Topoisomerase II gene mutations in tumors and tumor cell lines with microsatellite instability.

Genetic or epigenetic inactivation of the DNA mismatch repair genes in tumor precursor cells results in a strong mutator phenotype, known as the microsatellite mutator phenotype (MMP), or microsatellite instability (MSI). This mutator phenotype causes mutations in genes responsible for the regulation of cell growth and survival/death and thus promotes the development and progression of tumors. In the present study, we examined the DNA topoisomerase II genes (topIIalpha and topIIbeta) as mutational targets for MMP. We screened 10 MSI-positive human tumor cell lines and 30 MSI-positive colorectal tumors for mutations within the entire coding region of the topIIalpha gene and two coding poly(A)7 sequences of topIIbeta. Mutations in either the topIIalpha or topIIbeta gene were found with an overall frequency of 18% (in 10% of the primary tumors and in 44% of the cell lines). This indicates that modulation of the DNA topoisomerase II (TOPII) activity may be important for the development of MSI-positive cancer.