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Lack of MSH2 and MSH6 Characterizes Endometrial but not Colon Carcinomas in Hereditary Nonpolyposis Colorectal Cancer¹

Institute of Medical Radiobiology, University of Zürich, 8008 Zürich, Switzerland [P. S., K. T., J. J.]; Departments of Medical Genetics [A-L. M., S. A. K., R. S., P. P.] and Pathology [R. S., J. A.], Haartman Institute, University of Helsinki, 00014 Helsinki, Finland; Department of Obstetrics and Gynaecology, Helsinki University Central Hospital, 00290 Helsinki, Finland [R. B.]; Division of Human Cancer Genetics, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210 [P. P.]; and Division of Genetics, Department of Biosciences [R. V., M. N-L.], University of Helsinki, 00014 Helsinki, Finland

Hereditary nonpolyposis colorectal cancer syndrome is associated with an inherited predisposition to primarily colorectal cancer (CRC) and endometrial cancer (EC); however, the biological basis of the organ involvement remains unknown. As an attempt to explore whether the expression levels of MLH1, MSH2, and MSH6 may play a role, we used immunohistochemistry to study 42 ECs and 35 CRCs from patients carrying the same predisposing mutations. Among MSH2 mutation carriers, MLH1 was expressed in both tumor types, whereas MSH2 and, in many cases, also MSH6, were absent. Remarkably, among MLH1 mutation carriers, 54% of ECs (21 of 39), but none of the CRCs (0 of 32), lacked the MSH2 and/or MSH6 protein in addition to lacking MLH1 protein expression. These results demonstrate a marked difference between hereditary nonpolyposis colorectal cancer-related CRCs and ECs and suggest that the development of the latter tumors is selectively associated with the MSH2/MSH6 protein complex deficiency.

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