Related Experiment Videos
Extensive somatic microsatellite mutations in normal human tissue
S Vilkki1, J L Tsao, A Loukola
1Department of Medical Genetics, University of Helsinki, FIN-00014 Helsinki, Finland.
Abstract:
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.
Insights
Microsatellite instability, a hallmark of DNA mismatch repair (MMR) deficiency, can occur in normal tissues. Even without a cancer diagnosis, MMR-deficient cells accumulate mutations, suggesting early tumor progression events.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Microsatellite (MS) instability is a known characteristic of tumors with DNA mismatch repair (MMR) deficiencies.
- Typically, MS instability is absent in normal tissues adjacent to tumors.
- Rare cases of congenital MMR deficiencies show MS mutations in normal tissues.
Purpose of the Study:
- To investigate the presence and frequency of MS mutations in normal tissues from an individual with congenital MMR deficiency.
- To understand the early mutational events in MMR-deficient cells.
Main Methods:
- Autopsy tissues from a 4-year-old with congenital MMR deficiency (MLH1-/-) were analyzed.
- Microsatellite (MS) loci, specifically CA-repeat regions, were examined for mutations (insertions and deletions).
Main Results:
- Insertions and deletions were observed in CA-repeat MS loci within normal tissues.
- An estimated 0.26 to 1.4 mutations per MS locus per cell were found in normal tissues (heart, lymph node, kidney, bladder epithelium).
- Phenotypically normal MMR-deficient cells were found to commonly accumulate MS mutations.
Conclusions:
- Loss of MMR function leads to the accumulation of MS mutations even in phenotypically normal cells.
- The accumulation of MS mutations may be an early event in the progression of MMR-deficient tumors, potentially preceding a gatekeeper mutation.