DNA mutations in the D-Loop control region of the mitochondrial [MT] genome in breast tissues from women with or without cancer

To investigate the potential role of somatic mitochondrial DNA [mtDNA] mutations in tumorigenesis, the occurrence of mutations in mtDNA of breast carcinoma was studied. We chose to focus on the D-Loop [displacement loop] control region, which contains the L-strand [light strand] promoter, an mtTF1 binding site and the mt3 H-strand [heavy strand] control element. Previous studies had suggested that, this region contains an age-dependent mutation hotspot, i.e. T414G transversion. We postulated that if a similar phenomenon occurred in breast tissues, then tissue genotyping at the mtDNA locus might serve as a means of determining the cumulative mutation burden within the tissue independent of a person’s chronological age. To test the hypothesis that mutation frequency in mtDNA in human breast tissues 1] correlate with case versus control status and 2] correlate with age and presumably exposure, we sequenced breast tumors and normal adjacent tissues along with matched blood from 40 cancer cases and normal tissues and matched blood from 23 women without cancer. Unlike predicted, we found no evidence of T414G mutation, even in older women. We observed 7 other homoplasmic mutations in this region with a higher frequency in tissue samples from cancer cases than those in controls. Most of these mutations were T to C or C to T transitions, but one represented a differential length of CA repeats. No age dependency was observed in the occurrence of these mutations. While many mutations detected in tumors were also present in normal adjacent tissues, the mutation profiles were different in breast tissues and peripheral lymphocytes. These observations suggest that mutations in the D-loop region of the mtDNA in human breast tissues are not an age-dependent phenomenon, but rather reflect genomic instability in tumorigenesis