Systematic Detection of DNA Alteration in Cancer Tissue

  • Yasushi Okazaki
  • Tomoya Ohsumi
  • Hisato Okuizumi
  • William A. Held
  • Yoshihide Hayashizaki
Part of the Springer Lab Manuals book series (SLM)


Tumorigenesis is a multistep process involving both epigenetic and genetic alterations [1,2]. The identification of gain of function mutations in proto-oncogenes and loss of function mutations in tumor suppressor genes has provided a rationale for understanding tumorigenesis. However, the mutation of a single protooncogene or tumor suppressor gene is usually not sufficient to cause neoplastic growth. Tumor progression depends on secondary events which arise during cell proliferation. The genetic targets for these secondary events would be expected to depend on the initiating event as well as developmental and tissue-specific factors regulating cell proliferation. Additional steps involving angiogenesis, invasive growth, and metastasis generate more serious life-threatening malignant disease [3]. Although the “cast of characters” involved in these processes is large and growing, our understanding of the process is complicated by the large number of genes involved, developmental and tissue-specific differences in growth regulation, and the stochastic nature of the process.


Spot Intensity Simple Sequence Length Polymorphism Restriction Landmark Genomic Scanning Simple Sequence Length Polymorphism Restriction Landmark Genomic Scanning Profile 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Weinberg RA (1991) Tumor suppressor genes. Science 254:1138–1145PubMedCrossRefGoogle Scholar
  2. 2.
    Aaronson SA (1991) Growth factors and cancer. Science 254:1146–1153PubMedCrossRefGoogle Scholar
  3. 3.
    Adams JM, Cory S (1991) Transgenic models of tumor development. Science 254:1161–1167PubMedCrossRefGoogle Scholar
  4. 4.
    Laird PW, Jaenisch R (1994) DNA methylation and cancer. Hum Mol Genet 3:1487–1495PubMedGoogle Scholar
  5. 5.
    Counts JL, Goodman JI (1995) Alterations in DNA methylation may play a variety of roles in carcinogenesis. Cell 83:13–15PubMedCrossRefGoogle Scholar
  6. 6.
    Vachtenheim J, Horakova I, Novotna H (1994) Hypomethylation of CCGG sites in the 3′ region of H-ras protooncogene is frequent and is associatedwith H-ras allele loss in non-small cell lung cancer. Cancer Res 54:1145–1148PubMedGoogle Scholar
  7. 7.
    Ohtani-Fujita N, Fujita T, Aoike A, Osifchin NE, Robbins PD, Sakai T (1993) CpG methylation inactivates the promoter activity of the human retinoblastoma tumor-suppressor gene. Oncogene 8:1063–1067PubMedGoogle Scholar
  8. 8.
    Herman JG, Latif F, Weng Y, Lerman MI, Zbar B, Liu S, Samid D, Duan D-SR, Gnarra JR, Linehan WM, Baylin SB (1994) Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. Proc Natl Acad Sci USA 91:9700–9704PubMedCrossRefGoogle Scholar
  9. 9.
    Ottaviano YL, Issa J-P, Parl FF, Smith HS, Baylin SB, Davidson NE (1994) Methylation of the estrogen receptor gene CpG island marks loss of estrogen receptor expression in human breast cancer cells. Cancer Res 54:2552–2555PubMedGoogle Scholar
  10. 10.
    Issa J-PJ, Ottaviano YL, Celano P, Hamilton SR, Davidson NE, Baylin, SB (1994) Methylation of the oestrogen receptor CpG island links ageing and neoplasia in human colon. Nat Genet 7:536–540PubMedCrossRefGoogle Scholar
  11. 11.
    Wu J, Issa J-P, Herman J, Bassett DE Jr, Nelkin BD, Baylin SB (1993) Expression of an exogenous eukaryotic DNA methyltransferase gene induces transformation of NIH 3T3 cells. Proc Natl Acad Sci USA 90:8891–8895PubMedCrossRefGoogle Scholar
  12. 12.
    Kallioniemi A, Kallioniemi O-P, Sudar D, Rutovitz D, Gray JW, Waldman F, Pinkel D (1992) Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors. Science 258:818–821PubMedCrossRefGoogle Scholar
  13. 13.
    Lisitsyn NA, Lisitsina NM, Dalbagni G, Barker P, Sanchez CA, Gnarra J, Linehan WM, Reid BJ, Wigler MH (1995) Comparative genomic analysis of tumors: detection of DNA losses and amplification. Proc Natl Acad Sci USA 92:151–155PubMedCrossRefGoogle Scholar
  14. 14.
    Dietrich W, Katz H, Lincoln SE, Shin H-S, Friedman J, Dracopoli NC, Lander ES (1992) A genetic map of the mouse suitable for typing intraspecific crosses. Genetics 131:423–447PubMedGoogle Scholar
  15. 15.
    Hatada I, Hayashizaki Y, Hirotsune S, Komatusbara S, Mukai T (1991) A genomic scanning method for higher organisms using restriction sites as landmark. Proc Natl Acad Sci USA 88:9523–9527PubMedCrossRefGoogle Scholar
  16. 16.
    Ohsumi T, Okazaki Y, Okuizumi H, Shibata K, Hanami T, Mizuno Y, Takahara T, Sasaki N, Ueda M, Muramatsu M, Kerns KA, Chapman VM, Held WA, Hayashizaki Y (1995) Loss of hetrozygosity in chromosome 1, 5, 7 and 13 in mouse hepatoma detected by systematic genome-wide scanning using RLGS genetic map. Biochem Biophys Res Commun 212:632–639PubMedCrossRefGoogle Scholar
  17. 17.
    Dietrich WF, Miller J, Steen R, Merchant MA, Damron-Boles D, Husain Z, Dredge R, Daly MJ, Ingalls KA, O’Connor TJ, Evans CA, DeAngelis MM, Levinson DM, Kruglyak L, Goodman N, Copeland NG, Jenkins NA, Hawkins TL, Stein L, Page DC, Lander ES (1996) A comprehensive genetic map of the mouse genome. Nature 380:149–152PubMedCrossRefGoogle Scholar
  18. 18.
    Dib C, Faure S, Fizames C, Samson D, Drouot N, Vignal A, Millasseau P, Marc S, Hazan J, Seboun E, Lathrop M, Gyapay G, Morissette J, Weissenbach J (1996) A comprehensive genetic map of the human genome based on 5,264 microsatellites. Nature 380:152–154PubMedCrossRefGoogle Scholar
  19. 19.
    Dietrich WF, Radany EH, Smith JS, Bishop JM, Hanahan D, Lander ES (1994) Genome-wide search for loss of heterozygosity in transgenic mouse tumors reveals candidate tumor suppressor genes on chromosomes 9 and 16. Proc Natl Acad Sci USA 90:9451–9455CrossRefGoogle Scholar
  20. 20.
    Hayashizaki Y, Hirotsune S, Okazaki Y, Hatada I, Shibata H, Kawai J, Hirose K, Watanabe S, Fushiki S, Wada S, Sugimoto T, Kobayakawa K, Kawara T, Katsuki M, Sibuya T, Mukai T (1993) Restriction landmark genomic scanning method and its various applications. Electrophoresis 14:251–258PubMedCrossRefGoogle Scholar
  21. 21.
    Hirotsune S, Hatada I, Komatsubara H, Nagai H, Kanji K, Kobayakawa K, Kawara T, Nakagawara A, Fujii K, Mukai T, Hayashizaki Y (1992) New approach for detection of amplification in cancer DNA using Restriction Landmark Genomic Scanning. Cancer Res 52:3642–3647PubMedGoogle Scholar
  22. 22.
    Nagai H, Ponglikitmongkol M, Mita E, Ohmachi Y, Yoshikawa H, Saeki R, Yumoto Y, Nakanishi T, Matsubara K (1994) Aberration of genomic DNA in association with human hepatocellular carcinomas detected by 2-dimen-sional gel analysis. Cancer Res 54:1545–1550PubMedGoogle Scholar
  23. 23.
    Miwa W, Yashima K, Sekine T, Sekiya T (1995) Demethylation of a repetitive DNA sequence in human cancers. Electrophoresis 16:227–232PubMedCrossRefGoogle Scholar
  24. 24.
    Hayashizaki Y, Hirotsune S, Okazaki Y, Shibata H, Akasako A, Muramatsu M, Kawai J, Hirasawa T, Watanabe S, Shiroishi T, Moriwaki K, Taylor BA, Matsuda Y, Elliott RW, Manly KF, Chapman VM (1994) A genetic linkage map of the mouse using Restriction Landmark Genomic Scanning (RLGS). Genetics 138:1207–1238PubMedGoogle Scholar
  25. 25.
    Okuizumi H, Okazaki Y, Ohsumi T, Hanami T, Mizuno Y, Muramatsu M, Hayashizaki Y, Plass C, Chapman VM (1995) A single gel analysis of 575 dominant and codominant restriction landmark genomic scanning loci in mice interspecific backcross progeny. Electrophoresis 16:253–260PubMedCrossRefGoogle Scholar
  26. 26.
    Held WA, Mullins JJ, Kuhn NJ, Gallagher JF, Gu GD, Gross KW (1989) T antigen expression and tumorigenesis in transgenic mice containing a mouse major urinary protein/SV40 T antigen hybrid gene. EMBO J 8:183–191PubMedGoogle Scholar
  27. 27.
    Schumacher P, Held WA, Yang D, Biempica L, Rogler CE (1991) Selective amplification of periportal transitional cells precedes formation of hepatocellular carcinoma in SV40 large tag transgenic mice. Am J Pathol 139:231–241Google Scholar
  28. 28.
    Akama TO, Okazaki Y, Ito M, Okuizumi H, Konno H, Muramatsu M, Plass C, Held WA, Hayashizaki Y (1997) RLGS-M based genome-wide scanning of mouse liver tumors for alterations in DNA methylation status. Cancer Res, in pressGoogle Scholar
  29. 29.
    Held WA, Pazik J, O’Brien JG, Kerns K, Gobey M, Meis R, Kenny L, Rustum Y (1994) Genetic analysis of liver tumorigenesis in SV40 T antigen transgenic mice implies a role for imprinted genes. Cancer Res 54:6489–6495PubMedGoogle Scholar

Copyright information

© Springer Japan 1997

Authors and Affiliations

  • Yasushi Okazaki
  • Tomoya Ohsumi
  • Hisato Okuizumi
  • William A. Held
  • Yoshihide Hayashizaki

There are no affiliations available

Personalised recommendations