Molecular Diagnosis of Gastrointestinal Cancer

  • Wataru Yasui
  • Hiroshi Yokozaki
  • Eiichi Tahara


Multiple genetic alterations of oncogenes, tumor-suppressor genes, and DNA repair genes are involved in the conversion of normal cells to clinical cancers. These genetic alterations can be applied in a multistep mechanism of development and progression of gastrointestinal cancers, although common and distinct genetic changes are observed in esophageal, gastric, and colorectal carcinomas. Inactivation of the p53 gene, reactivation of telomerase, and anomalous CD44 expression are common events that serve as genetic markers for the differential diagnosis of cancer. Amplification of the cyclin D1 gene is preferentially found in esophageal cancer, whereas amplification of c-met is common in gastric cancer. The cyclin E gene amplification is frequently associated with both gastric and colorectal cancers. Deletion of the cyclin-dependent kinase inhibitor gene is often found in esophageal carcinoma cell lines. The scenario of multiple genetic alterations differs depending on the two histological types of gastric cancer, suggesting that they may have different genetic pathways. By applying these observations to routine clinical practice, we can facilitate and improve the differential diagnosis of cancer, obtain information of the grade of malignancy, foresee patient prognosis, identify patients at high risk for developing multiple cancers, and discover novel therapies for cancer. The molecular diagnosis of gastrointestinal cancers, which has been performed at Hiroshima City Medical Association Clinical Laboratory, may provide a new approach to cancer diagnosis for the twenty-first century. These advances raise a number of questions concerning the ethics of molecular diagnosis and treatment. The practical and ethical implications of identifying carriers of hereditary cancer should be considered in clinical and nonclinical contexts.


Gastric Cancer Familial Adenomatous Polyposis Esophageal Carcinoma Gastrointestinal Cancer Molecular Diagnosis 
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.


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  1. 1.
    Fearon ER, Vogelstein B (1990) A genetic model for colorectal tumorigenesis. Cell 61:759–767PubMedCrossRefGoogle Scholar
  2. 2.
    Tahara E (1993) Molecular mechanism of stomach carcinogenesis. J Cancer Res Clin Oncol 119:265–272PubMedCrossRefGoogle Scholar
  3. 3.
    Service RF (1994) Stalking the start of colon cancer. Science 263:1559–1560PubMedCrossRefGoogle Scholar
  4. 4.
    Tahara E, Semba S, Tahara H (1996) Molecular biological observation in gastric cancer. Semin Oncol 23:307–315PubMedGoogle Scholar
  5. 5.
    Hunter T, Pines J (1994) Cyclins and cancer II: cyclin D and CDK inhibitors come of age. Cell 79:573–582PubMedCrossRefGoogle Scholar
  6. 6.
    Sherr CJ (1994) G1 phase progression: cycling on cue. Cell 79:515–555CrossRefGoogle Scholar
  7. 7.
    Heichman KA, Roberts JM (1994) Rules to replicate by. Cell 79:557–562PubMedCrossRefGoogle Scholar
  8. 8.
    Karp JE, Broder S (1995) Molecular foundation of cancer: new targets for intervention. Nature Med 1:309–320PubMedCrossRefGoogle Scholar
  9. 9.
    Ruschoff J, Bocher T, Schlegel J, Stumm G, Hofstaedter F (1995) Microsatellite instability: new aspects in the carcinogenesis of colorectal carcinoma. Virchows Arch 426:215–222PubMedCrossRefGoogle Scholar
  10. 10.
    Liu B, Parsons R, Papadopoulos N, Nicolaides NC, Lynch HT, Watson P, Jass JR, Dunlop M, Wyllie A, Peltomaki P, de la Chapelle A, Hamilton SR, Vogelstein B, Kinzler KW (1996) Analysis of mismatch repair genes in hereditary nonpolyposis colorectal cancer patients. Nature Med 2:169–174PubMedCrossRefGoogle Scholar
  11. 11.
    Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL, Coviello GM, Wright WE, Weinrich SL, Shay JW (1994) Specific association of human telomerase activity with immortal cells and cancer. Science 266:2011–2015PubMedCrossRefGoogle Scholar
  12. 12.
    Tahara E (1995) Genetic alterations in human gastrointestinal cancers: the application to molecular diagnosis. Cancer 75S:1410–1417CrossRefGoogle Scholar
  13. 13.
    Tahara E, Kuniyasu H, Yasui W, Yokozaki H (1994) Gene alterations in intestinal metaplasia and gastric cancer. Eur J Gastroenterol Hepatol 6S:97–102Google Scholar
  14. 14.
    Semba S, Yokozaki H, Yamamoto S, Yasui W, Tahara E (1996) Microsatellite instability in precancerous lesions and adenocarcinomas of the stomach. Cancer 77/8S:1620–1627PubMedGoogle Scholar
  15. 15.
    Tahara E, Yasui W, Yokozaki H (1996) Abnormal growth factor network in neoplasia. In: Pusztai L, Lewis CE, Yap E (eds) Cell proliferation in cancer: regulatory mechanism of neoplastic cell growth. Oxford University Press, Oxford, pp 131–153Google Scholar
  16. 16.
    Yasui W, Ito H, Tahara E (1992) DNA analysis of archival material and its application to tumour pathology. In: Herrington CS, McGee JO’D (eds) Diagnostic molecular pathology, a practical approach. Oxford University Press, Oxford, pp 193–206Google Scholar
  17. 17.
    Yokozaki H, Tahara E (1995) PCR analysis of RNA. In: Levy ER, Herrington CS (eds) Nonisotopic methods in molecular biology, a practical approach. Oxford University Press, Oxford, pp 201–212Google Scholar
  18. 18.
    Borden EC, Waalen J, Liberati AM, Grignani F (1993) Molecular diagnosis and monitoring of leukemia and lymphoma. Leuk Res 17:1073–1078PubMedCrossRefGoogle Scholar
  19. 19.
    Herzog CE, Bates SE (1994) Molecular diagnosis of multidrug resistance. Cancer Treat Res 73:129–147PubMedCrossRefGoogle Scholar
  20. 20.
    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 the APC gene in 53 familial adenomatous polyposis patients. Proc Natl Acad Sci USA 89:4452–4456PubMedCrossRefGoogle Scholar
  21. 21.
    Takeguchi-Shirahama S, Koyama K, Miyauchi A, Wakasugi T, Oishi S, Takami H, Hikiji K, Nakamura Y (1995) Germline mutations of the RET proto-oncogene in eight Japanese patients with multiple endocrine neoplasia type 2A (MEN2A). Hum Genet 95:187–190Google Scholar
  22. 22.
    Horii A, Han H-J, 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 54:3373–3375PubMedGoogle Scholar
  23. 23.
    Yasui W, Tahara E (1993) Methods of oncology: molecular biology. In: Burghardt E, Webb MJ, Monaghan JM, Kindermann G (eds) Surgical gynecological oncology. Georg Theime Verlag, Stuttgart, pp 40–44Google Scholar
  24. 24.
    Lu S-H, Hsieh L-L, Luo F-C, Weinstein IB (1988) Amplification of the EGF receptor and c-myc genes in human esophageal cancers. Int J Cancer 42:502–505PubMedCrossRefGoogle Scholar
  25. 25.
    Yoshida K, Kuniyasu H, Yasui W, Kitadai Y, Toge T, Tahara E (1993) Expression of growth factors and their receptors in human esophageal carcinomas: regulation of expression by epidermal growth factor and transforming growth factor a. J Cancer Res Clin Oncol 119:401–407PubMedCrossRefGoogle Scholar
  26. 26.
    Jiang Wm Kahn SM, Tomita N, Zhang Y-J, Lu S-H, Weinstein IB (1992) Amplification and expression of the human cyclin D gene in esophageal cancer. Cancer Res 52:2980–2983PubMedGoogle Scholar
  27. 27.
    Yoshida K, Kawami H, Kuniyasu H, Nishiyama M, Yasui W, Hirai T, Toge T, Tahara E (1994) Coamplification of cyclin D, hst -1 and int -2 genes is a good biological marker of high malignancy for human esophageal carcinomas. Oncol Rep 1:493–496PubMedGoogle Scholar
  28. 28.
    Huang Y, Boynton RF, Blount PL, Silverstein RJ, Yin J, Tong Y, McDaniel TK, Newkirk C, Resau JH, Sridhara R, Reid BJ, Meltzer SJ (1992) Loss of heterozygosity involves multiple tumor suppressor genes in human esophageal cancers. Cancer Res 52:6525–6530PubMedGoogle Scholar
  29. 29.
    Aoki T, Mori T, XiQun D, Nishihira T, Matsubara T, Nakamura Y (1994) Allelotype study of esophageal carcinoma. Gene Chromosom Cancer 10:177–182CrossRefGoogle Scholar
  30. 30.
    Hollstein MC, Metcalf RA, Welsh JA, Montesano R, Harris CC (1990) Frequent mutation of the p53 gene in human esophageal cancer. Proc Natl Acad Sci USA 87:9958–9961PubMedCrossRefGoogle Scholar
  31. 31.
    Mori T, Miura K, Aoki T, Nishihira T, Mori S, Nakamura Y (1994) Frequent somatic mutation of the MTS1/CDK4I (multiple tumor suppressor/cyclin-dependent kinase 4 inhibitor) gene in esophageal squamous carcinoma. Cancer Res 54:3396–3397PubMedGoogle Scholar
  32. 32.
    Hollstein M, Sidransky D, Vogelstein B, Harris CC (1991) p53 mutations in human cancers. Science 253:49–53PubMedCrossRefGoogle Scholar
  33. 33.
    El-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer E, Kinzler KW, Vogelstein B (1993) WAF1, a potential mediator of p53 tumor suppression. Cell 75:817–825PubMedCrossRefGoogle Scholar
  34. 34.
    Smith ML, Chen I-T, Zhan Q, Bae I, Chen C-Y, Gilmer TM, Kastan MB, O’Connor PM, Fornace AJ Jr (1994) Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen. Science 266:1376–1380PubMedCrossRefGoogle Scholar
  35. 35.
    Miyashita T, Reed JC (1995) Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 80:293–299PubMedCrossRefGoogle Scholar
  36. 36.
    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 75:805–816PubMedCrossRefGoogle Scholar
  37. 37.
    Xiong Y, Hannon G, Zhang H, Casso D, Kobayashi R, Beach D (1993) p21 is a universal inhibitor of cyclin kinases. Nature 366:701–704PubMedCrossRefGoogle Scholar
  38. 38.
    Meltzer SJ, Yin J, Manin B, Mun-Gan R, Cottrell J, Hudson E, Redd JL, Krasna MJ, Abraham JM, Reid BJ (1994) Microsatellite instability occurs frequently and in both diploid and aneuploid cell populations of Barrett’-associated esophageal adenocarcinomas. Cancer Res 54: 3379–3382PubMedGoogle Scholar
  39. 39.
    Serrano M, Hannon GJ, Beach D (1993) A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 366:704–707PubMedCrossRefGoogle Scholar
  40. 40.
    Kamb A, Gruis NA, Weaver-Feldhaus J, Liu Q, Harshman K, Tavtigian SV, Stockert E, Day RSI, Johnson BE, Skolnick MH (1994) A cell cycle regulator potentially involved in genesis of many tumor types. Science 264:436–440PubMedCrossRefGoogle Scholar
  41. 41.
    Nobori T, Miura K, Wu DJ, Lois A, Takabayashi K, Carson DA (1994) Deletions of the cyclindependent kinase-4 inhibitor gene in multiple human cancers. Nature 368:753–756PubMedCrossRefGoogle Scholar
  42. 42.
    Hannon GJ, Beach D (1994) p15 INK4B is a potent effector of TGF-β-induced cell cycle arrest. Nature 371:257–261PubMedCrossRefGoogle Scholar
  43. 43.
    Polyak K, Kato JY, Solomon MJ, Sherr CJ, Massague J, Roberts JM, Koff A (1994) p27 KIP1, a cyclin-Cdk inhibitor, links transforming growth factor-β and contact inhibition to cell cycle arrest. Gene Dev 8:9–22PubMedCrossRefGoogle Scholar
  44. 44.
    Toyoshima H, Hunter T (1994) p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Cell 78:67–74PubMedCrossRefGoogle Scholar
  45. 45.
    Kitahara K, Yasui W, Yokozaki H, Semba S, Hamamoto T, Hisatsugu T, Tahara, E (1996) Expression of cyclin D1, CDK4 and p27K KIP1 is associated with the p16 MTS1 gene status in human esophageal carcinoma cell lines. J Exp Ther Oncol 1:7–12PubMedGoogle Scholar
  46. 46.
    Tsuda T, Tahara E, Kajiyama G, Sakamoto H, Terada M, Sugimura T (1989) High incidence of coamplification of hst-1 and int-2 genes in human esophageal carcinomas. Cancer Res 49:5505–5508PubMedGoogle Scholar
  47. 47.
    Schuuring E, Verhoeven E, Mooi WJ, Michalides RJAM (1992) Identification and cloning of two overexpressed genes, U21B31/PRAD1 and EMS1, within the amplified chromosome 11q13 region in human carcinomas. Oncogene 7:355–361PubMedGoogle Scholar
  48. 48.
    Kato J-Y, Matsushime H, Heibert SW, Ewen ME, Sherr CJ (1993) Direct binding of cyclin D to the retinoblastoma gene product (pRb) and pRb phosphorylation by the cyclin D-dependent kinase, CDK4. Gene Dev 7:331–342PubMedCrossRefGoogle Scholar
  49. 49.
    Ozawa S, Ueda M, Ando N, Shimizu N, Abe O (1989) Prognostic significance of epidermal gorwth factor receptor in esophageal squamous cell carcinomas. Cancer 63:2169–2173PubMedCrossRefGoogle Scholar
  50. 50.
    Yoshida K, Kyo E, Tsuda T, Tsujino T, Ito M, Niimoto M, Tahara E (1990) EGF and TGF-α, the ligands of hyperproduced EGFR in human esophageal carcinoma cells, acts as autocrine growth factors. Int J Cancer 45:131–135PubMedCrossRefGoogle Scholar
  51. 51.
    Tahara H, Kuniyasu H, Yokozaki H, Yasui W, Shay JW, Ide T, Tahara E (1995) Telomerase activity in preneoplastic and neoplastic gastric and colorectal lesions. Clin Cancer Res 1:1245–1251PubMedGoogle Scholar
  52. 52.
    Kuniyasu H, Yasui W, Kitadai Y, Yokozaki H, Ito H, Tahara E (1992) Frequent amplification of the c-met gene in scirrhous type stomach cancer. Biochem Biophys Res Commun 189:227–232PubMedCrossRefGoogle Scholar
  53. 53.
    Yokozaki H, Kuniyasu H, Kitadai Y, Nishimura K, Todo H, Ayhan A, Yasui W, Ito H, Tahara E (1992) p53 point mutations in primary human gastric carcinomas. J Cancer Res Clin Oncol 119:67–70PubMedCrossRefGoogle Scholar
  54. 54.
    Higashikawa K, Yokozaki H, Ue T, Taniyama K, Ishikawa T, Tahara E (1996) Evaluation of CD44 transcription variants in human digestive tract carcinomas and normal tissues. Int J Cancer 66:11–17PubMedCrossRefGoogle Scholar
  55. 55.
    Akama Y, Yasui W, Yokozaki H, Kuniyasu H, Kitahara K, Ishikawa T, Tahara E (1995) Frequent amplification of the cyclin E gene in human gastric carcinomas. Jpn J Cancer Res 86:617–621PubMedCrossRefGoogle Scholar
  56. 56.
    Akama Y, Yasui W, Kuniyasu H, Yokozaki H, Akagi M, Tahara H, Ishikawa T, Tahara E (1996) No point mutations but a codon 31 polymorphism and decreased expression of p21 ISDI1/WAF1/CIP1/MDA6 gene in human gastric carcinomas. Mol Cell Differ 4:187–198Google Scholar
  57. 57.
    Yasui W, Akama Y, Kuniyasu H, Yokozaki H, Semba S, Shimamoto F, Tahara E (1996) Expression of cyclin-dependent kinase inhibitor p21WAF1/CIP1 in non-neoplastic mucosa and neoplasia of the stomach: relation with p53 status and proliferative activity. J Pathol 180:122–128PubMedCrossRefGoogle Scholar
  58. 58.
    Yasui W, Kudo Y, Semba S, Yokozaki H, Tahara E (1997) Reduced expression of cyclin-dependent kinase inhibitor p27KIP1is associated with advanced stage and invasiveness of gastric carcinomas. Jpn J Cancer Res (in press)Google Scholar
  59. 59.
    Yokozaki H, Ito M, Yasui W, Kyo E, Kuniyasu H, Kitadai Y, Tsubouchi H, Daikuhara Y, Tahara E (1993) Biologic effect of hepatocyte growth factor on human gastric carcinoma cell lines. Int J Oncol 3:89–93PubMedCrossRefGoogle Scholar
  60. 60.
    Tahara E, Yokozaki H, Yasui W (1993) Growth factors in gastric cancer. In: Nishi M, Ichikawa H, Nakajima T, Maruyama K, Tahara E (eds) Gastric cancer. Springer, Tokyo, pp 209–217Google Scholar
  61. 61.
    Ito R, Kitadai Y, Kyo E, Yokozaki H, Yasui W, Yamashita U, Nikai H, Tahara E (1993) IL-la acts as an autocrine growth stimulator for human gastric carcinoma cells. Cancer Res 53:4102–4106PubMedGoogle Scholar
  62. 62.
    Nakayama H, Yasui W, Yokozaki H, Tahara E (1993) Reduced expression of nm23 is associated with metastasis of human gastric carcinomas. Jpn J Cancer Res 84:184–190PubMedCrossRefGoogle Scholar
  63. 63.
    Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, Nakamura Y, White R, Smith AMM, Bos JL (1988) Genetic alterations during colorectal tumor development. N Engl J Med 319:525–532PubMedCrossRefGoogle Scholar
  64. 64.
    Kinzler KW, Nilbert MC, Su LK, Vogelstein B, Bryan TM, Levy DB, Smith KJ, Preisinger AC, Hedge P, McKechnie D, Finniear R, Markham A, Groffen J, Boguski MS, Altshul SF, Horii A, Ando H, Miyoshi Y, Miki Y, Nishisho I, Nakamura Y (1991) Identification of FAP locus genes from chromosome 5q21. Science 253:661–665PubMedCrossRefGoogle Scholar
  65. 65.
    Harlow E, Williamson NM, Ralston R, Helfman DM, Adams TE (1985) Molecular cloning and in vitro expression of a cDNA clone for human cellular tumor antigen p53. Mol Cell Biol 5:1601–1610PubMedGoogle Scholar
  66. 66.
    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 247:49–56PubMedCrossRefGoogle Scholar
  67. 67.
    Lynch HT, Smyrk TC, Watson P, Lanspa SJ, Lynch JF, Lynch PM, Cavalieri RJ, Boland CR (1993) Genetics, natural history, tumor spectrum, and pathology of hereditary nonpolyposis colorectal cancer: an update review. Gastroenterology 104:1535–1549PubMedGoogle Scholar
  68. 68.
    Rubinfeld B, Souza B, Albert I, Muller O, Chamberlain SH, Masiarz FR, Munemitsu S, Polakis P (1993) Association of the APC gene product with β-catenin. Science 262:1731–1734PubMedCrossRefGoogle Scholar
  69. 69.
    Su L-K, Vogelstein B, Kinzler KW (1993) Association of the APC tumor suppressor protein with catenins. Science 262:1734–1737PubMedCrossRefGoogle Scholar
  70. 70.
    Miyoshi Y, Nagae H, Ando H, Horii A, Ichii S, Nakatsuru S, Aoki T, Miki Y, Mori T, Nakamura Y (1992) Somatic mutations of the APC gene in colorectal tumors. Hum Mol Genet 1:229–233PubMedCrossRefGoogle Scholar
  71. 71.
    Knudson AG (1985) Hereditary cancer, oncogenes, and antioncogenes. Cancer Res 45:1437–1443PubMedGoogle Scholar
  72. 72.
    Ichii S, Takeda S, Horii A, Nakatsuru S, Miyoshi Y, Emi M, Fujiwara Y, Koyama K, Furukawa J, Utsunomiya J, Nakamura Y (1993) Detailed analysis of genetic alterations in colorectal tumors from patients with and without familial adenomatous polyposis (FAP). Oncogene 8:2399–2405PubMedGoogle Scholar
  73. 73.
    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 327:293–297PubMedCrossRefGoogle Scholar
  74. 74.
    Forrester K, Almoguera C, Han K, Grizzle WE, Perucho M (1987) Detection of high incidence of K -ras oncogenes during human colon tumorigenesis. Nature 327:298–303PubMedCrossRefGoogle Scholar
  75. 75.
    Brumer GC, Loeb L (1989) Mutations in the KRAS2 oncogene during progressive stage of human colon carcinoma. Proc Natl Acad Sci USA 86:2403–2407CrossRefGoogle Scholar
  76. 76.
    Fujimori T, Satonaka K, Yamamura-Ideki Y, Nagasako K, Maeda S (1994) Non-involvement of ras mutations in flat colorectal adenomas and carcinomas. Int J Cancer 56:1–5Google Scholar
  77. 77.
    Minamoto T, Sawaguchi K, Mai M, Yamashita N, Sugimura T, Esumi H (1994) Infrequent K-ras activation in superficial-type (flat) adenomas and adenocarcinomas. Cancer Res 54:2841–2844PubMedGoogle Scholar
  78. 78.
    Jen J, Powell SM, Papadopoulos N, Smith KJ, Hamilton SR, Vogelstein B, Kinzler KW (1994) Molecular determinants of dysplasia in colorectal lesions. Cancer Res 54:5523–5526PubMedGoogle Scholar
  79. 79.
    Greenblatt MS, Bennett WP, Hollstein M, Harris CC (1994) Mutations in the p.53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res 54:4855–4878PubMedGoogle Scholar
  80. 80.
    Kikuchi-Yanoshita R, Konishi M, Ito S, Seki M, Tanaka K, Maeda Y, Iino H, Fukuyama M, Koike M, Mori T, Sakuraba H, Fukunari H, Iwama T, Miyaki M (1992) Genetic changes of both p.53 alleles associated with conversion from colorectal adenoma to early carcinoma in familial adenomatous polyposis and non-familial adenomatous polyposis patients. Cancer Res 52:3965–3971PubMedGoogle Scholar
  81. 81.
    Ayhan A, Yasui W, Yokozaki H, Ito H, Tahara E (1992) Genetic abnormalities and expression of p53 in human colon carcinomas. Int J Oncol 1:431–437PubMedGoogle Scholar
  82. 82.
    Yasui W, Kuniyasu H, Yokozaki H, Semba S, Shimamoto F, Tahara E (1996) Expression of cyclin E in colorectal adenomas and adenocarcinomas: correlation with expression of Ki-67 and p53 protein. Virchows Arch 429:13–19PubMedCrossRefGoogle Scholar
  83. 83.
    Hamelin R, Laurent PP, Olschwang S, Jego N, Asselain B, Remvikos Y, Girodet J, Salmon RJ, Thomas G (1994) Association of p53 mutations with short survival in colorectal cancer. Gastroenterology 106:42–48PubMedGoogle Scholar
  84. 84.
    Hedrick L, Cho KR, Fearon ER, Wu T-C, Kinzler KW, Vogelstein B (1994) The DCC gene product in cellular differentiation and colorectal tumorigenesis. Gene Dev 8:1174–1183PubMedCrossRefGoogle Scholar
  85. 85.
    Ookawa K, Sakamoto M, Hirohashi S, Yoshida Y, Sugimura T, Terada M, Yokota J (1993) Concordant p53 and DCC alterations and allelic losses on chromosome 13q and 14q associated with liver metastasis of colorectal carcinoma. Int J Cancer 53:382–387PubMedCrossRefGoogle Scholar
  86. 86.
    Tahara E (1990) Growth factors and oncogenes in human gastrointestinal carcinomas. J Cancer Res Clin Oncol 116:121–131PubMedCrossRefGoogle Scholar
  87. 87.
    Ciccodicola A, Dono R, Obici S, Simeone A, Zollo M, Persico MG (1989) Molecular characterization of a gene of the EGF family expressed in undifferentiated human NTRERA2 teratocarcinoma cells. EMBO J 8:1987–1991PubMedGoogle Scholar
  88. 88.
    Saeki T, Stromberg K, Qi C-F, Gullick WJ, Tahara E, Normanno N, Ciardiello F, Kenny N, Johnson GR, Salomon DS (1992) Differential immunohistochemical detection of amphiregulin and cripto in human normal colon and colorectal tumors. Cancer Res 52:3467–3473PubMedGoogle Scholar
  89. 89.
    Kuniyasu H, Yoshida K, Yokozaki H, Yasui W, Ito H, Toge T, Ciardiello F, Persico MG, Saeki T, Salomon DS, Tahara E (1991) Expression of cripto, a novel gene of the epidermal growth factor family, in human gastrointestinal carcinomas. Jpn J Cancer Res 82:969–973PubMedCrossRefGoogle Scholar
  90. 90.
    Shoyab M, McDonald VL, Bradley JG, Todaro GJ (1988) Amphiregulin, a bifunctional growthmodulating glycoprotein produced by the phorbol 12-myristate 13-acetate-treated human breast adenocarcinoma cell line MCF-7. Proc Natl Acad Sci USA 85:6528–6532PubMedCrossRefGoogle Scholar
  91. 91.
    Johnson GR, Saeki T, Gordon AW, Shoyab M, Salomon DS, Stromberg K (1992) Autocrine action of amphiregulin in a colon carcinoma cell line and immunocytochemical localization of amphiregulin in human colon. J Cell Biol 118:741–751PubMedCrossRefGoogle Scholar
  92. 92.
    Kitahara K, Yasui W, Kuniyasu H, Yokozaki H, Akama Y, Yunotani S, Hisatsugu T, Tahara E (1995) Concurrent amplification of cyclin E and CDK2 genes in colorectal carcinomas. Int J Cancer 62:25–28PubMedCrossRefGoogle Scholar
  93. 93.
    Matsumura Y, Tarin D (1992) Significance of CD44 gene products for cancer diagnosis and disease evaluation. Lancet 340:1053–1058PubMedCrossRefGoogle Scholar
  94. 94.
    Tolg C, Hofmann M, Herrlich P, Ponta H (1993) Splicing choice from ten variant exons establishes CD44 variability. Nucleic Acids Res 21:1225–1229PubMedCrossRefGoogle Scholar
  95. 95.
    Cooper DL, Dougherty GJ (1995) To metastasize or not? Selection of CD44 splice sites. Nature Med 1:635–637PubMedCrossRefGoogle Scholar
  96. 96.
    Yoshida K, Bolodeoku J, Sugino T, Goodison S, Matsumura Y, Warren BF, Toge T, Tahara E, Tarin D (1995) Abnormal retention of intron 9 in CD44 gene transcripts in human gastrointestinal tumors. Cancer Res 55:4273–4277PubMedGoogle Scholar
  97. 97.
    Weber GF, Ashkar S, Glimcher MJ, Cantor H (1996) Receptor-ligand interaction between CD44 and osteopontin (Efa-1). Science 271:509–512PubMedCrossRefGoogle Scholar
  98. 98.
    Postel EH, Berberich SJ, Flint SJ, Ferrone CA (1993) Human c-myc transcription factor PuF identified as nm23-H2 nucleoside diphosphate kinase, a candidate suppressor of tumor metastasis. Science 261:478–480PubMedCrossRefGoogle Scholar
  99. 99.
    Ayhan A, Yasui W, Yokozaki H, Kitadai Y, Tahara E (1993) Reduced expression of nm23 protein is associated with advanced tumor stage and distant metastases in human colorectal carcinomas. Virchows Arch B Cell Pathol 63:213–218CrossRefGoogle Scholar
  100. 100.
    Matsushita Y, Hoff SD, Nudelman ED, Otaka M, Hakomori S, Ota DM, Cleary KR, Irimura T (1991) Metastatic behavior and cell surface properties of HT-29 human colon carcinoma variant cells selected for their differential expression of sialyl-dimeric Lexantigen. Clin Exp Metastasis 9:283–299PubMedCrossRefGoogle Scholar
  101. 101.
    Berg EL, Robinson MK, Mansson O, Butcher EC, Magnani JL (1991) A carbohydrate domain common to both sialyl Lea and sialyl Lex is recognized by the endothelial cell leukocyte adhesion molecule ELAM-1. J Biol Chem 266:14869–14872PubMedGoogle Scholar
  102. 102.
    Nakamori S, Kameyama M, Imaoka S, Furukawa H, Ishikawa O, Sasaki Y, Kabuto T, Iwanaga T, Matsushita Y, Irimura T (1993) Increased expression of sialyl Lewisx antigen correlates with poor survival in patients with colorectal carcinoma: clinicopathological and immunohistochemical study. Cancer Res 53:3632–3637PubMedGoogle Scholar
  103. 103.
    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 colorectal cancer. Cell 75:1027–1038PubMedCrossRefGoogle Scholar
  104. 104.
    Leach FS, Nicolaides NC, Papadopoulos N, Liu B, Jen J, Parsons R, Pertomaki P, Sistonen P, Aaltonen LA, Nystrom-Lahti M, Guan X-Y, Zhang J, Melter PS, Yu J-W, Kao F-T, Chen DJ, Cerosaletti KM, Fournier REK, Todd S, Lewis T, Leach RJ, Naylor SL, Weissenbach J, Mecklin J-P, Jarvinen H, Petersen GM, Hamilton SR, Green J, Jass J, Watson P, Lynch HT, Trent JM, de la Chapelle A, Kinzler KW, Vogelstein B (1993) Mutation of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 75:1215–1225PubMedCrossRefGoogle Scholar
  105. 105.
    Bronner CE, Baker SM, Morrison PT, Warren G, Smith LG, Lescoe MK, Kane M, Erabino 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 hMLH1 is associated with hereditary nonpolyposis colorectal cancer. Nature 368:258–261PubMedCrossRefGoogle Scholar
  106. 106.
    Papadopoulos N, Nicolaides NC, Liu B, Wei Y-F, Rube SM, Carter KC, Rosen CA, Haseltine WA, Fleischmann RD, Fraser CM, Adams MD, Venter JC, Hamilton SR, Petersen GM, Watson P, Lynch HT, Peltomaki P, Mecklin J-P, de la Chapelle A, Kinzler KW, Vogelstein B (1994) Mutation of a mutL homolog in hereditary nonpolyposis colon cancer. Science 263:1625–1629PubMedCrossRefGoogle Scholar
  107. 107.
    Nicolaides NC, Papadopoulos N, Liu B, Wei Y-F, Carter KC, Rube SM, Rosen CA, Haseltine WA, Fleischmann RD, Fraser CM, Adams MD, Venter JC, Dunlop MG, Hamilton SR, Petersen GM, de la Chapelle A, Vogelstein B, Kinzler KW (1994) Mutation of two PMS homologues in hereditary nonpolyposis colon cancer. Nature 371:75–80PubMedCrossRefGoogle Scholar
  108. 108.
    Nystrom-Lahti N, Parsons R, Sistonen P, Pylkkanen L, Aaltonen LA, Leach F, Hamilton SR, Watson P, Bronson E, Fusaro R, Cavalieri J, Lynch J, Lanspa S, Smyrk T, Lynch P, Drouhard T, Kinzler KW, Vogelstein B, Lynch HT, de la Chapelle A, Peltomaki P (1994) Mismatch repair genes on chromosome 1p and 3p account for a major share of hereditary nonpolyposis colorectal cancer families evaluable by linkage. Am J Hum Genet 55:659–665PubMedGoogle Scholar
  109. 109.
    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-β receptor in colon cancer cells with microsatellite instability. Science 268:1336–1338PubMedCrossRefGoogle Scholar
  110. 110.
    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 β3 receptor type II gene mutation common in colon and gastric but rare in endometrial cancers with microsatellite instability. Cancer Res 55:554–5547Google Scholar
  111. 111.
    Ionov YM, Peinado A, Malkhosyan S, Shibata D, Perucho M (1993) Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 363:558–561PubMedCrossRefGoogle Scholar
  112. 112.
    Thibodeau SN, Bren G, Schaid D (1993) Microsatellite instability in cancer of the proximal colon. Science 260:816–819PubMedCrossRefGoogle Scholar
  113. 113.
    Counter CM, Avilion AA, LeFeuvre CE, Stewart NG, Greider CW, Harley CB, Bacchetti S (1992) Telomere shortening associated with chromosome instability is arrested in immortal cells which express telomerase activity. EMBO J 11:1921–1929PubMedGoogle Scholar
  114. 114.
    Rhyu MS (1995) Telomeres, telomerase and immortality. J Natl Cancer Inst 87:884–894PubMedCrossRefGoogle Scholar
  115. 115.
    Hastie ND, Dempster M, Dunlop MG, Thompson AM, Green DK, Allshire RC (1990) Telomere reduction in human colorectal carcinoma and with aging. Nature 346:866–868PubMedCrossRefGoogle Scholar
  116. 116.
    Chadeneau C, Hay K, Hirte HW, Gallinger S, Bacchetti S (1995) Telomerase activity associated with aquisition of malignancy in human colorectal cancer. Cancer Res 55:2533–2536PubMedGoogle Scholar
  117. 117.
    Tarin D (1995) A new strategy of molecular diagnosis of gastrointestinal cancer. Jpn J Cancer Res 86Google Scholar
  118. 118.
    Japanese Research Society for Gastric Cancer (1995) Japanese classification of gastric carcinoma, 1st English edm. Kanehara, TokyoGoogle Scholar
  119. 119.
    Ubel PA, DeKay ML, Baron J, Asch DA (1996) Cost-effectiveness analysis in a setting of budget constraints: is it equitable? N Engl J Med 334:1174–1177PubMedCrossRefGoogle Scholar
  120. 120.
    Williams JK, Lea DH (1995) Applying new genetic technologies: assessment and ethical considerations. Nurse Pract 20:21–76CrossRefGoogle Scholar
  121. 121.
    Parkers LS (1995) Ethical concerns in the research and treatment of complex disease. Trends Genet 11:520–523CrossRefGoogle Scholar
  122. 122.
    Berg K, Pettersson U, Riis P, Tranoy KE (1995) Genetic in democratic societies: the Nordic perspective. Clin Genet 48:199–208PubMedCrossRefGoogle Scholar
  123. 123.
    Burgess MM (1994) Ethical issues in prenatal testing. Clin Biochem 27:87–91PubMedCrossRefGoogle Scholar
  124. 124.
    De Wert G (1992) Predictive testing for Huntington disease and the right not to know: some ethical reflections. Birth Defects 28:133–138PubMedGoogle Scholar
  125. 125.
    Lennox A, Karlinsky H, Meschino W, Buchanan JA, Percy ME, Berg JM (1994) Molecular genetics predictive testing for Alzheimer’s disease: deliberations and preliminary recommendations. Alzheimer Dis Assoc Disord 8:126–147PubMedCrossRefGoogle Scholar
  126. 126.
    Hoshino K (1992) Bioethical issues and principles in cancer treatment. Jpn J Cancer Chemother 19:281–285Google Scholar
  127. 127.
    Vineis P, Soskolne CL (1993) Cancer risk assessment and management: an ethical perspective. J Occup Med 35:902–908PubMedCrossRefGoogle Scholar
  128. 128.
    Siegler M, Amiel S, Lantos J (1992) Scientific and ethical consequences of disease prediction. Diabetologia 35:S60–68PubMedCrossRefGoogle Scholar
  129. 129.
    Spigelman AD (1994) Familial adenomatous polyposis: recent genetic advances. Br J Surg 81:321–322PubMedCrossRefGoogle Scholar
  130. 130.
    Eeles RA, Stratton MR, Goldgar DE, Easton DF (1994) The genetics of familial breast cancer and their practical implications. Eur J Cancer 30A:1383–1390PubMedCrossRefGoogle Scholar
  131. 131.
    Kash KM (1995) Psychosocial and ethical implications of defining genetic risk for cancers. Ann NY Acad Sci 768:41–52PubMedCrossRefGoogle Scholar
  132. 132.
    Murray TH (1993) Ethics, genetic prediction, and heart disease. Am J Cardiol 72:80D–84DPubMedCrossRefGoogle Scholar

Copyright information

© Springer Japan 1997

Authors and Affiliations

  • Wataru Yasui
    • 1
  • Hiroshi Yokozaki
    • 1
  • Eiichi Tahara
    • 1
  1. 1.First Department of PathologyHiroshima University School of MedicineMinami-ku, Hiroshima 734Japan

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