Evidence for association of mitochondrial DNA sequence amplification and nuclear localization in human low-grade...

Gliomas are tumors which have been found to exhibit consistent genetic changes. Recent studies have shown mitochondrial DNA is also altered in these tumors, and include large deletions and gene amplification. Other studies of the mitochondrial genome in cancer have revealed a variety of different alterations, including the localization and insertion of mitochondrial DNA into the nucleus and nuclear genome in HeLa cells and diethylnitrosurea-induced hepatoma cells. Whether these changes are ontogenically early in the multistep pathway to the development of malignancy, or if this phenomenon occurs in human glial tumors is unknown. I sought to study these questions in a panel of unselected primary glial tumors of pathologically low grade. Fifteen tumors were assessed with a mitochondrial cDNA probe with homology to positions 1679-1948, and 2017-2057. All low-grade tumors revealed increases in copy number when compared to a normal brain control. Nuclear suspensions of these tumors were evaluated by fluorescent in situ hybridization (FISH), using the entire mitochondrial genome as a probe after labeling with rhodamine. All tumors showed evidence of mitochondrial sequence localization within the nuclei. A corresponding glioblastoma and two normal brain specimens were also evaluated which did not have amplification of the mitochondrial genome; FISH with the mitochondrial probe revealed minimal hybridization signal within the nuclei of these samples. Mitochondrial DNA nuclear localization can be found in primary low-grade brain neoplasms, and is correlated to increases in mitochondrial DNA.