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Structure of the Human MLH1 Locus and Analysis of a Large Hereditary Nonpolyposis Colorectal Carcinoma Kindred for mlh1 Mutations¹

Division of Cell and Molecular Biology [R. D. K., J. L., M. F. K.] and Molecular Biology Core Facility [R. D. K., P. T. M., C. E., E. M.], Dana-Farber Cancer Institute, Boston, Massachusetts 02115; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115 [R. D. K.]; Imperial Cancer Research Fund, Genetic Epidemiology Laboratory, St. James University Hospital, Leeds LS9 7TF, United Kingdom [N. R. H., D. T. B.]; Department of Surgery and Centre for Digestive Diseases, General Infirmary, Great George Street, Leeds LS1 3EX, United Kingdom [N. R. H., P. J. F.]; and Department of Human Genetics, 19/20 Claremont Place, University of Newcastle upon Tyne, Newcastle NE2 4AA, United Kingdom [J. B., P. C.]

Hereditary nonpolyposis colorectal carcinoma is a major cancer susceptibility syndrome known to be caused by inheritance of mutations in at least four genes such as hMSH2, hMLH1, hPMS1, and hPMS2 which encode components of a DNA mismatch repair system. The hMLH1 genomic locus on chromosome 3p has been cloned and shown to cover 58 kilobases of genomic DNA and contain 19 exons. The sequence of all of the intron-exon junctions has been determined and used to develop methods for analyzing each hMLH1 exon for mutations. Using these methods to analyze a 3p-linked hereditary nonpolyposis colorectal carcinoma kindred, we have demonstrated that cancer susceptibility in this family is due to the inheritance of a frame shift mutation in the hMLH1 gene.

¹ This work was supported by NIH Grants HG00305 and GM50006 (R. D. K) and CA06516 and AI28691 to the Dana-Farber Cancer Institute and by the Imperial Cancer Research Fund (N. R. H. P. C., D. T. B.).

² To whom correspondence should be addressed, at Division of Cell and Molecular Biology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115.

Received 11/30/94. Accepted 12/15/94.

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