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Multistep Carcinogenesis of Esophageal Carcinoma

  • Yusuke Nakamura
  • Takashi Tokino
  • Minoru Isomura
  • Johji Inazawa
  • Takahisa Aoki
  • Takahiro Mori
  • Mamoru Shimada
  • Koh Miura
  • Kazufumi Suzuki

Summary

To investigate genetic features of esophageal cancer, we have examined a large number of squamous cell carcinomas of the esophagus (ESCs) for loss of heterozygosity (LOH) using polymorphic DNA markers representing all autosomal chromosomes. Allelic losses at frequencies of at least 30% were observed at loci on chromosomal arms on 3p (33%), 3q (30%), 5q (36%), 9p (57%), 9q (60%), 10p (33%), 13q (43%), 17p (62%), 17q (46%), 18q (38%), 19q (32%), and 21q (37%). By comparing the LOH on each chromosomal arm with the clinicopathologic parameters of patients, we found a significant correlation between LOH on 19q and regional lymph node metastasis. Interestingly, the frequency of LOH on 17q was significantly higher in tumors from female patients (12 of 14 cases) than in those from male patients (20 of 56 cases) P =0.0009 by Fisher’s exact test). Subsequent analysis of allelic losses in DNA extracts isolated from 106 lesions among 32 patients with ESCs revealed that allelic losses on 3p or 17p occurred frequently even in dysplastic lesions, and that allelic losses on these chromosomal arms were observed in cancerous tissues as well. We detected allelic losses of the short and long arms of chromosome 9 at low frequency in lesions with mild dysplasia but often in lesions with severe dysplasia and in intraepithelial cancers. Our results suggested that inactivation of tumor suppressor genes on 3p and 17p occurs at an early stage of esophageal carcinogenesis, and that genes on 9p and 9q are likely to play important roles in malignant changes.

Keywords

Esophageal Cancer Esophageal Squamous Cell Carcinoma Esophageal Carcinoma Allelic Loss Epithelial Growth Factor Receptor 
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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References

  1. 1.
    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
  2. 2.
    Jiang W, 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
  3. 3.
    Mori M, Tokino T, Yanagisawa A, Kanamori M, Kato Y, Nakamura Y (1992) Association between chromosome 11q13 amplification and prognosis of patients with oesophageal carcinomas. Eur J Cancer 28A:755–757PubMedCrossRefGoogle Scholar
  4. 4.
    Victor T, Toit RD, Jordaan AM, Bester AJ, vanHelden PD (1990) No evidence for point mutations in codons 12, 13, and 61 of the ras gene in a high-incidence area for esophageal gastric cancers. Cancer Res 50:4911–4914PubMedGoogle Scholar
  5. 5.
    Huang Y, Boynton RF, Blount PL, Silverstein RJ, Yin J, Tong Y, McDaniel TK, Newkirk C, Resau JH, Sridhara R, Reid B, Meltzer SJ (1992) Loss of heterozygosity involves multiple tumor suppressor genes in human esophageal cancers. Cancer Res 52:6525–6530PubMedGoogle Scholar
  6. 6.
    Boynton RF, Huang Y, Blount PL, Reid BJ, Raskind WH, Haggitt RC, Newkirk C, Reseau JH, Yin J, McDaniel TK, Meltzer SJ (1991) Frequent loss of heterozygosity at the retinoblastoma locus in human esophageal cancers. Cancer Res 51:5766–5769PubMedGoogle Scholar
  7. 7.
    Boynton RF, Blount PL, Yin J, Brown VL, Huang Y, Tong Y, McDaniel T, Newkirk C, Resau JH, Raskind WH, Haggitt RC, Reid BJ, Meltzer SJ (1992) Loss of heterozygosity involving the APC and MCC genetic loci occurs in the majority of human esophageal cancers. Proc Natl Acad Sci USA 89:3385–3388PubMedCrossRefGoogle Scholar
  8. 8.
    Meltzer SJ, Yin J, Huang Y, McDaniel TK, Newkirk C, Iseri O, Vogelstein B, Resau JH (1991) Reducrion to homozygosity involving p53 in esophageal cancers demonstrated by the polymerase chain reaction. Proc Natl Acad Sci USA 88:4976–4980PubMedCrossRefGoogle Scholar
  9. 9.
    Hollstein MC, Metcalf RA, Welsh JA, Montesano R, Harris CC (1990) Frequent mutation of the p.53 gene in human esophageal cancer. Proc Natl Acad Sci USA 87:9958–9961PubMedCrossRefGoogle Scholar
  10. 10.
    Bennett WP, Hollstein MC, He A, Zhu SM, Resau JH, Trump BF, Metcalf RA, Welsh JA, Midgley C, Lane DP, Harris CC (1991) Archival analysis of p53 gene and protein alterations in Chinese esophageal cancer. Oncogene 6:1779–1784PubMedGoogle Scholar
  11. 11.
    Huang Y, Boynton RF, Blount PL, Silverstein RJ, Yin J, Tong Y, McDaniel TK, Newkirk C, Resau JH, Sridhara R, Reid B, Meltzer SJ (1992) Loss of heterozygosity involves multiple tumor suppressor genes in human esophageal cancers. Cancer Res 52:6525–6530PubMedGoogle Scholar
  12. 12.
    Wagata T, Ishizaki K, Imamura M, Shimada Y, Ikenaga M, Tobe T (1991) Deletion of 17p and amplification of the int-2 gene in esophageal carci-nomas. Cancer Res 51:2113–2117PubMedGoogle Scholar
  13. 13.
    Huang Y, Meltzer SJ, Yin J, Tong Y, Chang EH, Srivastava S, McDaniel TK, Boynton RF, Zou Z-Q (1993) Altered messenger RNA and unique mutational profiles of p53 and Rb in human esophageal carcinomas. Cancer Res 53: 1889–1894PubMedGoogle Scholar
  14. 14.
    Goudie DR, Yuille MAR, Affara NA, Ferguson-Smith MA (1993) Mapping of the gene for multiple self-healing squamous epithelioma by haplotype analysis in families with common ancestry. Cytogenet Cell Genet 64:114Google Scholar
  15. 15.
    Tsuchiya E, Nakamura Y, Weng S-Y, Nakagawa K, Tsuchiya S, Sugano H, Kitagawa T (1992) Allelotype of non-small cell lung carcinoma: comparison between loss of heterozygosity in squamous cell carcinoma and adenocarcinoma. Cancer Res 52:2478–2481PubMedGoogle Scholar
  16. 16.
    Huang DP, Lo K-W, Choi PHK, Ng AYT, Tsao S-Y, Yiu GKC, Lee JCK (1991) Loss of heterozygosity on the short arm of chromosome 3 in nasopharyngeal carcinoma. Cancer Genet Cytogenet 54:91–99PubMedCrossRefGoogle Scholar
  17. 17.
    Yokoyama S, Yamakawa K, Tsuchiya E, Murata M, Sakiyama S, Nakamura Y (1992) Deletion mapping on the short arm of chromosome 3 in squamous cell carcinoma and adenocarcinoma of the lung. Cancer Res 52:873–877PubMedGoogle Scholar
  18. 18.
    Mori T, Yanagisawa A, Kato Y, Miura K, Nishihira T, Mori S, Nakamura Y (1994) Accumulation of genetic alterations during esophageal carcinogenesis. Hum Mol Genet 3:1969–1971PubMedCrossRefGoogle Scholar
  19. 19.
    Cairns P, Shaw ME, Knowles MA (1993) Initiation of bladder cancer may involve deletion of a tumorsuppressor gene on chromosome 9. Oncogene 8:1083–1085PubMedGoogle Scholar
  20. 20.
    Habuchi T, Ogawa O, Kakehi Y, Ogura K, Koshiba M, Hamazaki S, Takahashi R, Sugiyama T, Yoshida O (1993) Accumulated allelic losses in the development of invasive urothelial cancer. Int J Cancer 53:579–584PubMedCrossRefGoogle Scholar
  21. 21.
    Orlow I, Lianes P, Lacombe L, Dalbagni G, Reuter VE, Cardo CC (1994) Chromosome 9 allelic losses and microsatellite alterations in human bladder tumors. Cancer Res 54:2848–2851PubMedGoogle Scholar
  22. 22.
    Merlo A, Gabrielson E, Askin F, Sidransky D (1994) Frequent loss of chromosome 9 in human primary non-small cell lung cancer. Cancer Res 54:640–642PubMedGoogle Scholar
  23. 23.
    Sato S, Nakamura Y, Tsuchiya E (1994) Difference of allelotype between squamous cell carcinoma and adenocarcinoma of the lung. Cancer Res 54:5652–5655PubMedGoogle Scholar
  24. 24.
    Wicking C, Berkman J, Wainwright B, Chenevix-Trench G (1994) Fine genetic mapping of the gene for nevoid basal cell carcinoma. Genomics 22:505–511PubMedCrossRefGoogle Scholar
  25. 25.
    Goldstein A, Stewart C, Bale SJ, Dean M (1994) Localization of the gene for the nevoid basal cell carcinoma syndrome (NBCCS). Am J Hum Genet 54:765–773PubMedGoogle Scholar
  26. 26.
    Hahn H, Christiansen J, Wicking C, Zaphiropoulos PG, Chidambaram A, Gerrard B, Vorechovsky I, Bale AE, Toftgard R, Dean M, Wainwright B (1996) A mammalian patched homolog is expressed in target tissues of sonic hedgehog and maps to a region associated with developmental abnormalities. J Biol Chem 271:12125–12128PubMedCrossRefGoogle Scholar
  27. 27.
    Suzuki K, Daigo Y, Fukuda S, Tokino T, Isomura M, Isono K, Wainwright B, Nakamura Y (1997) No evidence of mutation in the human PTC gene, re-sponsible for NBCC syndrome, in human primary squamous cell carcinomas of the esophagus and lung. Jpn J Cancer Res (in press)Google Scholar
  28. 28.
    Aaltonen LA, Peltomaki P, Leach FS, Sistonen P, Rylkkanen 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 260:812–816PubMedCrossRefGoogle Scholar
  29. 29.
    Peltomaki P, Lothe RA, Aaltonen LA, Pylkkanen L, Nystrom-Lahti M, Seruca R, David L, Holm R, Ryberg D, Haugen A, Brogger A, Borresen A-L, de la Chapelle (1993) A microsatellite instability is associated with tumors that characterize the heredi-tary non-polyposis colorectal carcinoma syndrome. Cancer Res 53:5853–5855PubMedGoogle Scholar
  30. 30.
    Honchel R, Halling KC, Schaid DJ, Pittelkow M, Thibodeau SN (1994) Microsatellite instability in Muir-Torre syndrome. Cancer Res 54:1159–1163PubMedGoogle Scholar
  31. 31.
    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 cancer. Cancer Res 54:3373–3375PubMedGoogle Scholar
  32. 32.
    Kuwano H, Morita M, Tsutsui S, Kido Y, Mori M, Sugimachi K (1991) Comparison of characteristics of esophageal squamous cell carcinoma associated with head and neck cancer and those with gastric cancer. J Surg Oncol 46:107–109PubMedCrossRefGoogle Scholar
  33. 33.
    Franceschi S, Talamini R, Barra S, Baron AE, Negri E, Bidoli E, Serraino D, Vecchia CL (1990) Smoking and drinking in relation to cancers of the oral cavity, pharynx, larynx, and esophagus in northern Itlay. Cancer Res 50:6502–6507PubMedGoogle Scholar

Copyright information

© Springer Japan 1997

Authors and Affiliations

  • Yusuke Nakamura
    • 1
  • Takashi Tokino
    • 1
  • Minoru Isomura
    • 1
  • Johji Inazawa
    • 1
  • Takahisa Aoki
    • 1
  • Takahiro Mori
    • 1
  • Mamoru Shimada
    • 1
  • Koh Miura
    • 1
  • Kazufumi Suzuki
    • 1
  1. 1.Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical ScienceUniversity of TokyoMinato-ku, Tokyo 108Japan

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