectal cancer. Science 251:1366–1370.PubMedGoogle Scholar
  50. 50.
    Marra G, Boland CR. 1995. Hereditary nonpolyposis colorectal cancer: the syndrome, the genes, and historical perspectives. J Natl Cancer Inst 87:1114–1125.PubMedGoogle Scholar
  51. 51.
    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.PubMedGoogle Scholar
  52. 52.
    Aaltonen LA, Peltomaki P, Leach FS, Sistonen P, Pylkkanen L, Mecklin J-P, Jarvinen H, Powell SM, Jen J, Hamilton SR, Petersen GM, Kinzler KW, Vogelstein B, de la Chapelle A. 1993. Clues to the pathogenesis of familial colorectal cancer. Science 260:812–816.PubMedGoogle Scholar
  53. 53.
    Thibodeau SN, Bren G, Schaid D. 1993. Microsatellite instability in cancer of the proximal colon. Science 260:816–819.PubMedGoogle Scholar
  54. 54.
    Fishel R, Lescoe MK, Rao MRS, 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.PubMedGoogle Scholar
  55. 55.
    Leach FS, Nicolaides NC, Papadopoulos N, et al. 1993. Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 75:1215–1225.PubMedGoogle Scholar
  56. 56.
    Liu B, Parsons RE, Hamilton SR, Petersen GM, Lynch HT, Watson P, Markowitz S, Willson JKV, Green J, de la Chapelle A, Kinzler KW, Vogelstein B. 1994. hMSH2 mutations in hereditary nonpolyposis colorectal cancer kindreds. Cancer Res. 54:4590–4594.PubMedGoogle Scholar
  57. 57.
    Bronner CE, Baker SM, Morrison PT, Warren G, Smith LG, Lescoe MK, Kane M, Earabino C, Lipford J, Lindblom A, Tannergard P, Bollag RJ, Godwin AR, Ward DC, Nordenskjold M, Fishel R, Kolodner R, Liskay RM. 1994. Mutation in the DNA mismatch repair gene homologue hMLH 1 is associated with hereditary non-polyposis colon cancer. Nature 368:258–261.PubMedGoogle Scholar
  58. 58.
    Papadopoulos N, Nicolaides NC, Wei Y-F, et al. 1994. Mutation of a mutL homolog in hereditary colon cancer. Science, 263:1625–1629.PubMedGoogle Scholar
  59. 59.
    Kolodner RD, Hall NR, Lipford J, Kane MF, Morrison PT, Finan PJ, Burn J, Chapman P, Earabino C, Merchant E, Bishop DT. 1995. Structure of the human MLHl locus and analysis of a large hereditary nonpolyposis colorectal carcinoma kindred for mlh1 mutations. Cancer Res 55:242–248.PubMedGoogle Scholar
  60. 60.
    Tannergard P, Lipford JR, Kolodner R, Frodin JE, Nordenskjold M, Lindblom A. 1995. Mutation screening in the hMLH1 gene in Swedish hereditary nonpolyposis colon cancer families. Cancer Res 55:6092–6096.PubMedGoogle Scholar
  61. 61.
    Nicolaides NC, Papadopoulos N, Liu B, et al. 1994. Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. Nature 371:75–80.PubMedGoogle Scholar
  62. 62.
    Parsons R, Li G, Longley MJ, Fang W, Papadopoulos N, Jen J, de la Chapelle A, Kinzler KW, Vogelstein B, Modrich P. 1993. Hypermutability and mismatch repair deficiency in RER+ tumor cells. Cell 75:1227–1236.PubMedGoogle Scholar
  63. 63.
    Umar A, Boyer JC, Thomas DC, Nguyen DC, Risinger JI, Boyd J, Ionov Y, Perucho M, Kunkel TA. 1994. Defective mismatch repair in extracts of colorectal and endometrial cancer cell lines exhibiting microsatellite instability. J Biol Chem 269:14367–14370.PubMedGoogle Scholar
  64. 64.
    Boyer JC, Umar A, Risinger JI, Lipford JR, Kane M, Yin S, Barrett JC, Kolodner RD, Kunkel TA. 1995. Microsatellite instability, mismatch repair deficiency, and genetic defects in human cancer cell lines. Cancer Res 55:6063–6070.PubMedGoogle Scholar
  65. 65.
    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.PubMedGoogle Scholar
  66. 66.
    Aquilina G, Hess P, Branch P, MacGeoch C, Casciano I, Karran P, Bignami M. 1994. A mismatch recognition defect in colon carcinoma confers DNA microsatellite instability and a mutator phenotype. Proc Natl Acad Sci USA 91:8905–8909.PubMedGoogle Scholar
  67. 67.
    Eshleman JR, Lang EZ, Bowerfind GK, Parsons R, Vogelstein B, Willson JKV, Veigl ML, Sedwick WD, Markowitz SD. 1995. Increased mutation rate at the hprt locus accompanies microsatellite instability in colon cancer. Oncogene 10:33–37.PubMedGoogle Scholar
  68. 68.
    Loeb LA. 1991. Mutator phenotype may be required for multistage carcinogenesis. Cancer Res 51:3075–3079.PubMedGoogle Scholar
  69. 69.
    Loeb LA. 1994. Microsatellite Instability: marker of a mutator phenotype in cancer. Cancer Res 54:5059–5063.PubMedGoogle Scholar
  70. 70.
    Chen JS, Heerdt BG, Augenlicht LH. 1995. Presence and instability of repetitive elements in sequences the altered expression of which characterizes risk for colonic cancer. Cancer Res 55:174–180.PubMedGoogle Scholar
  71. 71.
    Pretlow TP, Roukhadze E, O’Riordan MA, Chan JC, Amini SB, Stellato TA. 1994. Carcinoembryonic antigen in human colonic aberrant crypt foci. Gastroenterology 107:1719–1725.PubMedGoogle Scholar
  72. 72.
    Bordonaro M, Augenlicht L. Submitted. The 3’ untranslated region of the carcinoembryonic antigen gene plays a minimal role in the regulation of gene expression.Google Scholar
  73. 73.
    Wu S, Theodorescu D, Kerbel RS, Willson JKV, Mulder KM, Humphrey LE, Brattain MG. 1992. TGF-B1is an autocrine-negative growth regulator of human colon carcinoma FET cells in vivo as revealed by transfection of an antisense expression vector. J Cell Biol 116:187–196.PubMedGoogle Scholar
  74. 74.
    Markowitz S, Wang J, Myeroff L, Parsons R, Sun L, Lutterbaugh J, Fan RS, Zborowska E, Kinzler KW, Vogelstein B, Brattain M, Willson JKV. 1995. Inactivation of the type II TGF-B receptor in colon cancer cells with microsatellite instability. Science 268:1336–1338.PubMedGoogle Scholar
  75. 75.
    Myeroff LL, Parsons R, Kim S-J, Hedrick L, Cho KR, Orth K, Mathis M, Kinzler KW, Lutterbaugh J, Park K, Bang Y-J, Lee HY, Park J-G, Lynch HT, Roberts, AB, Vogelstein B, Markowitz SD. 1995. A transforming growth factor B receptor type II gene mutation common in colon and gastric but rare in endometrial cancers with microsatellite instability. Cancer Res 55:5545–5547.PubMedGoogle Scholar
  76. 76.
    Parsons R, Myeroff LL, Liu B, Willson JKV, Markowitz SD, Kinzler KW, Vogelstein B. 1995. Microsatellite instability and mutations of the transforming growth factor B type II receptor gene in colorectal cancer. Cancer Res 55:5548–5550.PubMedGoogle Scholar
  77. 77.
    Schlegel J, Stumm G, Scherthan H, Bocker T, Zirngibl H, Ruschoff J, Hofstadter F. 1995. Comparative genomic in situ hybridization of colon carcinomas with replication error. Cancer Res 55:6002–6005.PubMedGoogle Scholar
  78. 78.
    Peltomaki P, Aaltonen LA, Sistonene P, Pylkkanen L, Mecklin J-P, Jarvinen H, Green JS, Jass JR, Weber JL, Leach FS, Petersen GM, Hamilton SR, de la Chapelle A, Vogelstein B. 1993. Genetic mapping of a locus predisposing to human colorectal cancer. Science 260:810–812.PubMedGoogle Scholar
  79. 79.
    Aaltonen LA, Peltomaki P, Mecklin J-P, Jarvinen H, Jass JR, Green JS, Lynch HT, Watson P, Tallqvist G, Juhola M, Sistonen P, Hamilton SR, Kinzler KW, Vogelstein B, de la Chapelle A. 1994. Replication errors in benign and malignant tumors from hereditary nonpolyposis colorectal cancer patients. Cancer Res 54:1645–1648.PubMedGoogle Scholar
  80. 80.
    Liu B, Parsons R, Rapadopoulos N, Nicolaides NC, Lynch HT, Watson P, Jass JR, Dunlop M, Wyllie A, Peltomaki P, de la Chapelle A, Hamilton SR, Vogelstein B, Kinzler K. 1996. Analysis of mismatch repair genes in hereditary non-polyposis colorectal cancer patients. Nature Med 2:169–174.PubMedGoogle Scholar
  81. 81.
    Lothe RA, Peltomaki P, Meling GI, Aaltonen LA, Nystrom-Lahti M, Pylkkanen L, Heimdal K, Andersen TI, Moller P, Rognum TO, Fossa SD, Haldorsen T, Langmark F, Brogger A, de la Chapelle A, Borresen A. 1993. Genomic instability in colorectal cancer: relationship to clinicopathological variables and family history. Cancer Res 53:5849–5852.PubMedGoogle Scholar
  82. 82.
    Liu B, Nicolaides NC, Markowitz S, Willson JKV, Parsons RE, Jen J, Papadopolous N, Peltomaki P, de la Chapelle A, Hamilton SR, Kinzler K, Vogelstein B. 1995. Mismatch repair gene defects in sporadic colorectal cancers with microsatellite instability. Nature Genet 9:48–55.PubMedGoogle Scholar
  83. 83.
    Augenlicht LH, Richards C, Corner G, Pretlow TP. 1996. Evidence for genomic instability in human colonic aberrant crypt foci. Oncogene 12:1767–1772.PubMedGoogle Scholar
  84. 84.
    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.PubMedGoogle Scholar
  85. 85.
    Parsons R, Li G-M, Longley M, Modrich P, Liu B, Berk T, Hamilton SR, Kinzler KW, Vogelstein B. 1995. Mismatch repair deficiency in phenotypically normal human cells. Science 268:738–740.PubMedGoogle Scholar
  86. 86.
    Bos JL, Fearon ER, Hamilton SR, Verlaan-de Vries M, van Boom JH, van der Eb AJ, Vogelstein B. 1987. Prevalence of ras gene mutations in human colorectal cancers. Nature 327:293–297.PubMedGoogle Scholar
  87. 87.
    Forrester K, Almoguera C, Han K, Grizzle WE, Perucho M. 1987. Detection of high incidence of K-ras oncogenes during human colon tumorigenesis. Nature 327:298–303.PubMedGoogle Scholar
  88. 88.
    Pretlow TP, Brasitus TA, Fulton NC, Cheyer C, Kaplan EL. 1993. K-ras mutations in putative preneoplastic lesions in human colon. J Natl Cancer Inst 85:2004–2007.PubMedGoogle Scholar
  89. 89.
    Pretlow TP. 1995. Aberrant crypt foci and K-ras mutations: earliest recognized players or innocent bystanders in colon carcinogenesis. Gastroenterology 108:600–603.PubMedGoogle Scholar
  90. 90.
    Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, Nakamura Y, White R, Smits AMM, Bos JL. 1988. Genetic alterations during colorectal-tumor development. N Engl J Med 319:525–532.PubMedGoogle Scholar
  91. 91.
    Barbacid M. 1987. ras Genes Annu Rev Biochem 56:779–827.Google Scholar
  92. 92.
    Stokoe D, Macdonald SG, Cadwallader K, Symons M, Hancock JF. 1994. Activation of raf as a result of recruitment to the plasma membrane. Science 264:1463–1466.PubMedGoogle Scholar
  93. 93.
    Leevers SJ, Paterson HF, Marshall CJ. 1994. Nature 369:411.PubMedGoogle Scholar
  94. 94.
    Hall A. 1994. A biochemical function for ras — at last. Science 264:1413–1414.PubMedGoogle Scholar
  95. 95.
    Tong L, de Vos AM, Milburn MV, Jancarik J, Noguchi S, Nishimura S, Miura K, Ohtsuka E, Kim S-H. 1989. Structural differences between a ras oncogene protein and the normal protein. Nature 337:90–93.PubMedGoogle Scholar
  96. 96.
    Trahey M, McCormick F. 1987. A cytoplasmic protein stimulates normal N-ras p21 GTPase, but does not affect oncogenic mutants. Science 238:542–545.PubMedGoogle Scholar
  97. 97.
    Hancock JF, Magee AI, Childs JE, Marshall CJ. 1989. All ras proteins are polyisoprenylated but only some are palmitoylated. Cell 57:1167–1177.PubMedGoogle Scholar
  98. 98.
    Schafer WR, Kim R, Sterne R, Thorner J, Kim S-H, Rine J. 1989. Genetic and pharmacological suppression of oncogenic mutations in ras genes of yeast and humans. Science 245:379–385.PubMedGoogle Scholar
  99. 99.
    Casey PJ, Solski PA, Der CJ, Buss JE. 1989. p21ras is modified by a farnesyl isoprenoid. Proc Natl Acad Sci USA 86:8323–8327.PubMedGoogle Scholar
  100. 100.
    Jackson JH, Cochrane CG, Bourne JR, Solski PA, Buss JE, Der CJ. 1990. Farnesol modification of kirsten-ras exon 4B protein is essential for transformation. Proc Natl Acad Sci USA 87:3042–3046.PubMedGoogle Scholar
  101. 101.
    Clarke S, Vogel JP, Deschenes RJ, Stock J. 1988. Post-translational modification of the H-ras oncogene protein: evidence for a third class of protein carboxyl methyltransferase. Proc Natl Acad Sci USA 85:4643–4647.PubMedGoogle Scholar
  102. 102.
    Gutierrez L, Magee AI, Marshall CJ, Hancock JF. 1989. Post-translational processing of p21ras is two-step and involves carboxyl-methylation and carboxy-terminal proteolysis. EMBO J 8:1093–1098.PubMedGoogle Scholar
  103. 103.
    McGrath JP, Capon DJ, Smith DH. Chen EY, Seeburg PH, Goeddel DV, Levinson AD. 1983. Structure and organization of the human Ki-ras proto-oncogene and a related processed pseudogene. Nature 304:501–506.PubMedGoogle Scholar
  104. 104.
    Fabricant M, Broitman SA. 1990. Evidence for deficiency of low density lipoprotein receptor on human colonic carcinoma cell lines. Cancer Res 50:632–636.PubMedGoogle Scholar
  105. 105.
    Sidransky D, Tokino T, Hamilton SR, Kinzler KW, Levin B, Frost P, Vogelstein B. 1992. Identification of ras oncogene mutations in the stool of patients with curable colorectal tumors. Science 256:102–105.PubMedGoogle Scholar
  106. 106.
    Sheiness D, Bishop JM. 1979. DNA and RNA from uninfected vertebrate cells contain nucleotide sequences related to the putative tranforming gene of avian myelocytomatosis virus. J Virol 31:514–521.PubMedGoogle Scholar
  107. 107.
    Watson D, Psallidopoulos M, Samuel K, Dalla-Favera R, Papas T. 1983. Nucleotide sequence analysis of human c-myc locus, chicken homologue, and myelocytomatosis virus MC29 tranforming gene reveals a highly conserved gene product. Proc Natl Acad Sci USA 80:3642–3645.PubMedGoogle Scholar
  108. 108.
    Zimmerman K, Alt FW. 1990. Expression and function of myc family genes. Crit Rev Oncogen 2:75–95.Google Scholar
  109. 109.
    Spencer CA, Groudine M. 1991. Control of c-myc regulation in normal and neoplastic cells. Adv Cancer Res 56:1–48.PubMedGoogle Scholar
  110. 110.
    Ramsay GM, Moscovici G, Moscovici C, Bishop JM. 1990. Neoplastic transformation and tumorigenesis by the human protooncogene MYC. Proc Natl Acad Sci USA 87:2102–2106.PubMedGoogle Scholar
  111. 111.
    Yander G, Halsey H, Kenna M, Augenlicht LH. 1985. Amplification and elevated expression of c-myc in a chemically induced mouse colon tumor. Cancer Res 45:4433–4438.PubMedGoogle Scholar
  112. 112.
    Erisman MD, Rothberg PG, Diehl RE, Morse CC, Spandorfer JM, Astrin SM. 1985. Deregulation of c-myc gene expression in human colon carcinoma is not accompanied by amplification or rearrangement of the gene. Mol Cell Biol 5:1969–1976.PubMedGoogle Scholar
  113. 113.
    Erisman MD, Scott JK, Watt RA, Astrin SM. 1988. The c-myc protein is constitutively expressed at elevated levels in colorectal carcinoma cell lines. Oncogene 2:367–378.PubMedGoogle Scholar
  114. 114.
    Sikora A, Chan S, Evan G, Gabra H, Markham N, Stewart J, Watson J. 1987. c-myc oncogene expression in colorectal cancer. Cancer 59:1289–1295.PubMedGoogle Scholar
  115. 115.
    Finely GG, Schulz NT, Hill SA, Geiser JR, Pipas JM, Meisler AI. 1989. Expression of the myc gene family in different stages of human colorectal cancer. Oncogene 4:963–971.Google Scholar
  116. 116.
    Shtivelman E, Bishop JM. 1989. The PVT gene frequently amplifies with MYC in tumor cells. Mol Cell Biol 9:1148–1154.PubMedGoogle Scholar
  117. 117.
    Evan GI, Wyllie AH, Gilbert CS, Littlewood TD, Land H, Brooks M, Waters CM, Penn LZ, Hancock DC. 1992. Induction of apoptosis in fibroblasts by c-myc protein. Cell 69:119–128.PubMedGoogle Scholar
  118. 118.
    Bedi A, Pasricha PJ, Akhtar AJ, Barber JP, Bedi GC, Giardiello FM, Zehnbauer BA, Hamilton SR, Jones RJ. 1995. Inhibition of apoptosis during development of colorectal cancer. Cancer Res 55:1811–1816.PubMedGoogle Scholar
  119. 119.
    Calabretta B, Kaczmarek L, Ming P-ML, Au F, Ming S-C. 1985. Expression of c-myc and other cell cycle-dependent genes in human colon neoplasia. Cancer Res 45:6000–6004.PubMedGoogle Scholar
  120. 120.
    Bello-Fernandez C, Packham G, Cleveland JL. 1993. The ornithine decarboxylase gene is a transcriptional target of c-myc. Proc Natl Acad Sci USA 90:7804–7808.PubMedGoogle Scholar
  121. 121.
    Rosenwald IB, Rhoads DB, Callanan LD, Isselbacher KJ, Schmidt EV. 1993. Increased expression of eukaryotic translation initiation factors eIF-4E and eIF-2a in response to growth induction by c-myc. Proc Natl Acad Sci USA 90:6175–6178.PubMedGoogle Scholar
  122. 122.
    Pogue-Geile K, Geiser JR, Shu M, Miller C, Wool IG, Meisler AI, Pipas JM. 1991. Riboso-mal protein genes are overexpressed in colorectal cancer: isolation of a cDNA clone encoding the human S3 ribosomal protein. Mol Cell Biol 11:3842–3849.PubMedGoogle Scholar
  123. 123.
    Barnard GF, Staniunas RJ, Bao S, Mafune K-I, Steele GD, Gollan JL, Chen LB. 1992. Increased expression of human ribosomal phosphoprotein PO messenger RNA in hepatocellular carcinoma and colon carcinoma. Cancer Res 52:3067–3072.PubMedGoogle Scholar
  124. 124.
    KeFung C, Jones DV, Frazier ML. 1992. Expression of an elongation factor 1 gamma-related sequence in adenocarcinomas of the colon. Gastroenterology 103:98–102.Google Scholar
  125. 125.
    Wong JM, Mafune K-I, Yow H, Rivers EN, Ravikumar TS, Steele GD, Chen LB. 1993. Ubiquitin-ribosomal protein S27a gene overexpressed in human colorectal carcinoma is an early growth response gene. Cancer Res 53:1916–1920.PubMedGoogle Scholar
  126. 126.
    Lazaris-Karatzas A, Montine KS, Sonenberg N. 1990. Malignant transformation by a eukaryotic initiation factor subunit that binds to mRNA 5’cap. Nature 345:544–547.PubMedGoogle Scholar
  127. 127.
    Lazaris-Karatzas A, Smith MR, Frederickson RM, Jaramillo, ML, Liu Y, Kung H, Sonenberg N. 1992. Ras mediates translation initiation factor 4E-induced malignant transformation. Genes Dev 6:1631–1642.PubMedGoogle Scholar
  128. 128.
    Rodriguez-Alfageme C, Stanbridge EJ, Astrin SM. 1992. Suppression of deregulated c-MYC expression in human colon carcinoma cells by chromosome 5 transfer. Proc Natl Acad Sci USA 89:1482–1486.PubMedGoogle Scholar
  129. 129.
    Melhem MF, Meisler AI, Finley GG, Bryce WH, Jones MO, Tribby II, Pipas JM, Koski RA. 1992. Distribution of cells expressing myc proteins in human colorectal epithelium, polyps, and malignant tumors. Cancer Res 52:5853–5864.PubMedGoogle Scholar
  130. 130.
    Jones PA. 1996. DNA methylation errors and cancer. Cancer Res 56:2463–2467.PubMedGoogle Scholar
  131. 131.
    Feinberg AP, Vogelstein B. 1983. Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature 301:89–92.PubMedGoogle Scholar
  132. 132.
    Goelz SE, Vogelstein B, Hamilton SR, Feinberg AP. 1985. Hypomethylation of DNA from benign and malignant human colon neoplasms. Science 228:187–190.PubMedGoogle Scholar
  133. 133.
    Feinberg AP, Gehrke CW, Kuo KC, Ehrlich M. 1988. Reduced genomic 5-methylcytosine content in human colonic neoplasia. Cancer Res 48:1159–1161.PubMedGoogle Scholar
  134. 134.
    El-Deiry WS, Nelkin BD, Celano P, Yen R-WC, Falco JP, Hamilton SR, Baylin SB. 1991. High expression of the DNA methyltransferase gene characterizes human neoplastic cells and progression stages of colon cancer. Proc Natl Acad Sci USA 88:3470–3474.PubMedGoogle Scholar
  135. 135.
    Silverman AL, Park J-G, Hamilton SR, Gazdar AF, Luk GD, Baylin SB. 1989. Abnormal methylation of the calcitonin gene in human colonic neoplasms. Cancer Res 49:3468–3473.PubMedGoogle Scholar
  136. 136.
    Makos M, Nelkin BD, Lerman MI, Latif F, Zbar B, Baylin SB. 1992. Distinct hypermethylation patterns occur at altered chromosome loci in human lung and colon cancer. Proc Natl Acad Sci USA 89:1929–1933.PubMedGoogle Scholar
  137. 137.
    Laird PW, Jackson-Grusby L, Fazell A, Dickinson SL, Jung WE, Li E, Weinberg RA, Jaenisch R. 1995. Suppression of intestinal neoplasia by DNA hypomethylation. Cell 81:197–205.PubMedGoogle Scholar
  138. 138.
    Baker SJ, Fearon ER, Nigro JM, Hamilton SR, Preisinger AC, Jessup JM, vanTuinen P, Ledbetter DH, Barker DF, Nakamura Y, White R, Vogelstein B. 1989. Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science 244:217–221.PubMedGoogle Scholar
  139. 139.
    Isobe M, Emanuel B, Givol D, Oren M, Croce CM. 1986. Localization of gene for human p53 tumour antigen to band 17p13. Nature 320:84–85.PubMedGoogle Scholar
  140. 140.
    Baker SJ, Preisinger AC, Jessup JM, Paraskeva C, Markowitz S, Willson JKV, 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.PubMedGoogle Scholar
  141. 141.
    Kikuchi-Yanoshita R, Konishi M, Ito S, Seki M, Tanaka K, Maeda Y, lino H, Fukayama M, Koike M, Mori T, Sakuraba H, Fukunari H, Iwama T, Miyaki M. 1992. Genetic changes of both p53 alleles associated with the conversion from colorectal adenoma to early carcinoma in familial adenomatous polyposis and non-familial adenomatous polyposis patients. Cancer Res 52:3965–3971.PubMedGoogle Scholar
  142. 142.
    Baker SJ, Markowitz S, Fearon ER, Willson JKV, Vogelstein B. 1990. Suppression of human colorectal carcinoma cell growth by wild-type p53. Science 249:912–915.PubMedGoogle Scholar
  143. 143.
    Nigro JM, Baker SJ, Preisinger AC, Jessup JM, Hostetter R, Cleary K, Bigner SH, Davidson N, Baylin S, Devilee P, Glover T, Collins FS, Weston A, Modali R, Harris CC, Vogelstein B. 1989. Mutations in the p53 gene occur in diverse human tumor types. Nature 342:705–708.PubMedGoogle Scholar
  144. 144.
    Hollstein M, Sidransky D, Vogelstein B, Harris CC. 1991. p53 mutations in human cancers. Science 253:49–53.PubMedGoogle Scholar
  145. 145.
    Vogelstein B, Kinzler KW. 1992. p53 function and dysfunction. Cell 70:523–526.PubMedGoogle Scholar
  146. 146.
    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.PubMedGoogle Scholar
  147. 147.
    Kinzler KW, Vogelstein B. 1996. Life (and death) in a malignant tumour. Nature 379:19–20.PubMedGoogle Scholar
  148. 148.
    Lane DP, Crawford LV. 1979. T antigen is bound to a host protein in SV40-transformed cells. Nature 278:261–263.PubMedGoogle Scholar
  149. 149.
    Linzer DIH, Levine AJ. 1979. Characterization of a 54K dalton cellular SV40 tumor antigen present in SV40-transformed cells and uninfected embryonal carcinoma cells. Cell 17:43–52.PubMedGoogle Scholar
  150. 150.
    Oren M, Levine AJ. 1983. Molecular cloning of a cDNA specific for the murine p53 cellular tumor antigen. Proc Natl Acad Sci USA 80:56–59.PubMedGoogle Scholar
  151. 151.
    Kern SE, Kinzler KW, Bruskin A, Jarosz D, Friedman P, Prives C, Vogelstein B. 1991. Identification of P53 as a sequence-specific DNA-binding protein. Science 252:1708–1711.PubMedGoogle Scholar
  152. 152.
    Fields S, Jang SK. 1990. Presence of a potent transcription activating sequence in the p53 protein. Science 249:1046–1049.PubMedGoogle Scholar
  153. 153.
    Raycroft L, Wu H, Lozano G. 1990. Transcriptional activation by wild-type but not transforming mutants of the p53 anti-oncogene. Science 249:1049–1051.PubMedGoogle Scholar
  154. 154.
    Ginsberg D, Mechta F, Yaniv M, Oren M. 1991. Wild-type p53 can down-modulate the activity of various promotors. Proc Natl Acad Sci USA 88:9979–9983.PubMedGoogle Scholar
  155. 155.
    Kern SE, Pietenpol JA, Thiagalingam S, Seymour A, Kinzler KW, Vogelstein B. 1992. Oncogenic forms of p53 inhibit p53-regulated gene expression. Science 256:827–830.PubMedGoogle Scholar
  156. 156.
    Farmer G, Bargonetti J, Zhu H, Friedman P, Prywes R, Prives C. 1992. Wild-type p53 activates transcription in vitro. Nature 358:83–86.PubMedGoogle Scholar
  157. 157.
    Shiio Y, Yamamoto T, Yamaguchi N. 1992. Negative regulation of Rb expression by the p53 gene product. Proc Natl Acad Sci USA 89:5206–5210.PubMedGoogle Scholar
  158. 158.
    Agoff SN, Hou J, Linzer DIH, Wu B. 1993. Regulation of the human hsp70 promotor by p53. Science 259:84–87.PubMedGoogle Scholar
  159. 159.
    Diller L, Kassel J, Nelson CE, Gryka MA, Litwak G, Gebhardt M, Bressac B, Ozturk M, Baker SJ, Vogelstein B, Friend SH. 1990. p53 functions as a cell cycle control protein in osteosarcomas. Mol Cell Biol 10:5772–5781.PubMedGoogle Scholar
  160. 160.
    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.PubMedGoogle Scholar
  161. 161.
    Kuerbitz SJ, Plunkett BS, Walsh WV, Kastan MB. 1992. Wild-type p53 is a cell cycle checkpoint determinant following irradiation. Proc Natl Acad Sci USA 89:7491–7495.PubMedGoogle Scholar
  162. 162.
    Hartwell L. 1992. Defects in a cell cycle checkpoint may be responsible for the genomic instability of cancer cells. Cell 71:543–546.PubMedGoogle Scholar
  163. 163.
    Graeber TG, Osmanian C, Jacks T, Housman DE, Koch CJ, Lowe SW, Giaccia AJ. 1996. Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature 379:88–91.PubMedGoogle Scholar
  164. 164.
    Livingstone LR, White A, Sprouse J, Livanos E, Jacks T, Tisty TD. 1992. Altered cell cycle arrest and gene amplification potential accompancy loss of wild-type p53. Cell 70:923–935.PubMedGoogle Scholar
  165. 165.
    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.PubMedGoogle Scholar
  166. 166.
    El-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer E, Kinzler KW, Vogelstein B. 1993. WAFl, a potential mediator of p53 tumor suppression. Cell 75:817–825.PubMedGoogle Scholar
  167. 167.
    Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ. 1993. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell 75:805–816.PubMedGoogle Scholar
  168. 168.
    Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R, Beach D. 1993. p21 is a universal inhibitor of cyclin kinases. Nature 366:701–707.PubMedGoogle Scholar
  169. 169.
    Zhang W, Grasso L, McClain CD, Gambel AM, Cha Y, Travali S, Deisseroth AB, Mercer WE. 1995. p53-independent induction of WAF1/CIP1 in human leukemia cells is correlated with growth arrest accompanying monocyte/macrophage differentiation. Cancer Res 55:668–674.PubMedGoogle Scholar
  170. 170.
    Parker SB, Eichele G, Zhang P, Rawls A, Sands AT, Bradley A, Olson EN, Harper JW, Elledge SJ. 1995. p53-independent expression of p21 Cipl in muscle and other terminally differentiating cells. Science 267:1024–1027.PubMedGoogle Scholar
  171. 171.
    El-Deiry WS, Tokino T, Waldman T, Oliner JD, Velculescu VE, Burrell M, Hill DE, Healy E, Rees JL, Hamilton SR, Kinzler KW, Vogelstein B. 1995. Topological control of p21 wafl/ cipl expression in normal and neoplastic tissues. Cancer Res 55:2910–2919.PubMedGoogle Scholar
  172. 172.
    Michieli P, Chedid M, Lin D, Pierce JH, Mercer WE, Givol D. 1994. Induction of WAFl/ CIP1 by a p53-independent pathway. Cancer Res 54:3391–3395.PubMedGoogle Scholar
  173. 173.
    El-Deiry WS, Harper JW, O’Connor PM, Velculescu VE, Canman CE, Jackman J, Pietenpol JA, Burrell M, Hill DE, Wang Y, Wiman KG, Mercer WE, Kastan MB, Kohn KW, Elledge SJ, Kinzler KW, Vogelstein B. 1994. WAF1/CIP1 is induced in p53-mediated Gl arrest and apoptosis. Cancer Res 54:1169–1174.PubMedGoogle Scholar
  174. 174.
    Waldman T, Kinzler KW, Vogelstein B. 1995. p21 is necessary for the p53-mediated G1 arrest in human cancer cells. Cancer Res 55:5187–5190.PubMedGoogle Scholar
  175. 175.
    Waldman T, Lengauer C, Kinzler KW, Vogelstein B. 1996. Uncoupling of S phase and mitosis induced by anticancer agents in cells lacking p21. Nature 381:713–716.PubMedGoogle Scholar
  176. 176.
    Heerdt BG, Houston MA, Augenlicht LH. 1996. Mitochondrial function is a component of a pathway that commits colonic carcinoma cells to undergo short-chain fatty acid induced apoptosis.Google Scholar
  177. 177.
    Hamilton SR. 1992. Molecular genetic alterations as potential prognostic indicators in colorectal carcinoma. Cancer 69:1589–1591.PubMedGoogle Scholar
  178. 178.
    Jen J, Kim H, Piantadosi S, Liu Z-F, Levitt RC, Sistonen P, Kinzler K, Vogelstein B, Hamilton SR. 1994. Allelic loss of chromosome 18q and prognosis in colorectal cancer. N Engl J Med 331:213–221.PubMedGoogle Scholar
  179. 179.
    Fearon ER, Cho KR, Nigro JM, Kern SE, Simons JW, Ruppert JM, Hamilton SR, Preisinger AC, Thomas G, Kinzler KW, Vogelstein B. 1990. Identification of a chromosome 18q gene that is altered in colorectal cancers. Science 247:49–56.PubMedGoogle Scholar
  180. 180.
    Hedrick L, Cho KR, Fearon ER, Wu T-C, Kinzler KW, Vogelstein B. 1994. The DCC gene product in cellular differentiation and colorectal tumorigenesis. Genes Dev 8:1174–1183.PubMedGoogle Scholar
  181. 181.
    Reale MA, Gu G, Zafar AI, Getzenberg RH, Levine SM, Fearon ER. 1994. Expression and alternative splicing of the deleted in colorectal cancer (DCC) gene in normal and malignant tissues. Cancer Res 54:4493–4501.PubMedGoogle Scholar
  182. 182.
    Nigro JM, Cho KR, Fearon ER, Kern SE, Ruppert JM, Oliner JD, Kinzler KW, Vogelstein B. 1991. Scrambled exons. Cell 64:607–613.PubMedGoogle Scholar
  183. 183.
    Tanaka K, Oshimura M, Kikuchi R, Seki M, Hayashi T, Miyaki M. 1991. Suppression of tumorigenicity in human colon carcinoma cells by introduction of normal chromosome 5 or 18. Nature 349:340–342.PubMedGoogle Scholar
  184. 184.
    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.PubMedGoogle Scholar
  185. 185.
    Narayanan R, Lawlor KG, Schaapveld RQJ, Cho KR, Vogelstein B, Tran PB-V, Osborne MP, Telang NT. 1992. Antisense RNA to the putative tumor-suppressor gene DCC transforms Rat-1 fibroblasts. Oncogene 7:553–561.PubMedGoogle Scholar
  186. 186.
    Aruffo A, Stamenokvic I, Melnick M, Underhill CB, Seed B. 1990. CD44 is the principal cell surface receptor for hyaluronate. Cell 61:1303–1313.PubMedGoogle Scholar
  187. 187.
    Carter WG, Wayner EA. 1988. Characterization of the class III colagen receptor, a phospho-rylated, transmembrane glycoprotein expressed in nucleated human cells. J Biol Chem 263:4193–4201.PubMedGoogle Scholar
  188. 188.
    Jalkanen S, Jalkanen M. 1992. Lymphocyte CD44 binds the COOH-terminal heparin-binding domain of fibronectin. J Cell Biol 116:817–825.PubMedGoogle Scholar
  189. 189.
    Screaton GR, Bell MV, Jackson DG, Cornelis FB, Gerth U, Bell JI. 1992. Genomic structure of DNA encoding the lymphocyte homing receptor CD44 reveals at least 12 alternatively spliced exons. Proc Natl Acad Sci USA 89:12160–12164.PubMedGoogle Scholar
  190. 190.
    Heider KH, Hofmann M, Hors E, van den Berg F, Ponta H, Herrlich P, Pals ST. 1993. A human homologue of the rat metastasis-associated variant of CD44 is expressed in colorectal carcinomas and adenomatous polyps. J Cell Biol 120:227–233.PubMedGoogle Scholar
  191. 191.
    Lesley J, Hyman R, Kincade PW. 1993. CD44 and its interaction with extracellular matrix. Adv Immunol 54:271–335.PubMedGoogle Scholar
  192. 192.
    Matsumara Y, Turin D. 1992. Significance of CD44 gene products for cancer diagnosis and disease evaluation. Lancet 340:1053–1058.Google Scholar
  193. 193.
    Tanabe KK, Ellis LM, Saya H. 1993. Expression of CD44R1 adhesion molecule in colon carcinomas and metastases. Lancet 341:725–726.PubMedGoogle Scholar
  194. 194.
    Cooper DL, Dougherty GJ. 1995. To metastasize or not? Selection of CD44 splice sites. Nature Med 1:635–637.PubMedGoogle Scholar
  195. 195.
    Thompson J, Zimmermann W. 1988. The carcinoembryonic antigen gene family: structure, expression and evolution. Tumor Biol 9:63–83.Google Scholar
  196. 196.
    Gold P, Freedman SO. 1965. Specific carcinoembryonic antigens of the human digestive system. J Exp Med 122:467–481.PubMedGoogle Scholar
  197. 197.
    von Kleist S, Winkler J, Migule I, Bohm N. 1986. Carcinoembryonic antigen (CEA) expression in early embryogenesis: a study of the first trimester of gestation. Anticancer Res 6:1265–1272.Google Scholar
  198. 198.
    Nap M, Mollgard K, Burtin P, Fleuren GJ. 1988. Immunohistochemistry of carcinoembryonic antigen in the embryo, fetus and adult. Tumor Biol 9:145–153.Google Scholar
  199. 199.
    Huang JQ, Turbide C, Daniels E, Jothy S, Beauchemin N, 1990. Spatiotemporal expression of murine earcinoembryonic antigen (CEA) gene family members during mouse embryogen-esis. Development 110:573–588.PubMedGoogle Scholar
  200. 200.
    Beauchemin N, Benchimol S, Cournoyer D, Fuks A, Stanners CP. 1987. Isolation and characterization of full-length functional cDNA clones for human carcinoembryonic antigen. Mol Cell Biol 7:3221–3230.PubMedGoogle Scholar
  201. 201.
    Hefta SA, Hefta LJF, Lee TD, Paxton RJ, Shively JE. 1988. Carcinoembryonic antigen is anchored to membranes by covalent attachment to a glycosylphosphatidylinositol moiety: identification of the ethanolamine linkage site. Proc Natl Acad Sci USA 85:4648–4652.PubMedGoogle Scholar
  202. 202.
    Thompson J, Zimmermann W, Osthus-Bugat P, Schleussner C, Eades-Perner A-M, Barnert S, Von Kleist S, Willcocks T, Craig I, Tynan K, Olsen A, Mohrenweiser H. 1992. Long-range chromosomal mapping of the carcinoembryonic antigen (CEA) gene family cluster. Genomics 12:761–772.PubMedGoogle Scholar
  203. 203.
    Khan WN, Frangsmyr L, Teglund S, Israelsson A, Bremer K, Hammarstrom S. 1992. Identification of three new genes and estimation of the size of the carcinoembryonic antigen family. Genomics 14:384–390.PubMedGoogle Scholar
  204. 204.
    Oikawa S, Inuzuka C, Kuroki M, Matsuoka Y, Kosaki G, Nakazato H. 1989. Cell adhesion activity of non-specific cross-reacting antigen (NCA) and carcinoembryonic antigen (CEA) expressed on CHO cell surface: homophilic and heterophilic adhesion. Biochem Biophys Res Commun 164:39–45.PubMedGoogle Scholar
  205. 205.
    Benchimol S, Fuks A, Jothy S, Beauchemin N, Shirota K, Stanners CP. 1989. Carcinoembryonic antigen, a human tumor marker, functions as an intercellular adhesion molecule. Cell 57:327–334.PubMedGoogle Scholar
  206. 206.
    Ishii S, Steele G, Ford R, Paliotti G, Thomas P, Andrews C, Hansen HJ, Goldenberg DM, Jessup JM. 1994. Normal colonic epithelium adheres to carcinoembryonic antigen and type IV collagen. Gastroenterology 106:1242–1250.PubMedGoogle Scholar
  207. 207.
    Zhou H, Fuks A, Alcaraz G, Boiling T, Stanners CP. 1993. Homophilic adhesion between Ig superfamily carcinoembryonic antigen molecules involves double reciprocal bonds. J Cell Biol 122:951–960.PubMedGoogle Scholar
  208. 208.
    Zhou H, Stanner CP, Fuks A. 1993. Specificity of anti-carcinoembryonic antigen monoclonal antibodies and their effects on CEA-mediated adhesion. Cancer Res 53:3817–3822.PubMedGoogle Scholar
  209. 209.
    Cournoyer D, Beauchemin N, Boucher D, Benchimol S, Fuks A, Stanners CP. 1988. Transcription of genes of the carcinoembryonic antigen family in malignant and nonmalignant human tissues. Cancer Res 48:3153–3157.PubMedGoogle Scholar
  210. 210.
    Boucher D, Cournoyer D, Stanners CP, Fuks A. 1989. Studies on the control of gene expression of the carcinoembryonic antigen family in human tissue. Cancer Res 49:847–852.PubMedGoogle Scholar
  211. 211.
    Augenlicht L. 1994. Adhesion molecules, cellular differentiation, and colonic crypt architecture. Gastroenterology 107:1894–1898.PubMedGoogle Scholar
  212. 212.
    Augenlicht LH, Heerdt BG. 1994. Colonic carcinoma: a common tumor with multiple genomic abnormalities. In: Pretlow T, Pretlow T (ed), Biochemical and Molecular Aspects of Selected Cancers, vol 2. Academic Press: New York, pp 47–91.Google Scholar
  213. 213.
    Augenlicht LH, Taylor J, Anderson L, Lipkin M. 1991. Patterns of gene expression that characterize the colonic mucosa in patients at genetic risk for colonic cancer. Proc Natl Acad Sci USA 88:3286–3289.PubMedGoogle Scholar
  214. 214.
    Heerdt BG, Houston MA, Augenlicht LH. 1994. Potentiation by specific short-chain fatty acids of differentiation and apoptosis in human colonic carcinoma cell lines. Cancer Res 54:3288–3294.PubMedGoogle Scholar
  215. 215.
    Heerdt BG, Houston MA, Rediske JJ, Augenlicht LH. 1996. Steady-state levels of mitochondrial messenger RNA species characterize a predominant pathway culminating in apoptosis and shedding of HT29 human colonic carcinoma cells. Cell Growth Differ 7:101–106.PubMedGoogle Scholar
  216. 216.
    Augenlicht LH, Velcich A, Heerdt BG. 1995. Short chain fatty acids and molecular and cellular mechanisms of colonic cell differentiation and transformation. In American Institute of Cancer Research, (ed), Diet and Cancer: Molecular Mechanisms of Interactions, Plenum: New York.Google Scholar
  217. 217.
    Heerdt BG, Augenlicht LH. 1990. Absence of detectable deletions in the mitochondrial genome of human colon tumors. Cancer Commun 2:109–111.PubMedGoogle Scholar
  218. 218.
    Heerdt BG, Chen JS, Stewart LR, Augenlicht LH. 1994. Polymorphisms, but lack of mutations or instability, in the promotor region of the mitochondrial genome in human colonic tumors. Cancer Res 54:3912–3915.PubMedGoogle Scholar
  219. 219.
    Velcich A, Augenlicht LH. 1993. Regulated expression of an intestinal mucin gene in HT29 colonic carcinoma cells. J Biol Chem 268:13956–13961.PubMedGoogle Scholar
  220. 220.
    Velcich A, Palumbo L, Selleri L, Evans G, Augenlicht L. Submitted. Organization and regulatory aspects of the human MUC2 locus.Google Scholar
  221. 221.
    Derynk R, Gelbart WM, Harland RM, Heldin C-H, Kern SE, Massague J, Melton DA, Mlodzik M, Padgett RW, Roberts AB et al. 1996. Nomenclature: Vertebrate mediators of TFGB family signals. Cell 87:173.Google Scholar
  222. 222.
    Fazeli A, Dickinson SL, Hermiston ML, Tighe RV, Steen RG, Small CG, Stoeckli ET, Keino-Masu K, Masu M, Rayburn H, Simons J, Bronson RT, Gordon JI, Tessier-Lavigne M, Weinberg RA. 1997. Phenotype of mice lacking functional deleted in colorectal cancer (Dcc) gene. Nature 386:796–804.PubMedGoogle Scholar
  223. 223.
    Takaku K, Oshima M, Miyoshi H, Matsui M, Seidin MF, Taketo MM. 1998. Intestinal tumorigenesis in compound mutant mice of both Dpc4 (Smad4) and Apc genes. Cell 92:645–656.PubMedGoogle Scholar
  224. 224.
    Thiagalingam S, Lengauer C, Leach FS, Schutte M, Hahn SA, Overhauser J, Willson JKV, Markowitz S, Hamilton SR, Kern SE, Kinzler KW, Vogelstein B. Evaluation of candidate tumour suppressor genes on chromosome 18 in colorectal cancers. Nature Gen 13:343–346.Google Scholar

Copyright information

© Springer Science+Business Media New York 1998

Authors and Affiliations

  • Leonard H. Augenlicht

There are no affiliations available

Personalised recommendations