Extensive somatic microsatellite mutations in normal human tissue

Microsatellite (MS) instability occurs in tumors with DNA mismatch repair ( MMR) deficiencies but is typically absent in adjacent normal tissue, Howeve r, MS mutations have been observed in normal tissues from rare individuals with congenital MMR deficiencies. Autopsy tissues from a 4-year-old with co ngenital MMR deficiency (MLH1-/-) were examined for MS mutations. Insertion s 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 h eart, lymph node, kidney, and bladder epithelium. These findings illustrate that phenotypically normal MMR-deficient cells commonly accumulate MS muta tions. Loss of MMR and the accumulation of some MS mutations may occur earl y in MMR-deficient tumor progression, even before a gatekeeper mutation.