Originally published as JCO Early Release 10.1200/JCO.2005.03.7333 on August 14 2006

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Genotype-Phenotype Comparison of German MLH1 and MSH2 Mutation Carriers Clinically Affected With Lynch Syndrome: A Report by the German HNPCC Consortium

Timm Goecke, Karsten Schulmann, Christoph Engel, Elke Holinski-Feder, Constanze Pagenstecher, Hans K. Schackert, Matthias Kloor, Erdmute Kunstmann, Holger Vogelsang, Gisela Keller, Wolfgang Dietmaier, Elisabeth Mangold, Nicolaus Friedrichs, Peter Propping, Stefan Krüger, Johannes Gebert, Wolff Schmiegel, Josef Rueschoff, Markus Loeffler, Gabriela Moeslein

From University Hospital, Heinrich-Heine-University, Institute of Human Genetics and Department of Surgery, Düsseldorf; Ruhr-University Bochum, Department of Medicine and Institute of Human Genetics; St Josefs-Hospital Bochum-Linden, Bochum; University Leipzig, Institute of Medical Informatics, Statistics and Epidemiology, Leipzig; Ludwig-Maximilian-University, Institute of Medical Genetics; Technical University, Department of Surgery and Institute of Pathology, Munich; University Hospital, Institute of Human Genetics and Institute of Pathology, Bonn; University of Technology, Department of Surgical Research, Dresden; University Hospital, Department of Molecular Pathology, Institute of Pathology, Heidelberg; University Regensburg, Institute of Pathology, Regensburg; and the Klinikum Kassel, Institute of Pathology, Kassel, Germany

Address reprint requests to Timm Goecke, MD, Department of Human Genetics, Heinrich-Heine-Universität, Moorenstrasse 5, D-40225 Düsseldorf; e-mail: goecke{at}uni-duesseldorf.de

Purpose Lynch syndrome is linked to germline mutations in mismatch repair genes. We analyzed the genotype-phenotype correlations in the largest cohort so far reported.

Patients and Methods Following standard algorithms, we identified 281 of 574 unrelated families with deleterious germline mutations in MLH1 (n = 124) or MSH2 (n = 157). A total of 988 patients with 1,381 cancers were included in this analysis.

Results We identified 181 and 259 individuals with proven or obligatory and 254 and 294 with assumed MLH1 and MSH2 mutations, respectively. Age at diagnosis was younger both in regard to first cancer (40 v 43 years; P < .009) and to first colorectal cancer (CRC; 41 v 44 years; P = .004) in MLH1 (n = 435) versus MSH2 (n = 553) mutation carriers. In both groups, rectal cancers were remarkably frequent, and the time span between first and second CRC was smaller if the first primary occurred left sided. Gastric cancer was the third most frequent malignancy occurring without a similarly affected relative in most cases. All prostate cancers occurred in MSH2 mutation carriers.

Conclusion The proportion of rectal cancers and shorter time span to metachronous cancers indicates the need for a defined treatment strategy for primary rectal cancers in hereditary nonpolyposis colorectal cancer patients. Male MLH1 mutation carriers require earlier colonoscopy beginning at age 20 years. We propose regular gastric surveillance starting at age 35 years, regardless of the familial occurrence of this cancer. The association of prostate cancer with MSH2 mutations should be taken into consideration both for clinical and genetic counseling practice.

published online ahead of print at www.jco.org on August 14, 2006.

Supported by the Deutsche Krebshilfe (German Cancer Aid).

T.G. and K.S. contributed equally to this work.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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