Evaluating the performance of clinical criteria for predicting mismatch repair gene mutations in Lynch syndrome: a comprehensive analysis of 3,671 families.
GC-HNPCC - German Consortium for Hereditary Non-Polyposis Colorectal Cancer

Abstract (Expand)

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.

Authors: V. Steinke, S. Holzapfel, M. Loeffler, E. Holinski-Feder, M. Morak, H. K. Schackert, H. Gorgens, C. Pox, B. Royer-Pokora, M. von Knebel-Doeberitz, R. Buttner, P. Propping, C. Engel

Date Published: 1st Jul 2014

Publication Type: Not specified

Human Diseases: colon cancer

PREMM1,2,6
GC-HNPCC - German Consortium for Hereditary Non-Polyposis Colorectal Cancer

The PREMM1,2,6 has been developed as a pretest to decide whether patients suspected of having Lynch syndrome should be tested for germline mismatch repair gene mutations. "PREMM1,2,6" is a logistic regression model. It calculates the risk of having a mutation in the mismatch repair genes MLH1, MSH2 and MSH6 (for single genes and overall) based on the personal and familial cancer history of the proband (colorectal, endometrial, and other Lynch syndrome related cancers).

Creators: Silke Zachariae, Christoph Engel, Kastrinos et al.

Submitter: Silke Zachariae

PREMM5
GC-HNPCC - German Consortium for Hereditary Non-Polyposis Colorectal Cancer

The PREMM5 has been developed as a pretest to decide whether patients suspected of having Lynch syndrome should be tested for germline mismatch repair gene mutations. In contrast to "PREMM1,2,6" it can be used to predict mutation probabilities in unaffected index patients. "PREMM5" is a logistic regression model. It calculates the risk of having a mutation in the mismatch repair genes MLH1, MSH2/EPCAM, MSH6 and PMS2 (for single genes and overall) based on the personal and familial cancer history ...

Creators: Silke Zachariae, Christoph Engel, Kastrinos et al.

Submitter: Silke Zachariae

MMRpredict
GC-HNPCC - German Consortium for Hereditary Non-Polyposis Colorectal Cancer

Depending on the calculated mutation probability genetic counsellors can decide whether patients should undergo further analysis of microsatellite instability and immunohistochemistry. The model is recommended for patients with an age at colorectal cancer diagnosis of 55 or younger.

"MMRpredict" is a risk prediction model for patients with colorectal cancer (Barnetson et al. 2006). It calculates the risk of having a mutation in the mismatch repair genes MLH1, MSH2 and MSH6 (overall probability) ...

Creators: Christoph Engel, Silke Zachariae

Submitter: Silke Zachariae

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