Oncotarget

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Mitochondrial genome variation and prostate cancer: a review of the mutational landscape and application to clinical management

Anton M.F. Kalsbeek, Eva K.F. Chan, Niall M. Corcoran, Christopher M. Hovens and Vanessa M. Hayes _

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Oncotarget. 2017; 8:71342-71357. https://doi.org/10.18632/oncotarget.19926

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Abstract

Anton M.F. Kalsbeek1,2, Eva K.F. Chan1,2, Niall M. Corcoran3,4, Christopher M. Hovens3,4 and Vanessa M. Hayes1,2,5

1Laboratory for Human Comparative and Prostate Cancer Genomics, Genomics and Epigenetics Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia

2Medical Faculty, University of New South Wales, Randwick, New South Wales, Australia

3Australian Prostate Cancer Research Centre Epworth, Richmond, Victoria, Australia

4Departments of Urology and Surgery, Royal Melbourne Hospital, University of Melbourne, Melbourne, Victoria, Australia

5Central Clinical School, University of Sydney, Camperdown, New South Wales, Australia

Correspondence to:

Vanessa M. Hayes, email: [email protected]

Keywords: prostate cancer, mitochondrial genome, mtDNA variation, biomarkers

Received: January 11, 2017     Accepted: July 26, 2017     Published: August 04, 2017

ABSTRACT

Prostate cancer is a genetic disease. While next generation sequencing has allowed for the emergence of molecular taxonomy, classification is restricted to the nuclear genome. Mutations within the maternally inherited mitochondrial genome are known to impact cancer pathogenesis, as a result of disturbances in energy metabolism and apoptosis. With a higher mutation rate, limited repair and increased copy number compared to the nuclear genome, the clinical relevance of mitochondrial DNA (mtDNA) variation requires deeper exploration. Here we provide a systematic review of the landscape of prostate cancer associated mtDNA variation. While the jury is still out on the association between inherited mtDNA variation and prostate cancer risk, we collate a total of 749 uniquely reported prostate cancer associated somatic mutations. Support exists for number of somatic events, extent of heteroplasmy, and rate of recurrence of mtDNA mutations, increasing with disease aggression. While, the predicted pathogenic impact for recurrent prostate cancer associated mutations appears negligible, evidence exists for carcinogenic mutations impacting the cytochrome c oxidase complex and regulating metastasis through elevated reactive oxygen species production. Due to a lack of lethal cohort analyses, we provide additional unpublished data for metastatic disease. Discussing the advantages of mtDNA as a prostate cancer biomarker, we provide a review of current progress of including elevated mtDNA levels, of a large somatic deletion, acquired tRNAs mutations, heteroplasmy and total number of somatic events (mutational load). We confirm via meta-analysis a significant association between mtDNA mutational load and pathological staging at diagnosis or surgery (p < 0.0001).


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