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Mutation Screening in the hMLH1 Gene in Swedish Hereditary Nonpolyposis Colon Cancer Families¹

Department of Molecular Medicine, Clinical Genetics Unit [P. T., M. N., A. L.], and Department of Oncology, Radiumhemmet [J. E. F.], Karolinska Hospital, S-17176 Stockholm, Sweden, and Division of Human Cancer Genetics, Dana-Farber Cancer Institute, Boston, Massachusetts 02115 [J. R. L., R. K.]

Hereditary nonpolyposis colorectal cancer is caused by heritable defects in the DNA mismatch repair genes hMLH1, hMSH2, PMS1, and hPMS2. We have used denaturing gradient gel electrophoresis to analyze the 19 exons and exon-intron borders of hMLH1 in 39 Swedish hereditary nonpolyposis colorectal cancer families. Germline mutations were found in eight of these families: two splice mutations affecting exons 3 and 7, respectively, and six missense mutations, of which, four were in exon 2 and one each were in exons 1 and 16. The relatively high number of missense mutations raises several important clinical and technical issues. Such alterations can be identified only when using methods that target DNA or mRNA sequence alteration because they do not cause protein truncations detected by in vitro translation assays. Furthermore, the relationship between these missense mutations and the predisposition to colon cancer is difficult to determine without additional information; thus, genetic counseling based on mutation data is difficult.

¹ This study was supported by the Bert von Kantzows Foundation, the Swedish Cancer Society, the Ake Wibergs Foundation, the Marcus Borgströms Foundation, the Cancer Foundation in Stockholm, and NIH Grant GM50006.

² To whom requests for reprints should be addressed.

Received 8/ 2/95. Accepted 10/12/95.

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