Evaluating the performance of clinical criteria for predicting mismatch repair gene mutations in Lynch syndrome: A comprehensive analysis of 3,671 families

Verena Steinke, Stefanie Holzapfel, Markus Loeffler, Elke Holinski-Feder, Monika Morak, Hans K. Schackert, Heike Görgens, Christian Pox, Brigitte Royer-Pokora, Magnus Von Knebel-Doeberitz, Reinhard Büttner, Peter Propping, Christoph Engel

    Research output: Contribution to journalArticle

    17 Scopus citations

    Abstract

    Carriers of mismatch repair (MMR) gene mutations have a high lifetime risk for colorectal and endometrial cancers, as well as other malignancies. As mutation analysis to detect these patients is expensive and time-consuming, clinical criteria and tumor-tissue analysis are widely used as pre-screening methods. The aim of our study was to evaluate the performance of commonly applied clinical criteria (the Amsterdam I and II Criteria, and the original and revised Bethesda Guidelines) and the results of tumor-tissue analysis in predicting MMR gene mutations. We analyzed 3,671 families from the German HNPCC Registry and divided them into nine mutually exclusive groups with different clinical criteria. A total of 680 families (18.5%) were found to have a pathogenic MMR gene mutation. Among all 1,284 families with microsatellite instability-high (MSI-H) colorectal cancer, the overall mutation detection rate was 53.0%. Mutation frequencies and their distribution between the four MMR genes differed significantly between clinical groups (p < 0.001). The highest frequencies were found in families fulfilling the Amsterdam Criteria (46.4%). Families with loss of MSH2 expression had higher mutation detection rates (69.5%) than families with loss of MLH1 expression (43.1%). MMR mutations were found significantly more often in families with at least one MSI-H small-bowel cancer (p < 0.001). No MMR mutations were found among patients under 40-years-old with only colorectal adenoma. Familial clustering of Lynch syndrome-related tumors, early age of onset, and familial occurrence of small-bowel cancer were clinically relevant predictors for Lynch syndrome. What's new? Carriers of mismatch repair (MMR) gene mutations have a high lifetime risk for a wide range of malignancies - an autosomal-dominant genetic condition that is known as Lynch syndrome. As mutation analysis to detect these patients is expensive and time-consuming, clinical criteria are widely used for pre-screening. Only a few studies have however been conducted to investigate the predictive performance of such clinical criteria. This larger study identified familial clustering of Lynch syndrome-related tumours, early age of onset, and familial occurrence of small-bowel cancer as relevant predictors, which may assist clinicians in proving the existence of Lynch syndrome in a family.

    Original languageEnglish (US)
    Pages (from-to)69-77
    Number of pages9
    JournalInternational Journal of Cancer
    Volume135
    Issue number1
    DOIs
    StatePublished - Jul 1 2014

    Keywords

    • Bethesda guidelines
    • HNPCC
    • clinical diagnostic criteria
    • lynch syndrome
    • mismatch-repair defects

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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  • Cite this

    Steinke, V., Holzapfel, S., Loeffler, M., Holinski-Feder, E., Morak, M., Schackert, H. K., Görgens, H., Pox, C., Royer-Pokora, B., Von Knebel-Doeberitz, M., Büttner, R., Propping, P., & Engel, C. (2014). Evaluating the performance of clinical criteria for predicting mismatch repair gene mutations in Lynch syndrome: A comprehensive analysis of 3,671 families. International Journal of Cancer, 135(1), 69-77. https://doi.org/10.1002/ijc.28650