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Expression of the Human Mismatch Repair Gene hMSH2 in Normal and Neoplastic Tissues¹

The Johns Hopkins Oncology Center, Baltimore, Maryland 21231 [F. S. L., K. P., S. R. H., K. W. K., B. V.]; Oncogene Science, Cambridge, Massachusetts 02142 [M. B., K. A. J., D. H.]; Department of Surgery and MRC Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom EH4 2XU [M. D.]; Department of Pathology, University Medical School, Edinburgh, United Kingdom EH8 9AG [A. W.]; Department of Medical Genetics, University of Helsinki, Helsinki, Finland 00290 [P. P., A. d. I. C.]; Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205 [S. R. H.]; and Howard Hughes Medical Institute [K. P., B. V.]

Hereditary nonpolyposis colorectal cancer is caused by inherited mutations of mismatch repair genes. We developed monoclonal antibodies to the prototype human mismatch repair gene hMSH2 and used them to detect an immunoreactive protein of M_r 100,000 in mismatch-proficient cell lines. In addition, a M_r 150,000 protein coimmunoprecipitated with the hMSH2 gene product in cell lines expressing hMSH2. Immunohistochemistry demonstrated that the hMSH2 protein was exclusively nuclear. Whereas the hMSH2 protein was expressed in a variety of tissues, the most striking pattern was observed in esophageal and intestinal epithelia, where expression was limited to the replicating compartment. Neoplastic cells within benign and malignant mismatch repair-proficient tumors expressed the protein, but no hMSH2 immunoreactivity was observed in the colorectal tumors of patients with germline hMSH2 mutation. These results have implications for tumorigenic mechanisms and, potentially, for diagnosis.

¹ This work was supported by NIH Grants CA35494 and CA62924, The Clayton Fund, The Scottish Health Department, The Academy of Finland, The Finnish Cancer Societies, The Sigrid Jusilieus Foundation, and The Folkhason Institute of Genetics. B. V. is an American Cancer Society Research Professor and Investigator of the Howard Hughes Medical Institute.

² To whom requests for reprints should be addressed, at the Johns Hopkins Oncology Center, 424 North Bond Street, Baltimore, Maryland 21231.

Received 9/22/95. Accepted 11/29/95.

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