Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Microsatellite instability of selective target genes in HNPCC-associated colon adenomas

Oncogene volume 24, pages 2525–2535 (2005)Cite this article

Abstract

Microsatellite instability (MSI) occurs in most hereditary nonpolyposis colorectal cancers (HNPCC) and less frequently in sporadic tumors as the result of DNA mismatch repair (MMR) deficiency. Instability at coding microsatellites (cMS) in specific target genes causes frameshift mutations and functional inactivation of affected proteins, thereby providing a selective growth advantage to MMR deficient cells. At present, little is known about Selective Target Gene frameshift mutations in preneoplastic lesions. In this study, we examined 30 HNPCC-associated MSI-H colorectal adenomas of different grades of dysplasia for frameshift mutations in 26 cMS-bearing genes, which, according to our previous model, represent Selective Target genes of MSI. About 30% (8/26) of these genes showed a high mutation frequency (⩾50%) in colorectal adenomas, similar to the frequencies reported for colorectal carcinomas. Mutations in one gene (PTHL3) occurred significantly less frequently in MSI adenomas compared to published mutation rates in MSI carcinomas (36.0 vs 85.7%, P=0.023). Biallelic inactivation was observed in nine genes, thus emphasizing the functional impact of cMS instability on MSI tumorigenesis. Some genes showed a high frequency of frameshift mutations already at early stages of MSI colorectal tumorigenesis that increased with grade of dysplasia and transition to carcinoma. These include known Target Genes like BAX and TGFBR2, as well as three novel candidates, MACS, NDUFC2, and TAF1B. Overall, we have identified genes of potential relevance for the initiation and progression of MSI tumorigenesis, thus representing promising candidates for novel diagnostic and therapeutic approaches directed towards MMR-deficient tumors.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  • Aaltonen LA, Peltomaki P, Leach FS, Sistonen P, Pylkkanen L, Mecklin JP, Jarvinen H, Powell SM, Jen J and Hamilton SR . (1993). Science, 260, 812–816.

  • Akiyama Y, Iwanaga R, Saitoh K, Shiba K, Ushio K, Ikeda E, Iwama T, Nomizu T and Yuasa Y . (1997). Gastroenterology, 112, 33–39.

  • Alazzouzi H, Domingo E, Gonzalez S, Blanco I, Armengol M, Espin E, Plaja A, Schwartz S, Capella G and Schwartz Jr S . (2005). Hum. Mol. Genet., 14, 235–239.

  • Blackshear PJ . (1993). J. Biol. Chem., 268, 1501–1504.

  • Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW, Meltzer SJ, Rodriguez-Bigas MA, Fodde R, Ranzani GN and Srivastava S . (1998). Cancer Res., 58, 5248–5257.

  • Comai L, Zomerdijk JC, Beckmann H, Zhou S, Admon A and Tjian R . (1994). Science, 266, 1966–1972.

  • Duval A, Gayet J, Zhou XP, Iacopetta B, Thomas G and Hamelin R . (1999). Cancer Res., 59, 4213–4215.

  • Duval A and Hamelin R . (2002). Ann. Genet., 45, 71–75.

  • Duval A, Rolland S, Compoint A, Tubacher E, Iacopetta B, Thomas G and Hamelin R . (2001). Hum. Mol. Genet., 10, 513–518.

  • Fearon ER and Vogelstein B . (1990). Cell, 61, 759–767.

  • Furlan D, Casati B, Cerutti R, Facco C, Terracciano L, Capella C and Chiaravalli AM . (2002). J. Pathol., 197, 603–609.

  • Goel A, Arnold CN, Niedzwiecki D, Chang DK, Ricciardiello L, Carethers JM, Dowell JM, Wasserman L, Compton C, Mayer RJ, Bertagnolli MM and Boland CR . (2003). Cancer Res., 63, 1608–1614.

  • Grady WM, Rajput A, Myeroff L, Liu DF, Kwon K, Willis J and Markowitz S . (1998). Cancer Res., 58, 3101–3104.

  • Holm S . (1979). Scand J. Statist., 6, 65–70.

  • Iino H, Simms L, Young J, Arnold J, Winship IM, Webb SI, Furlong KL, Leggett B and Jass JR . (2000). Gut, 47, 37–42.

  • Ionov Y, Peinado MA, Malkhosyan S, Shibata D and Perucho M . (1993). Nature, 363, 558–561.

  • Kim NG, Rhee H, Li LS, Kim H, Lee JS, Kim JH, Kim NK and Kim H . (2002). Oncogene, 21, 5081–5087.

  • Kroemer G, Dallaporta B and Resche-Rigon M . (1998). Annu. Rev. Physiol., 60, 619–642.

  • Leist M, Single B, Castoldi AF, Kuhnle S and Nicotera P . (1997). J. Exp. Med., 185, 1481–1486.

  • Lengauer C, Kinzler KW and Vogelstein B . (1997). Nature, 386, 623–627.

  • Li LS, Kim NG, Kim SH, Park C, Kim H, Kang HJ, Koh KH, Kim SN, Kim WH, Kim NK and Kim H . (2003). Am. J. Pathol., 163, 1429–1436.

  • Li Y, Martin LD, Spizz G and Adler KB . (2001). J. Biol. Chem., 276, 40982–40990.

  • Loeffen JL, Triepels RH, van den Heuvel LP, Schuelke M, Buskens CA, Smeets RJ, Trijbels JM and Smeitink JA . (1998). Biochem. Biophys. Res. Commun., 253, 415–422.

  • Lothe RA . (1997). Mol. Med. Today, 3, 61–68.

  • Loukola A, Salovaara R, Kristo P, Moisio AL, Kaariainen H, Ahtola H, Eskelinen M, Harkonen N, Julkunen R, Kangas E, Ojala S, Tulikoura J, Valkamo E, Jarvinen H, Mecklin JP, de la CA and Aaltonen LA . (1999). Am. J. Pathol., 155, 1849–1853.

  • Lynch HT and de la Chapelle A . (2003). N. Engl. J. Med., 348, 919–932.

  • Malkhosyan S, Rampino N, Yamamoto H and Perucho M . (1996). Nature, 382, 499–500.

  • Markowitz S, Wang J, Myeroff L, Parsons R, Sun L, Lutterbaugh J, Fan RS, Zborowska E, Kinzler KW and Vogelstein B . (1995). Science, 268, 1336–1338.

  • Miyakura Y, Sugano K, Konishi F, Ichikawa A, Maekawa M, Shitoh K, Igarashi S, Kotake K, Koyama Y and Nagai H . (2001). Gastroenterology, 121, 1300–1309.

  • Mori Y, Yin J, Rashid A, Leggett BA, Young J, Simms L, Kuehl PM, Langenberg P, Meltzer SJ and Stine OC . (2001). Cancer Res., 61, 6046–6049.

  • Myeroff LL, Parsons R, Kim SJ, Hedrick L, Cho KR, Orth K, Mathis M, Kinzler KW, Lutterbaugh J and Park K . (1995). Cancer Res., 55, 5545–5547.

  • Parsons R, Myeroff LL, Liu B, Willson JK, Markowitz SD, Kinzler KW and Vogelstein B . (1995). Cancer Res., 55, 5548–5550.

  • Percesepe A, Pedroni M, Sala E, Menigatti M, Borghi F, Losi L, Viel A, Genuardi M, Benatti P, Roncucci L, Peltomaki P and Ponz de Leon M . (2000). Genes Chromosomes Cancer, 27, 424–429.

  • R Development Core Team (2004) R: a language and environment for statistical computing, 1.9.1, R Foundation for Statistical Computing, Vienna, Austria, ISBN 3-900051-00-3, http://www.R-project.org.

  • Rampino N, Yamamoto H, Ionov Y, Li Y, Sawai H, Reed JC and Perucho M . (1997). Science, 275, 967–969.

  • Rodriguez-Bigas MA, Boland CR, Hamilton SR, Henson DE, Jass JR, Khan PM, Lynch H, Perucho M, Smyrk T, Sobin L and Srivastava S . (1997). J. Natl. Cancer Inst., 89, 1758–1762.

  • Samowitz WS and Slattery ML . (1997). Gastroenterology, 112, 1515–1519.

  • Samowitz WS, Slattery ML, Potter JD and Leppert MF . (1999). Am. J. Pathol., 154, 1637–1641.

  • Schwartz Jr S, Yamamoto H, Navarro M, Maestro M, Reventos J and Perucho M . (1999). Cancer Res., 59, 2995–3002.

  • Shibata D, Peinado MA, Ionov Y, Malkhosyan S and Perucho M . (1994). Nat. Genet., 6, 273–281.

  • Souza RF, Appel R, Yin J, Wang S, Smolinski KN, Abraham JM, Zou TT, Shi YQ, Lei J, Cottrell J, Cymes K, Biden K, Simms L, Leggett B, Lynch PM, Frazier M, Powell SM, Harpaz N, Sugimura H, Young J and Meltzer SJ . (1996). Nat. Genet., 14, 255–257.

  • Sugai T, Takahashi H, Habano W, Nakamura S, Sato K, Orii S and Suzuki K . (2003). J. Pathol., 200, 168–176.

  • Sutter C, Gebert J, Bischoff P, Herfarth C and von Knebel Doeberitz M . (1999). Mol. Cell. Probes, 13, 157–165.

  • Thibodeau SN, Bren G and Schaid D . (1993). Science, 260, 816–819.

  • Vasen HF, Watson P, Mecklin JP and Lynch HT . (1999). Gastroenterology, 116, 1453–1456.

  • Woerner SM, Benner A, Sutter C, Schiller M, Yuan YP, Keller G, Bork P, von Knebel Doeberitz M and Gebert JF . (2003). Oncogene, 22, 2226–2235.

  • Woerner SM, Gebert J, Yuan YP, Sutter C, Ridder R, Bork P and von Knebel Doeberitz M . (2001). Int. J. Cancer, 93, 12–19.

  • Yagi OK, Akiyama Y, Nomizu T, Iwama T, Endo M and Yuasa Y . (1998). Gastroenterology, 114, 268–274.

Download references

Acknowledgements

We gratefully acknowledge the excellent technical assistance of B Kuchenbuch and I Voehringer. We also thank Axel Benner (Central Unit Biostatistics, German Cancer Research Center, Heidelberg, Germany) and Christoph Engel (Center for Documentation and Biometry, Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Germany) for excellent statistical advice. This work was funded by a grant of the Deutsche Krebshilfe to the German HNPCC Consortium.

Author information

Author notes

  1. Stefan M Woerner and Matthias Kloor: These two authors contributed equally to this work

Authors and Affiliations

  1. Institute of Molecular Pathology, University of Heidelberg, Germany

    Stefan M Woerner, Matthias Kloor, Magnus von Knebel Doeberitz & Johannes F Gebert

  2. Department of General Surgery, University of Göttingen, Germany

    Annegret Mueller

  3. Department of Pathology, Klinikum Kassel, Germany

    Josef Rueschoff

  4. Institute of Pathology, University Hospital Bonn, Germany

    Nicolaus Friedrichs & Reinhard Buettner

  5. Institute of Pathology, University of Heidelberg, Germany

    Moriz Buzello

  6. Department of Surgery, University of Heidelberg, Germany

    Peter Kienle & Hanns-Peter Knaebel

  7. Department of Internal Medicine, Knappschaftskrankenhaus, University of Bochum, Germany

    Erdmute Kunstmann

  8. Human Genetics, University of Bochum, Germany

    Erdmute Kunstmann

  9. Institute of Human Genetics, University Hospital Bonn, Germany

    Constanze Pagenstecher

  10. Department of Surgical Research, Dresden University of Technology, Germany

    Hans K Schackert

  11. Department of Surgery, University of Düsseldorf, Germany

    Gabriela Möslein

  12. Department of Surgery, University of Technology, Munich, Germany

    Holger Vogelsang

Authors
  1. Stefan M Woerner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Matthias Kloor
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Annegret Mueller
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Josef Rueschoff
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nicolaus Friedrichs
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Reinhard Buettner
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Moriz Buzello
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Peter Kienle
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hanns-Peter Knaebel
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Erdmute Kunstmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Constanze Pagenstecher
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Hans K Schackert
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Gabriela Möslein
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Holger Vogelsang
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Magnus von Knebel Doeberitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Johannes F Gebert
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

the German HNPCC Consortium

Corresponding author

Correspondence to Johannes F Gebert.

Appendix

Appendix

The German HNPCC-Consortium consists of the following centers (in alphabetic order): clinical centers in Bochum (in addition to author: Frank Brasch, Jörg T Epplen, Stefan Hahn, H-P Mueller, Karsten Schulmann, Jörg Willert, Wolf Schmiegel), Bonn (Peter Propping, Elisabeth Mangold, Waltraut Friedl, Christof Lamberti, Tilman Sauerbruch, Holger Lauschke), Düsseldorf (in addition to author: Anika Hansmann, Tilmann Vogel, Claudia Wieland, Timm Goecke, Christopher Poremba, Daniel Gödde), Dresden (in addition to author: Stefan Krüger, Jens Plaschke, Daniela E. Aust, Ruth Höhl, Steffen R. Pistorius), Heidelberg (in addition to authors: Mirjam Tariverdian, Uta Mazitschek, Friedrich Cremer, Monika Keller), München (in addition to author: Elke Holinski-Feder, Yvonne Müller-Koch, Christiane Tympner, Gisela Keller, Wolfgang Dietmaier, Petra Rümmele), center for reference pathology Kassel (in addition to author: Thomas Brodegger), and center for documentation and biometry in Leipzig (Christoph Engel, Jochen Forberg, Marlies Herold, Markus Loeffler).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Woerner, S., Kloor, M., Mueller, A. et al. Microsatellite instability of selective target genes in HNPCC-associated colon adenomas. Oncogene 24, 2525–2535 (2005). https://doi.org/10.1038/sj.onc.1208456

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1208456

Keywords

This article is cited by

Search

Advanced search

Quick links