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EXO1 Variants Occur Commonly in Normal Population

Evidence against a Role in Hereditary Nonpolyposis Colorectal Cancer¹

Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands 2333 [S. J-C., C. T., R. F., J. W.]; Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, Finland FIN-00014 [T. P., S. V., V. L., L. A. A., A. K.]; Molecular Diagnostic Laboratory, Department of Clinical Biochemistry, Aarhus University Hospital, Brendstrupgaardsvej, Aarhus N/Skejby, Denmark DK-8200 [F. W., T. F. O.]; Ludwig Institute for Cancer Research, University of California San Diego School of Medicine, La Jolla, California 92093-0660 [R. D. K.]; Department of Surgery, Jyväskylä Central Hospital, Jyväskylä, Finland FIN-40620 [J-P. M.]; Second Department of Surgery [H. J.] and Department of Oncology [L. A. A.], Helsinki University Central Hospital, Helsinki, Finland FIN-00029; Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey, SM2 5NG, United Kingdom [S. B., R. H.]; Unit of Medical Genetics, The Norwegian Radium Hospital, Oslo, Norway N-0310 [P. M.]; and Netherlands Foundation for the Detection of Hereditary Tumours, Leiden, the Netherlands 2333 [H. V.]

Mutations in the currently known mismatch repair genes cannot explain all cases of hereditary nonpolyposis colorectal cancer (HNPCC), and novel predisposing genes areactively sought. Recently, mutations in the DNA repair gene EXO1 havebeen implicated in HNPCC. One truncating and several missense changes were observed in familial colorectal cancer (CRC) cases but not in controls. We evaluated a series of European CRC patients and population controls to clarify whether EXO1 variants may indeed predispose to familial CRC. Several variants observed in patients were also observed in controls with similar frequencies, including the truncating variant proposed previously to be a disease-causing mutation. Thus, little evidence was obtained to support a major causative role of EXO1 in HNPCC, although we cannot exclude a role for EXO1 as a low penetrance cancer susceptibility or modifying gene.

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