title: Mutational load of the mitochondrial genome predicts pathological features and biochemical recurrence in prostate cancer.
abstract: Prostate cancer management is complicated by extreme disease heterogeneity, which is further limited by availability of prognostic biomarkers. Recognition of prostate cancer as a genetic disease has prompted a focus on the nuclear genome for biomarker discovery, with little attention given to the mitochondrial genome. While it is evident that mitochondrial DNA (mtDNA) mutations are acquired during prostate tumorigenesis, no study has evaluated the prognostic value of mtDNA variation. Here we used next-generation sequencing to interrogate the mitochondrial genomes from prostate tissue biopsies and matched blood of 115 men having undergone a radical prostatectomy for which there was a mean of 107 months clinical follow-up. We identified 74 unique prostate cancer specific somatic mtDNA variants in 50 patients, providing significant expansion to the growing catalog of prostate cancer mtDNA mutations. While no single variant or variant cluster showed recurrence across multiple patients, we observe a significant positive correlation between the total burden of acquired mtDNA variation and elevated Gleason Score at diagnosis and biochemical relapse. We add to accumulating evidence that total acquired genomic burden, rather than specific mtDNA mutations, has diagnostic value. This is the first study to demonstrate the prognostic potential of mtDNA mutational burden in prostate cancer.
authors.affiliation: Laboratory for Human Comparative and Prostate Cancer Genomics, Genomics and Epigenetics Division, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.|School of Medical Sciences, University of New South Wales, Randwick, NSW 2031, Australia.
authors.forename: Anton M F
authors.initials: AM
authors.lastname: Kalsbeek
authors.affiliation: Laboratory for Human Comparative and Prostate Cancer Genomics, Genomics and Epigenetics Division, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.|School of Medical Sciences, University of New South Wales, Randwick, NSW 2031, Australia.
authors.forename: Eva F K
authors.initials: EF
authors.lastname: Chan
authors.affiliation: Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia.|Central Clinical School, Sydney Medical School, University of Sydney, Camperdown, NSW 2050, Australia.|Cancer Research Division, The Kinghorn Cancer Centre/Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.
authors.forename: Judith
authors.initials: J
authors.lastname: Grogan
authors.affiliation: Laboratory for Human Comparative and Prostate Cancer Genomics, Genomics and Epigenetics Division, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.|School of Medical Sciences, University of New South Wales, Randwick, NSW 2031, Australia.
authors.forename: Desiree C
authors.initials: DC
authors.lastname: Petersen
authors.affiliation: Laboratory for Human Comparative and Prostate Cancer Genomics, Genomics and Epigenetics Division, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.
authors.forename: Weerachai
authors.initials: W
authors.lastname: Jaratlerdsiri
authors.affiliation: Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia.|Central Clinical School, Sydney Medical School, University of Sydney, Camperdown, NSW 2050, Australia.|Cancer Research Division, The Kinghorn Cancer Centre/Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.
authors.forename: Ruta
authors.initials: R
authors.lastname: Gupta
authors.affiliation: Laboratory for Human Comparative and Prostate Cancer Genomics, Genomics and Epigenetics Division, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.
authors.forename: Ruth J
authors.initials: RJ
authors.lastname: Lyons
authors.affiliation: Cancer Research Division, The Kinghorn Cancer Centre/Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.
authors.forename: Anne-Maree
authors.initials: AM
authors.lastname: Haynes
authors.affiliation: Cancer Research Division, The Kinghorn Cancer Centre/Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.|Chris O'Brien Lifehouse, Missenden Road, Camperdown, NSW 2050, Australia.
authors.forename: Lisa G
authors.initials: LG
authors.lastname: Horvath
authors.affiliation: Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia.|Central Clinical School, Sydney Medical School, University of Sydney, Camperdown, NSW 2050, Australia.|Cancer Research Division, The Kinghorn Cancer Centre/Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.
authors.forename: James G
authors.initials: JG
authors.lastname: Kench
authors.affiliation: Department of Urology, St. Vincent's Hospital, Darlinghurst, NSW 2010, Australia.
authors.forename: Phillip D
authors.initials: PD
authors.lastname: Stricker
authors.affiliation: Laboratory for Human Comparative and Prostate Cancer Genomics, Genomics and Epigenetics Division, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.|School of Medical Sciences, University of New South Wales, Randwick, NSW 2031, Australia.|Central Clinical School, Sydney Medical School, University of Sydney, Camperdown, NSW 2050, Australia.
authors.forename: Vanessa M
authors.initials: VM
authors.lastname: Hayes
mesh_terms: D000368:Aged; D004272:DNA, Mitochondrial; D005500:Follow-Up Studies; D054629:Genome, Mitochondrial; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery
chemical_list: D004272:DNA, Mitochondrial
keywords: mitochondrial genome; mutational load; prognostic biomarkers; prostate cancer