Mitochondrial genome in sporadic breast cancer: A case control study and a proteomic analysis in a Sinhalese cohort from Sri Lanka

Breast cancer is the commonest malignancy in women and the majority occurs sporadically with no hereditary predisposition. However, sporadic breast cancer has been studied less intensively than the hereditary form and to date hardly any predictive biomarkers exist for the former. Furthermore, although mitochondrial DNA variants have been reported to be associated with breast cancer, findings have been inconsistent across populations. Thus we carried out a case control study on sporadic breast cancer patients and healthy controls of Sinhalese ethnicity (N = 60 matched pairs) in order to characterize coding region variants associated with the disease and to identify any potential biomarkers. Mitochondrial genome was fully sequenced in 30 pairs and selected regions were sequenced in the remaining 30 pairs. Several in-silico tools were used to assess functional significance of the variants observed. A number of variants were identified among the patients and the controls. Missense variants identified were either polymorphisms or rare variants. Their prevalence did not significantly differ between patients and the healthy controls (matched for age, body mass index and menopausal status). MT-CYB, MT-ATP6 and MT-ND2 genes showed a higher mutation rate. A higher proportion of pre-menopausal patients carried missense and pathogenic variants. Unique combinations of missense variants were seen within genes and these occurred mostly in MT-ATP6 and MT-CYB genes. Such unique combinations that occurred exclusively among the patients were common in obese patients. Mitochondrial DNA variants may have a role in breast carcinogenesis in obesity and pre-menopause. Molecular dynamic simulations suggested the mutants, G78S in MT-CO3 gene and T146A in MT-ATP6 gene are likely to be more stable than their wild type counterparts.