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Prevalence of the mismatch-repair-deficient phenotype in colonic adenomas arising in HNPCC patients: results of a 5-year follow-up study

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Abstract

In hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, more than 90% of the carcinomas show microsatellite instability (MSI) due to a loss of mismatch repair (MMR) function. Although adenomas are very common in HNPCC and demonstrate an accelerated adenoma–carcinoma sequence, data about the prevalence and development of MSI in these early neoplastic lesions are lacking. To determine whether MSI and loss of MMR-protein expression are already present in early stages of tumorigenesis and could therefore be used as a screening tool to identify HNPCC patients before they develop an invasive carcinoma, we analyzed 71 adenomas of 36 HNPCC patients during a 5-year follow-up study. These 36 patients were part of a cohort of 122 HNPCC patients who were investigated at the Institute of Pathology, Klinikum Kassel, as part of the multicentric German HNPCC Consortium, which currently serves more than 2,880 registered families. The diagnosis of HNPCC was based either on the detection of a pathogenic germline mutation in the MSH2, MLH1, or MSH6 genes or in cases where a pathogenic mutation was not found; diagnosis of HNPCC was made, because all patients fulfilled the Amsterdam or Bethesda criteria and revealed a high degree of MSI (MSI-H) as well as loss of one of the MMR proteins by IHC in the cancer tissue. We found that most adenomas (58/71) were MSI-H and had loss of MMR-protein expression. Of the 71 adenomas, 3 were MSI-H with expression of all MMR proteins, and 3 out of 71 displayed loss of a MMR protein with the microsatellites being classified as microsatellite stable (MSS). However, 7 of the 31 adenomas that were located more than 5 cm away from the carcinoma revealed an MSS status (n=6) or low in MSI (n=1) and expressed all MMR proteins. In summary, a significant percentage of HNPCC-associated adenomas (7/31, 22.6%) developing at a distance of more than 5 cm from the corresponding carcinoma did not show the MSI-H MMR-deficient phenotype and expressed all MMR genes. To our knowledge, this is the first study that shows that in most HNPCC patients, the mutator pathway is already detectable in adenomas, but MMR-proficient adenomas can also be found. Therefore, screening for MMR deficiency should not be applied routinely in adenomas with the goal to identify HNPCC patients.

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Acknowledgements

This work was supported by the German Cancer Aid (Deutsche Krebshilfe) to J.R. and R.B. (grant 70-2401-Rü), the Deutsche Forschungsgemeinschaft to R.B. (Bu 672/10-1, 10-2), the German Ministry for Education and Research (BMBF) to J.R. (grant AN 020113007601).

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Authors and Affiliations

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

    Annegret Müller, Carmen Beckmann & Heinz Becker

  2. Institute of Pathology, Klinikum Kassel, Mönchebergstrasse 41–43, 34125, Kassel, Germany

    Annegret Müller, Gabriela Westphal & Josef Rüschoff

  3. Department of Pathology, Thomas Jefferson University, Philadelphia, PA, USA

    Tina Bocker Edmonston

  4. Institute of Pathology, University Hospital of Bonn, Bonn, Germany

    Nicolaus Friedrichs & Reinhard Büttner

  5. Institute of Pathology, University of Regensburg, Regensburg, Germany

    Wolfgang Dietmaier

  6. Institute of Pathology, University Clinic Bergmannsheil, Ruhr University Bochum, Bochum, Germany

    Frank E. Brasch

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

    Matthias Kloor

  8. Institute of Pathology, Heinrich-Heine-University, Düsseldorf, Germany

    Christoph Poremba

  9. Institute of Pathology, Technical University, Munich, Germany

    Gisela Keller

  10. Institute of Pathology, Technical University Dresden, Dresden, Germany

    Daniela E. Aust

  11. Department of General Surgery, Klinikum Kassel, Kassel, Germany

    Jürgen Faß

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  1. Annegret Müller
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German HNPCC Consortium

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Correspondence to Josef Rüschoff.

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An invited commentary on this paper is available at http://dx.doi.org/10.1007/s00384-005-0081-6

See Appendix A for a list of the members of this consortium.

Appendix

Appendix

The German HNPCC Consortium consists of the following centers (in alphabetical order): clinical centers in Bochum (in addition to the following authors: Jörg T. Epplen, Stefan Hahn, Erdmute Kunstmann, Christian Pox, and Jörg Willert), Bonn (in addition to the following authors: Elisabeth Mangold, Constanze Pagenstecher, Waltraut Friedl, Holger Lauschke, Andreas Hirner, Christof Lamberti, Peter Propping, and Tilman Sauerbruch), Düsseldorf (in addition to author PD G. Möslein, M.D.), Dresden (in addition to the following authors: Daniela E. Aust, Friedrich Balck, Ruth Höhl, Friedmar R. Kreuz, Stefan Krüger, Steffen R. Pistorius, and Jens Plaschke), Heidelberg (in addition to author Prof. Magnus von Knebel-Döberitz), München-Regensburg (in addition to the following authors: Wolfgang Dietmaier, Reinhard Kopp, Peter Lohse, Michael Muders, Yvonne Müller-Koch, and Holger Vogelsang), center for reference pathology Kassel (in addition to author Thomas Brodegger), and center for documentation and biometry in Leipzig (in addition to the following authors: Christoph Engel, Jochen Forberg, Marlies Herold, and Markus Löffler).

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German HNPCC Consortium., Müller, A., Beckmann, C. et al. Prevalence of the mismatch-repair-deficient phenotype in colonic adenomas arising in HNPCC patients: results of a 5-year follow-up study. Int J Colorectal Dis 21, 632–641 (2006). https://doi.org/10.1007/s00384-005-0073-6

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