Evaluating the performance of clinical criteria for predicting mismatch repair gene mutations in Lynch syndrome: A comprehensive analysis of 3671 families.

Steinke V, Holzapfel S, Loeffler M, Holinski-Feder E, Morak M, Schackert HK, Görgens H, Pox C, Royer-Pokora B, von Knebel-Doeberitz M, Büttner R, Propping P, Engel C; On behalf of the German HNPCC Consortium.

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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 tumour-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 tumour-tissue analysis in predicting MMR gene mutations. We analyzed 3671 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 1284 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 tumours, early age of onset, and familial occurrence of small-bowel cancer were clinically relevant predictors for Lynch syndrome. © 2013 Wiley Periodicals, Inc.