Evaluating the performance of clinical criteria for predicting mismatch repair gene mutations in Lynch syndrome: A comprehensive analysis of 3,671 families.
Steinke, Verena 1; Holzapfel, Stefanie 1; Loeffler, Markus 2; Holinski-Feder, Elke 3,4; Morak, Monika 3,4; Schackert, Hans K. 5; Gorgens, Heike 5; Pox, Christian 6; Royer-Pokora, Brigitte 7; von Knebel-Doeberitz, Magnus 8,9; Buttner, Reinhard 10; Propping, Peter 1; Engel, Christoph 2; on behalf of the German HNPCC Consortium
[Miscellaneous Article]
International Journal Of Cancer.
135(1):69-77, July 1, 2014.
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: 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.
(C) 2014 John Wiley & Sons, Ltd