Mitochondrial DNA Copy Number in Peripheral Blood Cells and Risk of Developing Breast Cancer

Increased mitochondrial DNA (mtDNA) copy number in peripheral blood cells (PBC) has been associated with the risk of developing several tumor types. Here we evaluate sources of variation of this biomarker and its association with breast cancer risk in a prospective cohort study. mtDNA copy number was measured using quantitative real-time PCR on PBC DNA samples from participants in the UK-based Breakthrough Generations Study. Temporal and assay variation was evaluated in a serial study of 91 women, with two blood samples collected approximately 6-years apart. Then, associations with breast cancer risk factors and risk were evaluated in 1,108 cases and 1,099 controls using a nested case-control design. In the serial study, mtDNA copy number showed low assay variation but large temporal variation [assay intraclass correlation coefficient (ICC), 79.3%-87.9%; temporal ICC, 38.3%). Higher mtDNA copy number was significantly associated with younger age at blood collection, being premenopausal, having an older age at menopause, and never taking HRT, both in cases and controls. Based on measurements in a single blood sample taken on average 6 years before diagnosis, higher mtDNA copy number was associated with increased breast cancer risk [OR (95% CI) for highest versus lowest quartile, 1.37 (1.02-1.83); P trend = 0.007]. In conclusion, mtDNA copy number is associated with breast cancer risk and represents a promising biomarker for risk assessment. The relatively large temporal variation should be taken into account in future analyses.