Novel strategy for optimal sequential application of clinical criteria, immunohistochemistry and microsatellite analysis in the diagnosis of hereditary nonpolyposis colorectal cancer
Corresponding Author
Christoph Engel
Institute of Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany
Fax: +49-341-9716109.
Institute for Medical Informatics, Statistics and Epidemiology, Haertelstrasse 16-18, 04107 Leipzig, GermanySearch for more papers by this authorJochen Forberg
Institute of Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany
Search for more papers by this authorElke Holinski-Feder
Department of Medical Genetics, Ludwig Maximilians University, Munich, Germany
Search for more papers by this authorConstanze Pagenstecher
Institute of Human Genetics, University Hospital, Bonn, Germany
Search for more papers by this authorJens Plaschke
Department of Surgical Research, Dresden University of Technology, Dresden, Germany
Search for more papers by this authorMatthias Kloor
Department of Molecular Pathology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany
Search for more papers by this authorChristopher Poremba
Department of Pathology, Heinrich Heine University, Düsseldorf, Germany
Search for more papers by this authorChristian P. Pox
Medical Department, Knappschaftskrankenhaus, Ruhr University Bochum, Bochum, Germany
Search for more papers by this authorJosef Rüschoff
Department of Pathology, Klinikum Kassel, Kassel, Germany
Search for more papers by this authorGisela Keller
Institute of Pathology, Klinikum rechts der Isar, Technical University, Munich, Germany
Search for more papers by this authorWolfgang Dietmaier
Institute of Pathology, University Regensburg, Regensburg, Germany
Search for more papers by this authorPetra Rümmele
Institute of Pathology, University Regensburg, Regensburg, Germany
Search for more papers by this authorNicolaus Friedrichs
Institute of Pathology, University of Bonn, Bonn, Germany
Search for more papers by this authorElisabeth Mangold
Institute of Human Genetics, University Hospital, Bonn, Germany
Search for more papers by this authorReinhard Buettner
Institute of Pathology, University of Bonn, Bonn, Germany
Search for more papers by this authorHans K. Schackert
Department of Surgical Research, Dresden University of Technology, Dresden, Germany
Search for more papers by this authorPeter Kienle
Department of Surgery, University Hospital of Heidelberg, Heidelberg, Germany
Search for more papers by this authorSusanne Stemmler
Institute of Human Genetics, Ruhr University Bochum, Bochum, Germany
Search for more papers by this authorGabriela Moeslein
Department of Surgery, Heinrich Heine University, Düsseldorf, Germany
Search for more papers by this authorMarkus Loeffler
Institute of Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany
Search for more papers by this authorthe German HNPCC Consortium
Search for more papers by this authorCorresponding Author
Christoph Engel
Institute of Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany
Fax: +49-341-9716109.
Institute for Medical Informatics, Statistics and Epidemiology, Haertelstrasse 16-18, 04107 Leipzig, GermanySearch for more papers by this authorJochen Forberg
Institute of Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany
Search for more papers by this authorElke Holinski-Feder
Department of Medical Genetics, Ludwig Maximilians University, Munich, Germany
Search for more papers by this authorConstanze Pagenstecher
Institute of Human Genetics, University Hospital, Bonn, Germany
Search for more papers by this authorJens Plaschke
Department of Surgical Research, Dresden University of Technology, Dresden, Germany
Search for more papers by this authorMatthias Kloor
Department of Molecular Pathology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany
Search for more papers by this authorChristopher Poremba
Department of Pathology, Heinrich Heine University, Düsseldorf, Germany
Search for more papers by this authorChristian P. Pox
Medical Department, Knappschaftskrankenhaus, Ruhr University Bochum, Bochum, Germany
Search for more papers by this authorJosef Rüschoff
Department of Pathology, Klinikum Kassel, Kassel, Germany
Search for more papers by this authorGisela Keller
Institute of Pathology, Klinikum rechts der Isar, Technical University, Munich, Germany
Search for more papers by this authorWolfgang Dietmaier
Institute of Pathology, University Regensburg, Regensburg, Germany
Search for more papers by this authorPetra Rümmele
Institute of Pathology, University Regensburg, Regensburg, Germany
Search for more papers by this authorNicolaus Friedrichs
Institute of Pathology, University of Bonn, Bonn, Germany
Search for more papers by this authorElisabeth Mangold
Institute of Human Genetics, University Hospital, Bonn, Germany
Search for more papers by this authorReinhard Buettner
Institute of Pathology, University of Bonn, Bonn, Germany
Search for more papers by this authorHans K. Schackert
Department of Surgical Research, Dresden University of Technology, Dresden, Germany
Search for more papers by this authorPeter Kienle
Department of Surgery, University Hospital of Heidelberg, Heidelberg, Germany
Search for more papers by this authorSusanne Stemmler
Institute of Human Genetics, Ruhr University Bochum, Bochum, Germany
Search for more papers by this authorGabriela Moeslein
Department of Surgery, Heinrich Heine University, Düsseldorf, Germany
Search for more papers by this authorMarkus Loeffler
Institute of Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany
Search for more papers by this authorthe German HNPCC Consortium
Search for more papers by this authorAbstract
Clinical criteria, microsatellite analysis (MSA) and immunohistochemistry (IHC) are important diagnostic tools for identification of hereditary nonpolyposis colorectal cancer (HNPCC) patients who are likely to carry pathogenic germline mutations in mismatch repair genes. Based on MSA and IHC results and subsequent mutation analyses of 1,119 unrelated index patients meeting the Amsterdam II criteria or the classical Bethesda guidelines, we analyzed the value of these tools to predict MLH1 and MSH2 mutations with the aim of establishing optimal strategies for their most efficient sequential use. The overall prevalence of pathogenic germline mutations in our cohort was 20.6% (95% CI = 18.3–23.0%) and 61.8% (95% CI = 56.8–66.6%), respectively, after MSA/IHC-based preselection. IHC was highly predictive (99.1%) and specific (99.6%) with regard to MSA. However, 14 out of 230 mutations (6%) escaped detection by IHC. Thus, IHC cannot be recommended to substitute MSA fully. Nonetheless, IHC is important to indicate the gene that is likely to be affected. To combine both methods efficiently, we propose a novel screening strategy that provides 2 alternative ways of sequential IHC and MSA application, either using IHC or MSA in the first place. A logistic regression model based on the age of the index patient at first tumor diagnosis and the number of fulfilled HNPCC criteria is used to allocate individual patients to that alternative pathway that is expected to be least expensive. A cost analysis reveals that about 25% of the costs can be saved using this strategy. © 2005 Wiley-Liss, Inc.
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