Cancer and Metastasis Reviews

, Volume 15, Issue 1, pp 53–76 | Cite as

Molecular and cellular biomarkers for field cancerization and multistep process in head and neck tumorigenesis

  • Vali A. Papadimitrakopoulou
  • Dong M. Shin
  • Waun K. Hong


One way to explain the development of head and neck cancer is through the theories of field cancerization, i.e., the exposure of an entire field of tissue to repeated carcinogenic insult, and multistep process, i.e., development of multiple cancers in a predisposed field through a series of recognizable states. Recent molecular genetic studies of histologically normal and prealignant epithelia of high-risk subjects and studies of malignant tumors in aerodigestive tract epithelia have identified a continuum of accumulated specific genetic alterations that possibly occur during the clonal evolution of tumors, namely, during the multistep process. Second primary or multiple primary tumors arise in the same fields as independent clones, with similar but unique molecular genetic and/or cellular alterations. Consequently, the assessment of these genetic and phenotypic alterations has been integrated into clinical chemoprevention trials in an effort to identify biomarkers that are also risk predictors and intermediate end points. This review covers candidate biomarkers of the processes of field cancerization and multistep tumor development in aerodigestive tract epithelia, including general and specific genetic markers, proliferation markers, and squamous differentiation markers.

Key words

field cancerization multistep tumorigenesis biomarkers aerodigestive tract epithelium 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Boring CC, Squires TS, Tong T: Cancer statistics 1994. CA Cancer 44: 7–26, 1994Google Scholar
  2. 2.
    Parkin DM, Laara E, Muir CS: Estimates of the worldwide frequency of sixteen major cancers in 1980. Int J Cancer 41: 184–197, 1988Google Scholar
  3. 3.
    DeVesa SS, Blot WJ, Stone BJ, Miller BA, Tarone RE, Fraumeni JF: Recent cancer trends in the United States. J Natl Cancer Inst 87: 175–182, 1995Google Scholar
  4. 4.
    Vokes EE, Weichselbaum RR, Lippman SM, Hong WK: Head and neck cancer. N Engl J Med 328: 184–193, 1993Google Scholar
  5. 5.
    Wolf G, Lippman SM, Laramore G, Hong WK: Head and neck cancer. In: Holland JF, Frei E, Bast RC, Kufe DW, Morton DL, Weichselbaum R (eds) Cancer Medicine, 3rd ed. Lea & Febiger, 1993, pp 1211–1275Google Scholar
  6. 6.
    Sporn MB: Carcinogenesis and cancer-different perspectives on the same disease. Cancer Res 51: 6215–6218, 1991Google Scholar
  7. 7.
    Lippman SM, Benner SE, Hong WK: Cancer chemoprevention. J Clin Oncol 12: 851–873, 1994Google Scholar
  8. 8.
    Boone C, Kelloff GJ, Malone WE: Identification of candidate cancer chemoprevention agents and their evaluation in animal models and human clinical trials: A review. Cancer Res 50: 2–9, 1990Google Scholar
  9. 9.
    Meyskens FLJr: Coming of age: The chemoprevention of cancer. N Engl J Med 323: 825–827, 1990Google Scholar
  10. 10.
    Weber BL: Susceptibility genes for breast cancer. N Engl J Med 331: 1523–1524, 1994Google Scholar
  11. 11.
    Early Breast Cancer Trialists' Collaborative Group: Systemic temic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. Lancet 339: 1–15, 71–84, 1992Google Scholar
  12. 12.
    Hong WK, Lippman SM, Wolf GT: Recent advances in head and neck cancer: Larynx preservation and cancer chemoprevention. Cancer Res 53: 5113–5120, 1994Google Scholar
  13. 13.
    Heyne K, Lippman SM, Lee JS, Hong WK: The incidence of second primary tumors in long term survivors of small cell lung cancer. J Clin Oncol 10: 1519–1524, 1992Google Scholar
  14. 14.
    Lippman SM, Hong WK: Not yet standard: Retinoids versus second primary tumors. J Clin Oncol 11: 1204–1207, 1993Google Scholar
  15. 15.
    Benner SE, Lippman SM, Hong WK: Chemoprevention of second primary tumors: A model for intervention trials. Eur J Cancer 30A: 727–729, 1994Google Scholar
  16. 16.
    Schatzkin A, Freedman LS, Schiffman MN, Dawsey SM: Validation of intermediate endpoints in cancer research. J Natl Cancer Inst 82: 1746–1752, 1990Google Scholar
  17. 17.
    Zelen M: Are primary cancer prevention trials feasible? J Natl Cancer Inst 80: 1442–1444, 1988Google Scholar
  18. 18.
    Stockman MS, Gupta PK, Pressman NJ, Mulshine JL: Considerations in bringing a cancer biomarker to clinical application. Cancer Res 52 (suppl): 2711–2718, 1992Google Scholar
  19. 19.
    Lippman SM, Spitz MR, Huber MH, Hong WK: Strategies for chemoprevention study of premalignancy and second primary tumors in the head and neck. Curr Opin Oncol 7: 234–241, 1995Google Scholar
  20. 20.
    Lippman SM, Lee JS, Lotan R, Hittelman W, Wargovich MJ, Hong WK: Biomarkers as intermediate end points in chemoprevention trials. J Natl Cancer Inst 82: 555–560, 1990Google Scholar
  21. 21.
    Lippman SM, Benner SE, Hong WK: The chemoprevention of cancer. In: Greenwald P, Kramer BS, Weed DL (eds) Cancer Prevention and Control. Marcel Dekker Inc. New York, 1995, pp 329–352Google Scholar
  22. 22.
    Sharma S, Stutzman JD, Kellof GJ, Steele VE: Screening of potential chemopreventive agents using biochemical markers of carcinogenesis. Cancer Res 54: 5848–5855, 1994Google Scholar
  23. 23.
    Shin DM, Hittelman WN, Hong WK: Biomarkers in upper aerodigestive tract tumorigenesis. Cancer Epidemiol Biomarkers Prev 3: 697–709, 1994Google Scholar
  24. 24.
    Hong WK, Lippman SM, Hittelman WN, Lotan R: Retinoid chemoprevention of aerodigestive cancer: From basic research to the clinic. Clin Cancer Res 1: 677–686, 1995Google Scholar
  25. 25.
    Slaughter DP, Southwick HW, Smejkal W: Field cancerization in oral stratified squamous epithelium: Clinical implications of multicentric origin. Cancer 6: 963–968, 1953Google Scholar
  26. 26.
    Lippman SM, Hong WK: Retinoid chemoprevention of upper aerodigestive tract carcinogenesis. In: De Vita VT, Hellman S, Rosenberg SA (eds) Important Advances in Oncology. JB Lippincot Co, Philadelphia, 1992, pp 93–109Google Scholar
  27. 27.
    Cooper JS, Pajak TF, Rubin P, Tupchong L, Brady LW, Leibel SA, Laramore GE, Marcial VA, Davis LW, Cox JD: Second malignancies in patients who have head and neck cancers: Incidence, effect on survival and implications for chemoprevention based on the RTOG experience. Int J Radiat Oncol Biol Phys 17: 449–456, 1989Google Scholar
  28. 28.
    De Vries N, Snow GB: Prevention of second primary cancers in head and neck patients: New perspectives. Am J Otolaryngol 9: 151–154, 1988Google Scholar
  29. 29.
    Lippman SM, Hong WK: Second malignant tumors in head and neck squamous cell carcinoma: The overshadowing threat for patients with early stage disease (Editorial). Int J Radiat Oncol Biol Phys 17: 691–694, 1989Google Scholar
  30. 30.
    Johnson BE, Linnoila RI, Williams JP, Venzon DJ, Okunieff P, Anderson GB, Richardson GE: Risk of second aerodigestive cancers increase in patients who survive free of small cell lung cancer for more than two years. J Clin Oncol 13: 101–111, 1995Google Scholar
  31. 31.
    Tepperman BS, Fitzpatrick PJ: Second respiratory and upper digestive tract cancers after oral cancer. Lancet 2: 547–549, 1981Google Scholar
  32. 32.
    McDonald S, Haie C, Rubin R, Nelson D, Divers LD: Second malignant tumors in patients with laryngeal carcinoma: Diagnosis, treatment and prevention. Int J Radiat Oncol Biol Phys 17: 457–465, 1989Google Scholar
  33. 33.
    Licciardello JT, Spitz MR, Hong WK: Multiple primary cancer in patients with cancer of the head and neck: Second cancer of the head and neck, esophagus and lung. Int J Radiat Oncol Biol Phys 17: 467–476, 1989Google Scholar
  34. 34.
    Vikram B: Changing patterns of failure in advanced head and neck cancer. Arch Otolaryngol 110: 564–565, 1984Google Scholar
  35. 35.
    Auerbach O, Stout AP, Hammond EC, Garfinkle L: Changes in bronchial epithelium in relation to cigarette smoking and in relation to lung cancer. N Engl J Med 265: 253–267, 1961Google Scholar
  36. 36.
    Aldaz CM, Conti CJ, Klein-Szanto AJP, Slaga TJ: Progressive dysplasia and aneuploidy are hallmarks of mouse skin papillomas: Relevance to malignancy. Proc Natl Acad Sci USA 84: 2029–2032, 1987Google Scholar
  37. 37.
    Konishi F, Morson BC: Pathology of colorectal carcinomas: A colonoscopic survey. J Clin Pathol 35: 830–841, 1982Google Scholar
  38. 38.
    Boone C, Kelloff GJ, Steele VE: Natural history of intraepithelial neoplasia in humans with implications for cancer chemoprevention strategy. Cancer Res 52: 1651–1659, 1992Google Scholar
  39. 39.
    Sozzi G, Miozzo M, Donghi R, Pilotti S, Cariani CT, Pastorino V, Della Porta G, Pierotti MA: Deletions of 17p and p53 mutations in preneoplastic lesions of the lung. Cancer Res 52: 6079–6082, 1992Google Scholar
  40. 40.
    Lee JS, Pathak S, Hopwood V, Tomasovic B, Mullins JD, Baker FL, Spitzer G, Neidhart JA: Involvement of chromosome 7 in primary lung cancer and nonmalignant normal lung tissue. Cancer Res 47: 6349–6352, 1987Google Scholar
  41. 41.
    Hittelman WN, Lee JS, Cheong N, Shin DM, Hong WK: The chromosome view of ‘field cancerization’ and multistep tumorigenesis. In: Pastorino U, Hong WK (eds) Implication for Chemoprevention Approaches in Chemoprevention Cancer. Thieme Verlag, Stuttagart, 1991, pp 41–47Google Scholar
  42. 42.
    Kim SY, Lee JS, Ro JY, Gay M, Hong WK, Hittelman WN: Interphase cytogenetics in paraffin sections of lung tumors by non-isotopic in situ hybridization: Mapping genotype/phenotype heterogeneity. Am J Pathol 142: 307–317, 1993Google Scholar
  43. 43.
    Voravud N, Shin DM, Ro JY, Lee JS, Hong WK, Hittelman WN: Increased polysomies of chromosomes 7 and 17 during head and neck multistage tumorigenesis. Cancer Res 53: 2874–2883, 1993Google Scholar
  44. 44.
    Sundaresan V, Ganly P, Hasleton P, Rudd R, Sinhha G, Bleehen NM, Rabbits P: p53 and chromosome 3 abnormalities, characteristic of malignant lung tumors, are detectable in preinvasive lesions of the bronchus. Oncogene 7: 1989–1997, 1992Google Scholar
  45. 45.
    Hung J, Kishimoto Y, Sugio K, Virmani A, McIntire DD, Minna JD, Gazdar AF: Allele-specific chromosome 3p deletions occur at an early stage in the pathogenesis of lung carcinoma. JAMA 273: 558–563, 1995Google Scholar
  46. 46.
    Kishimoto Y, Sugio K, Hung JY, Virmani AK, McIntire DD, Minna JD, Gazdar A: Allele-specific loss in the chromosome 9p loci in preneoplastic lesion accompanying non-small cell lung cancer. J Natl Cancer Inst 87: 1224–1229, 1995Google Scholar
  47. 47.
    Sugio K, Kishimoto Y, Virmani A, Hung JY, Gazdar AF: K-ras mutations are a relatively late event in the pathogenesis of lung carcinomas. Cancer Res 54: 5811–5915, 1994Google Scholar
  48. 48.
    Chung KY, Muchopadhyay T, Casson A, Ro JY, Goepfert H, Hong WK, Roth JA: Discordant p53 mutations in primary head and neck cancers and corresponding second primary cancers of the upper aerodigestive tract. Cancer Res 53: 1676–1683, 1993Google Scholar
  49. 49.
    Farber E: The multistep nature of cancer development. Cancer Res 44: 4217–4223, 1984Google Scholar
  50. 50.
    Vogelstein B, Fearon ER, Hamilton SR: Genetic alterations during colorectal tumor development. J Engl J Med 319: 525–532, 1988Google Scholar
  51. 51.
    Bouquot JE, Weiland LH, Kurland LT: Leukoplakia and carcinoma in situ synchronously associated with invasive oral/oropharyngeal carcinoma in Rochester, Minn., 1935–1984. Oral Surg Oral Med Oral Pathol 65: 199–207, 1985Google Scholar
  52. 52.
    Einhorn J, Wersall J: Incidence of oral carcinoma in patients with leukoplakia of the oral mucosa. Cancer 20: 2189–2193, 1967Google Scholar
  53. 53.
    Mashberg AL: Erythroplasia vs. leukoplakia in the diagnosis of ealry asymptomatic oral squamous carcinoma. N Engl J Med 297: 109–110, 1977Google Scholar
  54. 54.
    Sklar G: Oral leukoplakia. N Engl J Med 315: 1544–1546, 1986Google Scholar
  55. 55.
    Silverman SJr, Gorsky M, Lozada F: Oral leukoplakia and malignant transformation: A follow-up study of 257 patients. Cancer 53: 563–568, 1984Google Scholar
  56. 56.
    Stich HF: Micronucleated exfoliated cells as indicators for genotoxic damage and as markers in chemoprevention trials. J Nutr Growth Cancer 4: 9–18, 1987Google Scholar
  57. 57.
    Rosin MP, Dunn BP, Stich HF: Use of intermediate endpoints in quantitating the response of precancerous lesions to chemopreventive agents. Can J Physiol Pharmacol 65: 483–487, 1987Google Scholar
  58. 58.
    Lippman SM, Peters E, Wargovich M: Bronchial micronuclei as a marker of an ‘early’ stage of carcinogenesis in human tracheobronchial epithelium. Int J Cancer 45: 811–815, 1990Google Scholar
  59. 59.
    Stich HF, Rosin MP, Vallejera MO: Reduction with vitamin A and beta-carotene administration of the proportion of micronucleated buccal mucosal cells in Asian betel nut and tobacco chewers. Lancet 1: 1204–1206, 1984Google Scholar
  60. 60.
    Stich HF, Rosin MP, Hornby AP: Remission of oral leukoplakias and micronuclei in tobacco/betel quid chewers treated with beta-carotene and beta-carotene and vitamin A. Int J Cancer 42: 195–199, 1988Google Scholar
  61. 61.
    Munoz N, Hayashi M, Bang LJ, Wahrendorf J, Massimo C, Bosch FX: Effect of riboflavin, retinol, and zinc on micronuclei of buccal mucosa and of esophagus: A randomized double-blind intervention study in China. J Natl Cancer Inst 79: 687–691, 1987Google Scholar
  62. 62.
    Benner SE, Lippman SM, Wargovich MJ, Velasco M, Peters EJ, Morice RC, Hong WK: Micronuclei in bronchial biopsy specimens from heavy smokers: Characterization of an intermediate marker of lung carcinogenesis. Int J Cancer 52: 44–47, 1992Google Scholar
  63. 63.
    Benner SE, Lippman SM, Wargovich MJ, Lee JJ, Velasco M, Martin JW, Toth BB, Hong WK: Micronuclei, a biomarker for chemoprevention trials: Results of a randomized study in oral premalignancy. Int J Cancer 59: 457–459, 1994Google Scholar
  64. 64.
    Mitelman F: Catalog of chromosome aberrations in cancer, 3rd ed. Alan R. Liss, New York, 1988Google Scholar
  65. 65.
    Jin Y, Higashi K, Mandahl N, Heim S, Wennerberg J, Biorklund A, Dictor M, Mitelman F: Frequent rearrangement of chromosomal bands 1p22 and 11q13 in squamous cell carcinoma of the head and neck. Genes Chromosom Cancer 2: 198–204, 1990Google Scholar
  66. 66.
    Osella P, Carlson A, Wyandt H, Milungky A: Cytogenetic studies of eight squamous cell carcinomas of the head and neck. Cancer Genet Cytogenet 59: 73–78, 1992Google Scholar
  67. 67.
    Jin Y, Mertens F, Mandahl N, Heim S, Olegard C, Wennerberg J, Biorklund A, Mitelman F: Chromosome abnormalities in eighty-three head and neck squamous cell carcinomas: Influence of culture conditions on karyotypic pattern. Cancer Res 53: 2140–2146, 1993Google Scholar
  68. 68.
    Tessier JR: The chromosomal analysis of human solid tumors: A triple challenge. Cancer Genet Cytogenet 37: 103–125, 1989Google Scholar
  69. 69.
    Carey TE, Van Dyke DL, Worsham MJ: Nonrandom chromosome aberrations and clonal populations in head and neck cancer. Anticancer Res 13: 2561–2568, 1993Google Scholar
  70. 70.
    Van Dyke DL, Worsham MJ, Benninger MS, Krause CJ, Baker SR, Wolf GT, Drumheller T, Tilley BC, Carey TE: Recurrent cytogenetic abnormalities in squamous cell carcinomas of the head and neck region. Genes Chromosom Cancer 9: 192–206, 1994Google Scholar
  71. 71.
    Cowan JM, Beckett MA, Weichselbaum RR: Chromosome changes characterizing in vitro response to radiation in human squamous cell carcinoma lines. Cancer Res 53: 5542–5547, 1993Google Scholar
  72. 72.
    Lee JS, Pathak S, Hopwood V, Tomasovic B, Mullins TD, Baker FL, Spitzer G, Neidhart JA: Involvement of chromosome 7 in primary lung tumor and nonmalignant normal lung tissue. Cancer Res 47: 6349–6352, 1987Google Scholar
  73. 73.
    Mertens F, Jin Y, Heim S, Mandahl N, Johnsson N, Mertens O, Persson B, Salesmark L, Wennerberg J, Mitelman F: Clonal structural chromosome aberration in nonneoplastic cells of the skin and upper aerodigestive tract. Genes Chromosom Cancer 4: 235–240, 1992Google Scholar
  74. 74.
    Pinkel D, Straume T, Gray JW: Cytogenetic analysis using quantitative, high sensitivity fluorescence hybridization. Proc Natl Acad Sci USA 83: 2934–2938, 1986Google Scholar
  75. 75.
    Cremer T, Lichter P, Borde J, Ward DC, Manuelidis L: Detection of chromosome aberrations in metaphase and interphase tumor cells by in situ hybridization using chromosome-specific library probes. Hum Genet 80: 235–246, 1988Google Scholar
  76. 76.
    Matsumura K, Kallioniemi A, Kallioniemi O, Chen L, Smith HS, Pinkel D, Gray J, Waldman FM: Deletion of chromosome 17q loci in breast cancer cells detected by fluorescence in situ hybridization. Cancer Res 52: 3474–3477, 1992Google Scholar
  77. 77.
    Arnoldus EPJ, Dreef EJ, Noordemeer IA, Verheggen MM, Thierry RF, Peters ACB, Cornelisse CJ, Van der Ploeg M, Raap AK: Feasibility of in situ hybridization with chromosome-specific DNA probes on paraffin wax-embedded tissue. J Clin Pathol 44: 503–513, 1991Google Scholar
  78. 78.
    Hopman AHN, Van Hooren E, Van de Kaa CA, Vooijs PGP, Ramaekers FCS: Detection of numerical chromosome aberrations using in situ hybridization in paraffin sections of routinely processed bladder cancers. Mod Pathol 4: 503–513, 1991Google Scholar
  79. 79.
    Dhingra K, Sahin A, Supak J, Kim SY, Hortobagyi G, Hittelman WN: Chromosome in situ hybridization on formalin-fixed mammary tissue using non-isotopic, non-fluorescent probes: Technical considerations and biological implications. Breast Cancer Res Treat 23: 201–210, 1992Google Scholar
  80. 80.
    Lee JS, Kim SY, Hong WK, Lippman SM, Ro JY, Gay ML, Hittelman WN: Detection of chromosomal polysomy in oral leukoplakia, a premalignant lesion. J Natl Cancer Inst 85: 1951–1954, 1993Google Scholar
  81. 81.
    Kallioniemi A, Kallioniemi OP, Sudar D, Rutovitz D, Gray JW, Waldman F, Pinkel D: Comparative genomic hybridization for cytogenetic analysis of solid tumors. Science (Washington, DC) 258: 818–821, 1992Google Scholar
  82. 82.
    Speicher MR, Howe C, Crotty P, Du Manoir S, Costa J, Ward DC: Comparative genomic hybridization detects novel deletions and amplifications in head and neck squamous cell carcinomas. Cancer Res 55: 1010–1013, 1995Google Scholar
  83. 83.
    Knudson AGJr: Hereditary cancer, oncogenes, and antioncogenes. Cancer Res 45: 1437–1443, 1985Google Scholar
  84. 84.
    Weber JL, May PE: Abundant class of human DNA polymorphisms which can be typed using the polymerase chain reaction. Am J Hum Genet 44: 388–396, 1989Google Scholar
  85. 85.
    Ah-See KW, Cooke TG, Pickford IR, Soutar D, Balmain A: An allelotype of squamous carcinoma of the head and neck using microsatellite markers. Cancer Res 54: 617–1621, 1994Google Scholar
  86. 86.
    Nawroz H, Van der Riet P, Hruban RH, Koch WM, Ruppert JM, Sidransky D: Allelotype of head and neck squamous cell carcinoma. Cancer Res 54: 1152–1155, 1994Google Scholar
  87. 87.
    El-Naggar AK, Lee MS, Wang G, Luna MA, Goepfert H, Batsakis JG: Polymerase chain reaction-based restriction fragment length polymorphism analysis of the short arm of chromosome 3 in primary head and neck squamous carcinoma. Cancer 72: 881–886, 1993Google Scholar
  88. 88.
    Latif F, Fivosh M, Glenn G, Tory K: Chromosome 3p deletions in head and neck carcinomas. Statistical ascertainment of allelic loss. Cancer Res 52: 1451–1456, 1992Google Scholar
  89. 89.
    Yokoyama S, Yamakawa K, Tsuchiya E, Murata M, Sakiyama S, Nakamura Y: Deletion mapping on the short arm of chromosome 3 in squamous cell carcinoma and adenocarcinoma of the lung. Cancer Res 52: 873–877, 1992Google Scholar
  90. 90.
    Kratzke RA, Simizu E, Kaye FJ: Oncogenes in human lung cancer. Cancer Treat Res 63: 61–85, 1992Google Scholar
  91. 91.
    Hibi K, Takahashi T, Yamakawa K, Ueda R, Sekido Y, Ariyoshi Y: Three distinct regions involved in 3p deletions in human lung cancer. Oncogene 7: 445–449, 1992Google Scholar
  92. 92.
    Killary AM, Wolf ME, Giambernardi TA, Naylor SL: Definition of tumor suppressor locus within human chromosome 3p21–22. Proc Natl Acad Sci USA 89: 10877–10881, 1992Google Scholar
  93. 93.
    Maestro R, Gasparotto D, Vuksavljevic T, Barzan L, Sulfaro S, Boiocchi M: Three discrete regions of deletion in head and neck cancers. Cancer Res 53: 5775–5779, 1993Google Scholar
  94. 94.
    Wu CL, Sloan P, Read AP, Harris R, Thakker N: Deletion mapping on the short arm of chromosome 3 in squamous cell carcinoma of the oral cavity. Cancer Res 54: 6484–6488, 1994Google Scholar
  95. 95.
    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, Altschul SF, Horii A, Ando H, Miyoshi Y, Miki Y, Nishisho I, Nakamura Y: Identification of FAP locus genes from chromosome 5q21. Science (Washington, DC) 253: 661–665, 1991Google Scholar
  96. 96.
    Boynton RF, Blount PL, Yin J, Brown VL, Huang Y, Tong Y, McDaniel T, Newkirk C, Resan JH, Raskind WH, Haggit RC, Reid BJ, Meltzer SJ: Loss of heterozygosity involving the APC and MCC genetic loci in the majority of human esophageal cancers. Proc Natl Acad Sci USA 89: 3385–3388, 1992Google Scholar
  97. 97.
    Thompson AM, Morris RG, Wallace M, Wyllie AH, Sreel CM, Carter DC: Allele loss from 5q21 (APC/MCC) and 18q21 (DCC) and DCC mRNA expression in breast cancer. Br J Cancer 68: 64–68, 1993Google Scholar
  98. 98.
    Olopade OI, Bohlander SK, Pomykala H, Maltepe E, Van Melle E, Le Beau MM, Diaz MO: Mapping of the shortest region of overlap of deletions of the short arm of chromosome 9 associated with human neoplasia. Genomics 14: 437–443, 1992Google Scholar
  99. 99.
    James CD, Collins VP, Allalunis-Turner MJ, Days RS: Localization of chromosome 9p homozygous deletions in glioma cell lines with markers constituting a continuous linkage map. Cancer Res 53: 3674–3676, 1993Google Scholar
  100. 100.
    Fountain JW, Karayiorgou M, Ernsthoff MS, Kirkwood JM, Vlock DR, Titus-Ernsthoff L, Bouchard B, Vijayasaradhi S, Houghton AN, Lahti J, Kidd VJ, Housman DE, Dracopoli NC: Homozygous deletions within human chromosome band 9p21 in melanoma. Proc Natl Acad Sci USA 89: 10557–10561, 1992Google Scholar
  101. 101.
    Cairns P, Tokino K, Eby E, Sidransky D: Homozygous deletions of 9p21 in primary human bladder tumors detected by comparative multiplex polymerase chain reaction. Cancer Res 54: 1422–1424, 1994Google Scholar
  102. 102.
    Merlo A, Gabrielson E, Askin F, Sidransky D: Frequent loss of chromosome 9 in human primary non-small cell lung cancer. Cancer Res 54: 640–642, 1994Google Scholar
  103. 103.
    Lammie GA, Fantl V, Smith R, Schuuring E, Brookes S, Michalides R, Dickson C, Arnold A, Peters G: D11S287, a putative oncogene on 11q13, is amplified and expressed in squamous cell and mammary carcinomas and linked to BCL-1. Oncogene 6: 439–444, 1991Google Scholar
  104. 104.
    Berenson JR, Yan J, Micke RA: Frequent amplification of the bcl-1 locus in head and neck squamous cell carcinomas. Oncogene 4: 1111–1116, 1989Google Scholar
  105. 105.
    Sommers KD, Cartwright SL, Schechter GL: Amplifications in the int-2 gene in human head and neck squamous cell carcinomas. Oncogene 5: 915–920, 1990Google Scholar
  106. 106.
    Yoo GH, Xu HJ, Brennan JA, Westra W, Hruban RH, Koch WM, Benedict WF, Sidransky D: Infrequent inactivation of the retinoblastoma gene despite frequent loss of chromsome 13q in head and neck squamous cell carcinoma. Cancer Res 54: 4603–4606, 1994Google Scholar
  107. 107.
    Hall A: ras and GAP: Who's controlling whom? Cell 1: 921–923, 1990Google Scholar
  108. 108.
    Bos JL: ras oncogenes in human cancer: A review. Cancer Res 49: 4682–4689, 1989Google Scholar
  109. 109.
    Lemoine NR, Mayall ES, Wyllie FS, Williams ED, Goyns M, Stringer B, Wynford-Thomas D: High frequency of ras oncogene activation in all stages of human thyroid tumorigenesis. Oncogene 4: 159–164, 1989Google Scholar
  110. 110.
    Vis Vanathan KV, Pocock RD, Summerhayes IC: Preferential and novel activation of H-ras in human bladder carcinomas. Oncogene 3: 77–86, 1988Google Scholar
  111. 111.
    Almoguera C, Shibata D, Forrester K, Martin J, Armheim N, Perucho M: Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell 53: 549–554, 1988Google Scholar
  112. 112.
    Bos JL, Fearon ER, Hamilton JR, Verlaan-de Vries M, Van Boom JH, Van der Eb AJ, Vogelstein B: Prevalence of ras gene mutations in human colorectal cancer. Nature (Lond.) 327: 293–297, 1987Google Scholar
  113. 113.
    Rodenhuis S, Slebos RJ, Boot AJM, Evers SG, Mooi NJ, Wagenaar SS, Van Bodegom PC, Bos JL: Incjdence and possible clinical significance of K-ras oncogene activation in adenocarcinoma of the human lung. Cancer Res 48: 5738–5741, 1988Google Scholar
  114. 114.
    Suzuki Y, Orita M, Shiraishi M, Hayashi K, Sekiya T: Detection of ras oncogene mutations in human lung cancers by single strand conformation polymorphism analysis of polymerase chain reaction products. Oncogene 5: 1037–1043, 1990Google Scholar
  115. 115.
    Furth ME, Davis LJ, Fleurdelys B, Scolnick EM: Monoclonal antibodies to the p21 products of the transforming gene of Harvey murine sarcoma virus and of the cellular ras gene family. J Virol 43: 294–304, 1982Google Scholar
  116. 116.
    Sheng ZM, Barrois M, Klijanienko J, Micheau C, Richard JM, Rio G: Analysis of the c-Ha-ras-1 gene for deletion, mutation, amplification and expression in lymph node metastases of human head and neck cancer. Br J Cancer 62: 398–404, 1990Google Scholar
  117. 117.
    Rumsby G, Carter RC, Gusterson BA: Low incidence of ras oncogene activation in human squamous cell carcinomas. Br J Cancer 61: 365–368, 1990Google Scholar
  118. 118.
    Saranath D, Chang SE, Bhoite LT, Panchall RG, Kerr IB, Mehta AR, Johnson NW, Deo MG: High frequency mutation in codons 12 and 61 of Ha-ras oncogene in tobacco related human oral carcinomas. Br J Cancer 63: 573–578, 1991Google Scholar
  119. 119.
    Kuo MYP, Chang HH, Hahn LJ, Wang JT, Chiang CP: Elevated ras p21 expression in oral premalignant lesions and squamous cell carcinomas in Taiwan. J Oral Pathol Med 24: 255–260, 1995Google Scholar
  120. 120.
    Yamamoto T, Nishida T, Miyajima M, Kawai S, Ooi T, Toyoshima K: The erb B gene of the avian erythroblastosis virus is a member of the src gene family. Cell 35: 71–78, 1983Google Scholar
  121. 121.
    Derynck R: Transforming growth factor-α. Cell 54: 593–595, 1988Google Scholar
  122. 122.
    Cohen S, Carpenter G, King L: Epidermal growth factor receptor protein kinase interactions. J Biol Chem 255: 4834–4842, 1980Google Scholar
  123. 123.
    Ushiro H, Cohen S: Identification of phosphotyrosine as a product of epidermal growth factor-activated protein kinase in A431 cell membranes. J Biol Chem 255: 8363–8365, 1980Google Scholar
  124. 124.
    Cohen S, Ushiro H, Stoscheck C, Gill GN: Regulation of the epidermal growth factor by phosphorylation. J Cell Biochem 29: 195–208, 1985Google Scholar
  125. 125.
    Velu TJ, Beguinot L, Vass WC, Willingham MC, Merlino GT, Pastan I, Lowy DR: Epidermal growth factor dependent transformation by a human EGF receptor protooncogene. Science (Washington, DC) 238: 1408–1410, 1987Google Scholar
  126. 126.
    Eisbruch A, Blick M, Lee JS, Sacks PJ, Gutterman J: Analysis of epidermal growth factor receptor gene in fresh human head and neck tumors. Cancer Res 47: 3603–3605, 1987Google Scholar
  127. 127.
    Todd R, Donoff BR, Gertz R, Chang A, Chow P, Matossian K, McBride J, Chiang T, Gallagher GT, Wong D: TGF-α and EGF receptor mRNAs in human oral cancers. Carcinogenesis 10: 1553–1556, 1989Google Scholar
  128. 128.
    Maxwell SA, Sacks PJ, Gutterman GU, Gallick GE: Epidermal growth factor receptor protein-tyrosine kinase activity in human cell lines established from squamous carcinomas of the head and neck. Cancer Res 49: 1130–1137, 1989Google Scholar
  129. 129.
    Santini J, Formento JL, Francoval M, Milano G, Schneider M, Dassonville O, Dernard F: Characterization, quantitation and potential clinical value of the epidermal growth factor receptor in head and neck squamous cell carcinomas. Head Neck 13: 132–139, 1991Google Scholar
  130. 130.
    Wong DTW, Biswas DK: Expression of c-erb B oncogene in DMBA-induced hamster oral carcinomas. Oncogene 2: 67–72, 1987Google Scholar
  131. 131.
    Grandis JR, Tweardy DJ: Elevated levels of transforming growth factor alpha and epidermal growth factor receptor messenger RNA are early markers of carcinogenesis in head and neck cancer. Cancer Res 53: 3579–3584, 1993Google Scholar
  132. 132.
    Shin DM, Ro JY, Hong WK, Hittelman WN: Dysregulation of epidermal growth factor receptor expression in premalignant lesions during head and neck tumorigenesis. Cancer Res 54: 3153–3159, 1994Google Scholar
  133. 133.
    Leonard JH, Kearsley JH, Chenevix-Trench G, Hayward NK: Analysis of gene amplification in the head and neck squamous cell carcinomas. Int J Cancer 48: 511–515, 1991Google Scholar
  134. 134.
    Faust JB, Meeker TC: Amplification and expression of the bcl-1 gene in human solid tumor cell lines. Cancer Res 52: 2460–2463, 1992Google Scholar
  135. 135.
    Yoshida T, Miyagawa K, Odagiri H, Sakamoto H, Little PFR, Terada M: Genomic sequence of hst, a transforming gene encoding a protein homologous to fibroblast growth factors and the Int-2 encoded protein. Proc Natl Acad Sci USA 84: 7305–7309, 1987Google Scholar
  136. 136.
    Rosenberg CL, Wong E, Petty EM, Balf AE, Tsujimoto Y, Harris NL, Arnold A: PRAD1, a candidate BCL1 oncogene: mapping and expression in centrocytic lymphoma. Proc Natl Acad Sci USA 88: 9638–9642, 1991Google Scholar
  137. 137.
    Motokura T, Bloom T, Kim HG, Juppner H, Ruderman JV, Kronenberg HM, Arnold AA: A novel cyclin encoded by BCL-1-linked candidate oncogene. Nature (Lond.) 350: 512–515, 1991Google Scholar
  138. 138.
    Kerlseder J, Zeillinger R, Schneeberger C, Czerwenka K, Speiser P, Kubista E, Birnbaum D, Gaudray P, Theillet C: Pattern of DNA amplification at band q13 of chromosome 11 in human breast cancer. Genes Chromosom Cancer 9: 43–48, 1994Google Scholar
  139. 139.
    Williams ME, Gaffey MJ, Weiss LM, Wilczynski SP, Schuuring E, Levine PA: Chromosome 11q13 amplification in head and neck squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 119: 1238–1243, 1993Google Scholar
  140. 140.
    Jiang W, Kahn SM, Zhou P, Zhang Y, Cacace AM, Infante AS, Doi S, Santella RM, Weinstein IB: Overexpression of cyclin D1 in rat fibroblasts causes abnormalities in growth control, cell cycle progression and gene expression. Oncogene 8: 3447–3457, 1993Google Scholar
  141. 141.
    Dowdy SF, Hinds PW, Louie K, Reed SI, Arnold A, Weinberg RA: Physical interaction of the retinoblastoma protein with human D cyclins. Cell 73: 499–511, 1993Google Scholar
  142. 142.
    Matsushine H, Ewin ME, Strom DK, Kato J-Y, Hanks SK, Roussel M, Sherr CJ: Identification and properties of an atypical catalytic subunit (p34 p5K-J3/cdk4) for mammalian D type G1 cyclins. Cell 71: 323–334, 1992Google Scholar
  143. 143.
    Bates S, Parry D, Bonetta L, Vousden K, Dickson C, Peters G: Absence of cyclin D/cdk complexes in cells lacking functional retinoblastoma protein. Oncogene 9: 1633–1640, 1994Google Scholar
  144. 144.
    Quelle DE, Ashmun RA, Shurtleff SA, Kato JY, Bar-Sagi D, Roussel MF, Sherr CJ: Overexpression of mouse D-type cyclins accelerates G1 phase in rodent fibroblasts. Genes Dev 7: 1559–1571, 1993Google Scholar
  145. 145.
    Hinds PH, Dowdy SF, Eaton EN, Arnold A, Weinberg RA: Function of a human cyclin gene as an oncogene. Proc Natl Acad Sci USA 91: 709–713, 1994Google Scholar
  146. 146.
    Callender T, El-Naggar AK, Lee MS, Frankenthaler R, Luna MA, Batsakis JG: PRAD-1(CCND1)/cyclin D1 oncogene amplification in primary head and neck squamous cell carcinoma. Cancer 74: 152–158, 1994Google Scholar
  147. 147.
    Parise O, Janot F, Guerry R, Fortin A, Luboinski B, Tursz T, Schwaab G, Busson P: Cromosome 11q13 gene amplifications in head and neck squamous cell carcinomas: Relation with lymph node invasion. Int J Oncol 5: 309–313, 1994Google Scholar
  148. 148.
    Michalides R, Van Veelen N, Hart A, Loftus B, Wientjens E, Balm A: Overexpression of cyclin D1 correlates with recurrence in a group of forty-seven operable squamous cell carcinomas of the head and neck. Cancer Res 55: 975–978, 1995Google Scholar
  149. 149.
    Lebwohl DE, Muise-Helmericks R, Sepp-Lorenzino L, Serve S, Timaul M, Bol R, Borgen P, Rosen NA: A truncated cyclin D1 gene encodes a stable mRNA in a human breast cancer cell line. Oncogene 9: 1925–1929, 1994Google Scholar
  150. 150.
    Roh HJ, Shin DM, Lee JS, Ro JY, Tainsky MA, Hong WK, Hittelman WN: Visualization of int-2 amplification in premalignant lesions during head and neck tumorigenesis (Abstract). Proc Am Assoc Cancer Res 35: 117, 1994Google Scholar
  151. 151.
    Hartwell LH, Kastan MB: Cell cycle control and cancer. Science 266: 1821–1828, 1994Google Scholar
  152. 152.
    Greenblatt MS, Bennett WP, HOllstein M, Harris CC: Mutations in the p53 tumor suppressor gene: Clues to cancer etiology and molecular pathogenesis. Cancer Res 54: 4855–4878, 1994Google Scholar
  153. 153.
    Brachman DG, Graves D, Vokes E, Beckett M, Haraf D, Montag A, Dumphy E, Mick R, Yandell D, Weichselbaum RR: Occurrence of p53 gene deletion and human papilloma virus infection in head and neck cancer. Cancer Res 52: 4382–4386, 1992Google Scholar
  154. 154.
    Gusterson BA, Anbazhagan R, Warren W, Midgely C, Lane DP, O'Hare M, Stamps A, Carter R, Jayatilake H: Expression of p53 in premalignant and malignant squamous epithelium. Oncogene 6: 1785–1789, 1991Google Scholar
  155. 155.
    Field JK, Spandidos SA, Malliri A, Gosney JR, Yiagnisis M, Stell PM: Elevated p53 expression correlates with a history of heavy smoking in squamous cell carcinomas of the head and neck. Br J Cancer 64: 573–577, 1991Google Scholar
  156. 156.
    Boyle JO, Koch W, Hruban RH, Van der Riet P, Sidransky D: The incidence of p53 mutations increase with progression of head and neck cancer. Cancer Res 53: 4477–4480, 1993Google Scholar
  157. 157.
    Brennan JA, Mao L, Hruban RH, Boyle JO, Eby YJ, Koch WM, Goodman SN, Sidransky D: Molecular assessment of histopathological staging in squamous-cell carcinoma of the head and neck. N Engl J Med 332: 429–435, 1995Google Scholar
  158. 158.
    Shin DM, Kim J, Ro JY, Hittelman J, Roth JA, Hong WK, Hittelman WN: Activation of p53 gene expression in premalignant lesions during head and neck tumorigenesis. Cancer Res 54: 321–326, 1994Google Scholar
  159. 159.
    Ziegler A, Jonason AS, Leffel DJ, Simon JA, Sharma HW, Kimmelman J, Remington L, Jacks T, Brash DE: Sunburn and p53 in the onset of skin cancer. Nature (Lond.) 372: 773–776, 1994Google Scholar
  160. 160.
    Shin DM, Ro JY, Shah T, Hong WK, Hittelman WN: p53 expression and genetic instability in head and neck multistep tumorigenesis (Abstract). Proc Am Assoc Cancer Res 35: 944, 1994Google Scholar
  161. 161.
    Chung KY, Mukhopadhyay T, Kim J, Casson A, Ro JY, Goepfert H, Hong WK, Roth JA: Discordant p53 gene mutations in primary head and neck cancers and corresponding second primary cancers of the upper aerodigestive tract. Cancer Res 53: 1676–1683, 1993Google Scholar
  162. 162.
    Nees M, Homann N, Discher H, Andl T, Enders C, Harrold-Mende C, Schulmann A, Bosch FX: Expression of mutated p53 occurs in tumor-distant epithelial of head and neck cancer patients: A possible molecular basis for the development of multiple tumors. Cancer Res 53: 4189–4196, 1993Google Scholar
  163. 163.
    Lippman SM, Shin DM, Lee JJ, Batsakis JG, Lotan R, Tainsky MA, Hittelman WN, Hong WK: p53 and retinoid chemoprevention of oral carcinogenesis. Cancer Res 55: 16–19, 1995Google Scholar
  164. 164.
    Lippman SM, Batsakis JG, Toth BB, Weber RS, Lee JJ, Martin JW, Hays GL, Goepfert H, Hong WK: Comparison of low-dose isotretinoin with beta-carotene to prevent oral carcinogenesis. N Engl J med 328: 15–20, 1993Google Scholar
  165. 165.
    Maxwell SA. Mukhopadhyay T: Transient stabilization of p53 in non-small cell lung cultures arrested for growth by retinoic acid. Exp Cell Res 214: 67–74, 1994Google Scholar
  166. 166.
    Shin DM, Lee JS, Choi G, Shaw T, Hyne K, Earley C, Shin HJC, Ro JY, Hong WK, Hittelman WN: Prognostic significance of p53 expression in head and neck squamous cell carcinoma (HNSCC) (Abstract). Proc Am Soc Clin Oncol 13: 293, 1994Google Scholar
  167. 167.
    Clayman GL, El-Naggar AK, Roth LA, Zhang WW, Goepfert H, Taylor DL, Liu TJ: In vivo therapy with p53 adenovirus for microscopic residual head and neck squamous carcinoma. Cancer Res 55: 1–6, 1995Google Scholar
  168. 168.
    Xu L, Davidson BJ, Murty VVVS, Li R-G Sacks P, Garin-Chesa P, Schantz SP, Chaganti RSK: p53 gnee mutations and CCND1 gene amplification in head and neck squamous cell carcinoma cell lines. Int J Cancer 59: 383–387, 1994Google Scholar
  169. 169.
    Bartkova J, Lukas J, Muller J, Strauss M, Gusterson B, Bartek J: Abnormal patterns of D-type cyclin expression and G1 regulation in human head and neck cancer. Cancer Res 55: 949–956, 1995Google Scholar
  170. 170.
    El-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer E, Kinzler KW, Vogelstein B: WAF1, a potential mediator of p53 tumor suppression. Cell 75: 817–825, 1993Google Scholar
  171. 171.
    Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ: The p21 cdk-interacting protein Cipl is a potent inhibitor of G1 cyclin-dependent kinases. Cell 75: 805–816, 1993Google Scholar
  172. 172.
    Michieli P, Chedid M, Lin D, Pierce JH, Mercer WE, Givol D: Induction of WAF1/C1P1 by a p53-independent pathway. Cancer Res 54: 3391–3395, 1994Google Scholar
  173. 173.
    Parker SB, Eichele G, Zhang P, Rawls A, Sands AT, Bradley A, Olson EN, Harper JW, Elledge SJ: p53-independent expression of p21Cipl in muscle and other terminally differentiating cells. Science (Washington, DC) 267: 1024–1027, 1995Google Scholar
  174. 174.
    Halevy O, Novitch BG, Spicer DB, Skapek SX, Rhee J, Hannon GJ, Beach D, Lassar AB: Correlation of terminal cell cycle arrest of skeletal muscle with induction of p21 by MyoD. Science (Washington, DC). 267: 1018–1021, 1995Google Scholar
  175. 175.
    Lee SJ, Ha MJ, Lee J, Trepel JB: p53-independent induction of the cyclin-dependent kinase inhibitor p21 in prostate and breast carcinoma cells treated with an inhibitor of the HMG-CoA reductase pathway (Abstract). Proc Am Assoc Cancer Res 36: 581, 1995Google Scholar
  176. 176.
    Hwang MS, Thompson KL, Ahn CH: p53-independent induction of p21WAF1 and apoptosis by all-trans-retinoic acid and 9-cis retinoic acid in human prostate cancer cell lines (Abstract). Proc Am Assoc Cancer Res 36: 10, 1995Google Scholar
  177. 177.
    Li R, Waga S, Hannon GJ, Beach D, Stillman B: Differential effects by the p21 CDK inhibitor on PCNA-dependent DNA replication and repair. Nature (Lond.) 371: 534–537, 1994Google Scholar
  178. 178.
    Shiohara M, El-Deiry WS, Wada M, Nakamaki T, Takeuchi S, Yang R, Chen DL, Vogelstein B, Koeffler HP: Absence of WAF1 mutations in a variety of human malignancies. Blood 84: 3781–3784, 1994Google Scholar
  179. 179.
    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: Topological control of p21waf1/cip1 expression in normal and neoplastic tissues. Cancer Res 55: 2910–2919, 1995Google Scholar
  180. 180.
    Lipkin M, Bell B, Sherlock P: Cell proliferation kinetics in the gastrointestinal tract of man: I. Cell renewal in colon and rectum. J Clin Invest 42: 767, 1963Google Scholar
  181. 181.
    Lipkin M, Sherlock P, Bell B: Cell proliferation kinetics in the gastrointestinal tract of man: II. Cell renewal in stomach, ileum, colon and rectum. Gastroenterology 45: 721, 1963Google Scholar
  182. 182.
    Serrano M, Hannon G, Beach D: A new regulatory motif in cell cycle control causing specific inhibition of cyclin D/CDK4. nature (Lond.) 366: 704–707, 1993Google Scholar
  183. 183.
    Van der Riet P, Nawroz H, Hruban RH, Corio R, Tokino K, Koch W, Sidransky D: Frequent loss of chromosome 9p21–22 early in head and neck cancer progression. Cancer Res 54: 1156–1158, 1994Google Scholar
  184. 184.
    Kamb A, Gruis NA, Weaverfeldhaus J, Liu QY, Harshman K: A cell cycle regulator potentially involved in genesis of many tumor types. Science 264: 436–440, 1994Google Scholar
  185. 185.
    Cairns P, Mao L, Merlo A, Lee DJ, Schwab D, Eby Y, Tokino K, Van der Riet P, Blaugrund JE, Sidransky D: Low rate of p16 (MTS1) mutations in primary tumors with 9p loss. Science (Washington, DC) 265: 415–417, 1994Google Scholar
  186. 186.
    Zhang SY, Klein-Szanto AJP, Sauter ER, Shafarenko M, Mitsunaga S, Nobori T, Carson DA, Ridge JA, Goodrow TL: Higher frequency of alterations in the p16/CDKN2 gene in squamous cell carcinoma cell lines than in primary tumors of the head and neck. Cancer Res 54: 5050–5053, 1994Google Scholar
  187. 187.
    Lydiatt WM, Murty VVVS, Davidson BJ, Xu L, Dyomina K, Sacks PG, Schantz SP, Chaganti RSK: Homozygous deletions and loss of expression of the CDKN2 gene occur frequently in head and neck squamous cell carcinoma cell lines but infrequently in primary tumors. Genes Chromosom Cancer 13: 94–98, 1995Google Scholar
  188. 188.
    Spruck CH, Gonzales-Zulueta M, Shibata A, Simoneau AR, Lin MF, Gonzales F, Tsai YC, Jones PA: p16 gene in uncultured tumors. Science (Washington, DC) 265: 415–416, 1994Google Scholar
  189. 189.
    Merlo A, Herman JG, Mao L, Lee DJ, Gabrielson E, Burger P, Baylin SB, Sidransky D: 5′ CpG island methylation is associated with transciptional silencing of the tumor suppressor p16/CDKN2/MTSl in human cancers. Nature Med 1: 686–692, 1995Google Scholar
  190. 190.
    Bravo R, Frank R, Blundell PA, MacDonald-Bravo H: Cyclin/PCNA is the auxiliary protein of DNA polymerasedelta. Nature (Lond.) 326: 515–517, 1987Google Scholar
  191. 191.
    Baserga R: Growth regulation of the PCNA gene. J Cell Sci 98: 433–436, 1991Google Scholar
  192. 192.
    Celis JE, Celis A: Cell cycle-dependent variations in the distribution of the nuclear protein cyclin proliferating cell nuclear antigen in cultured cells: Subdivision of phase. Proc Natl Acad Sci USA 82: 326203266, 1985Google Scholar
  193. 193.
    Shin DM, Voravud N, Ro JY, Lee JS, Hong WK, Hittelman WN: Sequential upregulation of proliferating cell nuclear antigen in head and neck tumorigenesis: A potential biomarker. J Natl Cancer Inst 85: 971–978, 1993Google Scholar
  194. 194.
    Huang WY, Coltrera M, Schubert M, Morton T, Truelove E: Histopathologic evaluation of proliferating cell nuclear antigen (PC10) in oral epithelial hyperplasias and premalignant lesions. Oral Surg Oral Med Oral Pathol 78: 748–754, 1994Google Scholar
  195. 195.
    Gorgoulis V, Zoumpourlis V, Rassidakis G, Karameris A, Barbatis C, Spandidos DA, Kittas C: Molecular analysis of p53 gene in laryngeal premalignant and malignant lesions: p53 protein immunohistochemical expression is positively related to proliferating cell nuclear antigen labelling index. Virchows Arch 426: 339–344, 1995Google Scholar
  196. 196.
    Girod SC, Pape HD, Krueger GR: p53 and PCNA expression in carcinogenesis of the oropharyngeal mucosa. Eur J Cancer B Oral Oncol 30b: 419–423, 1994Google Scholar
  197. 197.
    Jetten AM: Multistep process of squamous differentiation of tracheobronchial epithelial cells. Role of retinoids. Dermatologica 175: 37–44, 1987Google Scholar
  198. 198.
    Moll R, Franke WW, Schiller DL: The catalog of human cytokeratins: Patterns of expression in normal epithelia, tumors and cultured cells. Cell 31: 11–24, 1982Google Scholar
  199. 199.
    Kim KH, Schwartz F, Fuchs E: Difference sin keratin synthesis between normal epithelial cells and squamous cell carcinomas are mediated by vitamin A. Proc Natl Acad Sci USA 81: 4280–4284, 1984Google Scholar
  200. 200.
    Rutten AAJJL, Bruyntjes JP, Ramaekers FCS: Effect of cigarette smoke condensate and vitamin A depletion on keratin expression patterns in cultured hamster tracheal epithelium: An immunohistomorphological study using monoclonal antibodies to keratins. Virchows Arch [B] 56: 111–117, 1989Google Scholar
  201. 201.
    Lindberg K, Rheinwald JG: Suprabasal 40 kd keratin (K19): Expression as immunohistological marker of premalignancy in oral epithelium. Am J Pathol 134: 419–426, 1989Google Scholar
  202. 202.
    Gimenez-Conti IB, Shin D, Bianchi AB, Roop DR, Hong WK, Conti CJ, Slaga TJ: Changes in keratin expression during 7,12-dimethylbenz(a) anthracene-induced hamster cheek pouch carcinogenesis. Cancer Res 50: 4441–4445, 1990Google Scholar
  203. 203.
    Copper MP, Braakhuis BJM, De Vries N, Van Dongen GAMS, Nauta JJ, Snow G: A panel of biomarkers of carcinogenesis of the upper aerodigestive tract as potential intermediate endpoints in chemoprevention trials. Cancer 71: 825–830, 1993Google Scholar
  204. 204.
    Thatcher SM: Purification of keratinocyte transglutaminase and its expression during squamous differentiation. J Invest Dermatol 92: 578–584, 1989Google Scholar
  205. 205.
    Said JW, Nash G, Sassoon AF, Shintaku IP, Banks-Schlegel S: Invoducrin in lung tumors: A specific marker for squamous differentiation. Lab Invest 49: 563–568, 1983Google Scholar
  206. 206.
    Itoiz ME, Conti CJ, Gimenez-Conti JB, Lafranchi HE, Fernandez-Alonso GI, Klein-Szanto AJP: Immunodetection of involucrin in lesions of the oral mucosa. J Oral Pathol 15: 205–208, 1986Google Scholar
  207. 207.
    Lippman SM, Lee JS, Lotan R, Hong WK: Chemoprevention of upper aerodigestive tract cancers: A report of the Upper Aerodigestive Cancer Task Force workshop. Head Neck Surg 12: 5–20, 1990Google Scholar
  208. 208.
    Lotan R: Effects of vitamin A and its analogs (retinoids) on normal and neoplastic cells. Biochim Biophys Acta 605: 33–91, 1980Google Scholar
  209. 209.
    Lippman S, Toth B, Batsakis J: The evaluation of biologic markers as intermediate endpoints in a chemoprevention trial of 13-cis-retinoic acid (13cRA) in human premalignant oral lesions (Abstract). Proc Am Soc Clin Oncol 8: 168, 1989Google Scholar
  210. 210.
    Sellers TA, Potter JD, Bailey-Wilson JE, Rich SS, Rothschild H, Elsta RC: Lung cancer detection and prevention: Evidence for an interaction between smoking and genetic predisposition. Cancer Res 52: 2694–2697, 1992Google Scholar
  211. 211.
    Harris CC: Interindividual variation among humans in carcinogen metabolism, DNA adduct formation and DNA repair. Carcinogenesis 10: 1563–1566, 1989Google Scholar
  212. 212.
    Hagmar L, Brogger A, Hansteen IL, Heim S, Hogstedt B, Knudsen L, Lambert B, Linnainmaa K, Mitelman F, Nordenson I, Reuterwall C, Salomaa S, Skerfving S, Sorsa M: Cancer risk in humans predicted by increased levels of chromosomal aberrations in lymphocytes: Nordic study group on the health risk of chromosome damage. Cancer Res 54: 2919–2922, 1994Google Scholar
  213. 213.
    Hsu TC: Genetic predisposition to cancer with special reference to mutagen sensitivity. In Vitro Cell Dev Biol 23: 591–603, 1987Google Scholar
  214. 214.
    Spitz MR, Fueger JJ, Beddingfield NA, Annegers JF, Hsu TC, Newell GR, Schantz SP: Chromosome sensitivity to bleomycin-induced mutagenesis, an independent risk factor for upper aerodigestive tract cancer. Cancer Res 49: 4626–4628, 1989Google Scholar
  215. 215.
    Spitz MR, Fueger JJ, Halabi S, Schantz SP, Sample D, Hsu TC: Mutagen sensitivity in upper aerodigestive tract cancer: A case control analysis. Cancer Epidemiol Biomarkers Prev 2: 329–333, 1993Google Scholar
  216. 216.
    Spitz MR, Hoque A, Trizna Z, Schantz SP, Amos CI, King TM, Bondy ML, Hong WK, Hsu TC: Mutagen sensitivity as a risk factor for second malignant tumors following malignancies of the upper aerodigestive tract. J Natl Cancer Inst 86: 1681–1684, 1994Google Scholar
  217. 217.
    Cloos J, Braakhuis BJ, Steen I, Copper MP, De Vries N, Nauta JJ, Snow GB: Increased mutagen sensitivity in head-and-neck squanmous-cell carcinoma patients, particularly those with multiple primary tumors. Int J Cancer 56: 816–819, 1994Google Scholar
  218. 218.
    Dave BJ, Hsu TC, Hong WK, Pathak S: Nonrandom distribution of mutagen-induced chromosome breaks in lymphocytes of patients with different malignancies. Int J Oncol 5: 733–740, 1994Google Scholar
  219. 219.
    McGlynn KA, Buetow KH: Metabolic and H-ras polymorphisms in genetic susceptibility. Cancer Bull 46: 220–227, 1994Google Scholar
  220. 220.
    Lippman SM, Kessler JF, Meyskens FL: Retinoids as preventive and therapeutic anticancer agents. Cancer Treat Rep 71: 391–405, 1987Google Scholar
  221. 221.
    Moon TE, Cartmel B, Levine N, Arizona Skin Cancer Study Group: Chemoprevention and etiology of non-melanoma skin cancers, program, and abstracts. 17th Annual Meeting of the American Society of Preventive Oncology, Tucson, March 20–23, 1993Google Scholar
  222. 222.
    Meyskens FL, Surwit E, Moon TE, Cilders JM, Davis JR, Dorr RT, Johnson CS, Alberts DS: Enhancement of regression of cervical intraepithelial neoplasia II (moderate dysplasia) with topically applied all-trans-retinoic acid: A randomized trial. J Natl Cancer Inst 86: 539–543, 1994Google Scholar
  223. 223.
    Pastorino U, Ifante M, Maioli M: Adjuvant treatment of stage I lung cancer with high-dose vitamin. Am J Clin Oncol 11: 1216–1222, 1993Google Scholar
  224. 224.
    Kraemer KH, DiGiovanna JJ, Moshell AN Tarone RE, Deck GL: Prevention of skin cancer in xeroderma pigmentosum with the use of oral isotretinoin. N Engl J Med 318: 1633–1637, 1988Google Scholar
  225. 225.
    Smith MA, Parkinson DR, Cheson BD, Friedman MA: Retinoids in cancer therapy. J Clin Oncol 10: 839–864, 1992Google Scholar
  226. 226.
    Gudas LJ, Sporn MB, Roberts AB: Cellular biology and biochemistry of the retinoids. In: Sporn MB, Roberts AB, Goodman DS (eds) The Retinoids: Biology, Chemistry, and Medicine. Reven Press, New York, 1994, pp 443–520Google Scholar
  227. 227.
    Lotan R: Retinoids and squamous cell differentiation. In: Hong WK, Lotan R (eds) Retinoids in Oncology. Marcel Dekker, New York, 1993, pp 43–72Google Scholar
  228. 228.
    Borden EC, Lotan R, Levens D, Young CW, Waxman S: Differentiation therapy of cancer: laboratory and clinical investigations (meeting report). Cancer Res 53: 4109–4115, 1993Google Scholar
  229. 229.
    Leroy P, Krust A, Kastner P, Mendelsohn C, Zelent A, Chambon P: Retinoic acid receptors. In: Morriss-Kay G (ed) Retinoids in Normal Development and Teratogenesis. Oxford University Press, New York, 1992, pp 7025Google Scholar
  230. 230.
    Huang M, Ye Y, Chen S, Chai J, Lu J, Zhoa L, Gu L, Wang Z: Use of all-trans-retinoic acid in the treatment of acute promyelocytic leukemia. Blood 72: 567–572, 1988Google Scholar
  231. 231.
    Moasser MM, DeBlasio A, Dmitrovsky E: Response and resistance to retinoic acid are mediated through the retinoic acid nuclear receptor gamma in human teratocarcinomas. Oncogene 9: 833–840, 1994Google Scholar
  232. 232.
    Zou CP, Clifford JL, Xu XC, Sacks PG, Chambon P, Hong WK, Lotan R: Modulation by retinoic acid (RA) of squamous cell differentiation, cellular RA-binding proteins, and nuclear RA receptors in human head and neck squamous cell carcinoma cell lines. Cancer Res 54: 5479–5487, 1994Google Scholar
  233. 233.
    Xu XC, Ro JY, Lee JS, Shin DM, Hong WK, Lotan R: Differential expression of nuclear retinoid receptors in normal, premalignant, and malignant head and neck tissues. Cancer Res 54: 3580–3587, 1994Google Scholar
  234. 234.
    Lotan R, Sozzi G, Ro J, Lee J, Pastorino U, Pilotti S, Kurie J, Hong WK, Xu X: Selective suppression of retinoic acid receptor β (RAR β) expression in squamous metaplasia, and in non-small cell lung cancers (NSCLC) compared to normal bronchial epithelium (Abstract). Proc Am Soc Clin Oncol 14: 61, 1995Google Scholar
  235. 235.
    Hu L, Crowe DL, Rheiwald JG, Chambon P, Gudas LJ: Abnormal expression of retinoic acid receptors and keratin 19 by human oral and epidermal squamous cell carcinoma cell lines. Cancer Res 51: 3972–3981, 1991Google Scholar
  236. 236.
    Gebert JF, Moghal N, Frangioni JV, Sugarbaker DJ, Neel BG: High frequency of retinoic acid receptor beta abnormalities in human lung cancer. Oncogene 6: 1859–1868, 1991Google Scholar
  237. 237.
    Lotan R, Xu X-C, Lippman SM, Ro JY, Lee JS, Lee JJ, Hong WK: Suppression of retinoic acid receptor β in premalignant oral lesions and its upregulation by isotretinoin. N Engl J Med 332: 1405–1410, 1995Google Scholar

Copyright information

© Kluwer Academic Publishers 1996

Authors and Affiliations

  • Vali A. Papadimitrakopoulou
    • 1
  • Dong M. Shin
    • 1
  • Waun K. Hong
    • 1
  1. 1.Department of Thoracic/Head and Neck Medical OncologyThe University of Texas M.D. Anderson Cancer CenterHoustonUSA

Personalised recommendations