Deep sequencing reveals the mitochondrial DNA variation landscapes of breast-to-brain metastasis blood samples

Rhiannon Lloyd, Lewis A. Cockram, Timothy J. Littlewood, Kathleen Keatley, Diana M. Eccles, Qian An

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Breast-to-brain metastasis (BBM) often represents a terminal event, due to the inability of many systemic treatments to cross the blood-brain barrier (BBB), rendering the brain a sanctuary site for tumour cells. Identifying genetic variations that can predict the patients who will develop BBM would allow targeting of adjuvant treatments to reduce risk while disease bulk is minimal. Germ-line genetic variations may contribute to whether a BBM forms by influencing the primary tumour sub-type that presents, or by influencing the host-response to the tumour or treatment regimen, or by facilitating transition of tumour cells across the BBB and establish a viable brain metastasis. The role of mitochondrial DNA (mtDNA) variants specifically in BBM is underexplored. Consequently, using a sensitive deep-sequencing approach, we characterised the mtDNA variation landscapes of blood samples derived from 13 females who were diagnosed with early onset breast cancer and later went on to develop BBM. We also predicted the potential pathogenic significance of variations identified in all mtDNA-encoded oxidative phosphorylation (OXPHOS) proteins using 3D protein structural mapping and analysis, to identify variations worthy of follow-up. From the 70 variations found in protein coding regions, we reveal novel links between 3 specific mtDNA variations and altered OXPHOS structure and function in 23% of the BBM samples. Further studies are required to confirm the origin of mtDNA variations, whether they correlate with 1) the predicted alterations in mitochondrial function and 2) increased risk of developing breast brain metastasis using a much larger cohort of samples.
Original languageEnglish
Pages (from-to)703-713
Number of pages11
JournalMitochondrial DNA Part A: DNA Mapping, Sequencing, and Analysis
Issue number5
Early online date15 Jul 2017
Publication statusPublished - 1 Sept 2018


  • mtDNA
  • OXPHOS and long PCR
  • breast cancer
  • 3D protein structural mapping and analysis
  • breast-to-brain metastasis


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