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Extensive Somatic Microsatellite Mutations in Normal Human Tissue¹

Department of Medical Genetics, University of Helsinki, FIN-00014 Helsinki, Finland [S. V., A. L., L. A. A.]; Department of Pathology, Norris Cancer Center, University of Southern California School of Medicine, Los Angeles, California 90033 [J-L. T., D. S.]; Departments of Pathology [R. H.] and Clinical Genetics [O. V.], Oulu University Hospital, FIN-90220 Oulu, Finland; and The Family Federation of Finland, FIN-00101 Helsinki, Finland [M. P.]

Microsatellite (MS) instability occurs in tumors with DNA mismatch repair (MMR) deficiencies but is typically absent in adjacent normal tissue. However, MS mutations have been observed in normal tissues from rare individuals with congenital MMR deficiencies. Autopsy tissues from a 4-year-old with congenital MMR deficiency (MLH1-/-) were examined for MS mutations. Insertions and deletions were observed in CA-repeat MS loci. Approximately 0.26 to 1.4 mutations per MS locus per cell were estimated to be present in normal heart, lymph node, kidney, and bladder epithelium. These findings illustrate that phenotypically normal MMR-deficient cells commonly accumulate MS mutations. Loss of MMR and the accumulation of some MS mutations may occur early in MMR-deficient tumor progression, even before a gatekeeper mutation.

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