Mitogenomic Alterations in Breast Cancer: Identification of Potential Biomarkers of Risk and Prognosis

Alterations in the mitochondrial genome (mtDNA) have been shown to be key in cancer development and could be useful as biomarkers for diagnosis, prognosis, and treatment. To identify mtDNA variants associated with breast cancer, we analyzed the whole mtDNA sequence from paired tissues (tumor-peripheral blood) of women with this malignancy and from peripheral blood samples of healthy women. The mtDNA mutational landscape, heteroplasmy levels of the variants, and mitochondrial ancestry were established. Comparative analysis between cases and controls revealed significant differences in the number and location of variants, as well as in the heteroplasmy levels. Cases showed higher mutation number in <i>MT-ND5</i>, tRNAs, and rRNAs genes; increased proportion of missense variants; and elevated mtDNA content, than controls. Notably, a high blood mtDNA mutational burden (OR = 3.83, CI: 1.89-7.95, <i>p</i> = 5.3 × 10^-5) and five mtDNA variants showed association with the risk of breast cancer. Furthermore, a low tumor mutational burden (HR = 7.82, CI: 1.0-63.6, <i>p</i> = 0.05) and the haplogroup L (HR = 12.16, CI: 2.0-72.8, <i>p</i> = 0.0062) were associated with decreased overall and disease-free survival, respectively. Our study adds evidence of the potential usefulness of mtDNA variants as risk and prognosis biomarkers for breast cancer.