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

Abstract

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 ( topIIα and topIIβ) 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 topIIα gene and two coding poly(A) 7 sequences of topIIβ. Mutations in either the topIIα or topIIβ 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.