POLYMORPHISMS, BUT LACK OF MUTATIONS OR INSTABILITY, IN THE PROMOTOR REGION OF THE MITOCHONDRIAL GENOME IN HUMAN COLONIC TUMORS

The region of the human mitochondrial D-loop has been sequenced from D NA of colonic tumors and paired normal colonic tissue to determine if mutations in the promoters for the heavy or light strands are responsi ble for the decrease in mitochondrial gene expression present in colon ic tumors. No mutations were detected in the colonic tumors, but new p olymorphisms, including a sequence analogous to CA microsatellites in genomic DNA, were revealed. These polymorphisms are restricted to posi tions within the D-loop which are not essential for accurate and effic ient in vitro mitochondrial transcription. Thus, these data confirm th e boundaries of the functional heavy and light strand promoters determ ined by in vitro assays. Further, although some of the tumors investig ated show genomic microsatellite instability similar to that recently reported for colonic tumors, the CA polymorphic region in the mitochon drial D-loop does not show coincident instability in the tumors. There fore, as in yeast, there may be both a mitochondrial and a nuclear enz yme responsible for mismatch repair, with only the latter involved in generation of instability in some human colon cancers. In summary, our data do not find any structural alterations in the D-loop region of t he human mitochondrial genome encompassing the heavy and light strand promoters which can account for the decreased expression of the mitoch ondrial genome in colonic tumors.