Mutations in the mitochondrial DNA D-loop region and breast cancer risk
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Mitochondrial genome alterations have been suggested to play an important role in carcinogenesis. The D-loop region of mitochondrial DNA (mtDNA) contains essential transcription and replication elements, and mutations in this region may serve as a potential sensor for cellular DNA damage and a marker for cancer development. Using data and samples from the Shanghai Breast Cancer Study, we investigated MnlI restriction sites located between nucleotides 16,106 and 16,437 of the mtDNA D-loop region to evaluate restriction fragment length polymorphism (RFLP) patterns in tumor tissue from 501 primary breast cancer patients when compared with tumor tissue from 203 women with benign breast disease (BBD). RFLP patterns in correspondingly paired, adjacent, non-tumor tissues taken from 120 primary breast cancer patients and 59 BBD controls were also evaluated. Five common RFLP patterns were observed, and no significant differences were observed in the distribution of these patterns between tumor and adjacent non-tumor tissue samples from breast cancer patients and tissue samples from BBD controls. On the other hand, somatic MnlI site mutations, defined as a difference in MnlI RFLP pattern between tumor tissue and the corresponding, adjacent, non-tumor tissue, occurred more frequently in breast cancer patients (28.3%) than in BBD patients (15.3%) (P = 0.05) and more frequently in proliferative BBD (13.0%) than in non-proliferative BBD (7.1%). Our data suggest that somatic MnlI site mutations may play a role in the pathogenesis of breast cancer.
KeywordsMitochondrial DNA MnlI restriction site mutation Breast cancer risk
Benign breast disease
Mitochondrial single-stranded DNA-binding protein
Reactive oxygen species
We thank Ms. Qing Wang for her excellent technical laboratory assistance and Ms. Bethanie Hull for technical assistance in manuscript preparation. This study would not have been possible without the support of all of the study participants and research staff of the Shanghai Breast Cancer Study. This research was supported by United States Department of Defense Breast Cancer Research Program grant DAMD17-02-1-0603 and National Cancer Institute grants R01 CA064277 and R01 CA90899.
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