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

Deep sequencing reveals the mitochondrial DNA variation landscapes of breast-to-brain metastasis blood samples
Deep sequencing reveals the mitochondrial DNA variation landscapes of breast-to-brain metastasis blood samples
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 subtype 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 characterized 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 three 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, and whether they correlate with (1) the predicted alterations in mitochondrial function and (2) increased risk of developing breast-to-brain metastasis using a much larger cohort of samples.
McGeehan, Rhiannon E.
2710c820-7815-455d-90f5-25e3ffe80c4b
Cockram, Lewis A.
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Littlewood, D. Timothy J.
ece75bf4-f5d1-4d14-9f9d-8ab855f0b75f
Keatley, Kathleen
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Eccles, Diana M.
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An, Qian
8bcdd913-04fb-4e75-b3b8-a88925e185ef
McGeehan, Rhiannon E.
2710c820-7815-455d-90f5-25e3ffe80c4b
Cockram, Lewis A.
16af2f20-c9bb-4be9-a616-c2ab7d12f236
Littlewood, D. Timothy J.
ece75bf4-f5d1-4d14-9f9d-8ab855f0b75f
Keatley, Kathleen
936dbc63-6cc3-42c7-be53-19aec0fc5917
Eccles, Diana M.
5b59bc73-11c9-4cf0-a9d5-7a8e523eee23
An, Qian
8bcdd913-04fb-4e75-b3b8-a88925e185ef

McGeehan, Rhiannon E., Cockram, Lewis A., Littlewood, D. Timothy J., Keatley, Kathleen, Eccles, Diana M. and An, Qian (2017) Deep sequencing reveals the mitochondrial DNA variation landscapes of breast-to-brain metastasis blood samples. Mitochondrial DNA: Part A. (doi:10.1080/24701394.2017.1350950).

Record type: Article

Abstract

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 subtype 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 characterized 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 three 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, and whether they correlate with (1) the predicted alterations in mitochondrial function and (2) increased risk of developing breast-to-brain metastasis using a much larger cohort of samples.

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BBM_mt_paper_MtDNA_part_A - Accepted Manuscript
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Accepted/In Press date: 2 July 2017
e-pub ahead of print date: 15 July 2017

Identifiers

Local EPrints ID: 422100
URI: http://eprints.soton.ac.uk/id/eprint/422100
PURE UUID: 567e81ef-dddc-440c-bab1-b05dcd9641d9
ORCID for Diana M. Eccles: ORCID iD orcid.org/0000-0002-9935-3169

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Date deposited: 16 Jul 2018 16:30
Last modified: 16 Mar 2024 05:38

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Contributors

Author: Rhiannon E. McGeehan
Author: Lewis A. Cockram
Author: D. Timothy J. Littlewood
Author: Kathleen Keatley
Author: Diana M. Eccles ORCID iD
Author: Qian An

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