Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 Sep 22;8(1):656.
doi: 10.1038/s41467-017-00377-y.

Mitochondrial mutations drive prostate cancer aggression

Julia F Hopkins  1 , Veronica Y Sabelnykova  2 , Joachim Weischenfeldt  3   4 , Ronald Simon  5 , Jennifer A Aguiar  2 , Rached Alkallas  2 , Lawrence E Heisler  2 , Junyan Zhang  6 , John D Watson  2 , Melvin L K Chua  6 , Michael Fraser  6 , Francesco Favero  4 , Chris Lawerenz  7 , Christoph Plass  8 , Guido Sauter  5 , John D McPherson  9 , Theodorus van der Kwast  10 , Jan Korbel  3 , Thorsten Schlomm  11 , Robert G Bristow  12   13   14 , Paul C Boutros  15   16   17
Affiliations

Mitochondrial mutations drive prostate cancer aggression

Julia F Hopkins et al. Nat Commun. .

Abstract

Nuclear mutations are well known to drive tumor incidence, aggression and response to therapy. By contrast, the frequency and roles of mutations in the maternally inherited mitochondrial genome are poorly understood. Here we sequence the mitochondrial genomes of 384 localized prostate cancer patients, and identify a median of one mitochondrial single-nucleotide variant (mtSNV) per patient. Some of these mtSNVs occur in recurrent mutational hotspots and associate with aggressive disease. Younger patients have fewer mtSNVs than those who diagnosed at an older age. We demonstrate strong links between mitochondrial and nuclear mutational profiles, with co-occurrence between specific mutations. For example, certain control region mtSNVs co-occur with gain of the MYC oncogene, and these mutations are jointly associated with patient survival. These data demonstrate frequent mitochondrial mutation in prostate cancer, and suggest interplay between nuclear and mitochondrial mutational profiles in prostate cancer.In prostate cancer, the role of mutations in the maternally-inherited mitochondrial genome are not well known. Here, the authors demonstrate frequent, age-dependent mitochondrial mutation in prostate cancer. Strong links between mitochondrial and nuclear mutational profiles are associated with clinical aggressivity.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing financial interests.

Figures

Fig. 1
Fig. 1
Panorama of mitochondrial mutations in prostate cancer. a The top panel displays the number of mtSNVs per patient sorted first by T-Category and then by the number of mtSNVs; histogram bars are colored by the average difference in the heteroplasmy fraction (∆HF) between tumor and normal samples, light-blue 20–40%, medium-blue 40–60%, dark-blue ≥60%. A heatmap showing the location of each mtSNV on the mitochondrial genome (middle), where the color of each dot represents ∆HF. The mitochondrial genome is represented on the left. The bottom panel shows the clinical covariates for all 384 patients: Age, Gleason Score, PSA, and T-Category. Bottom right: Associations between the covariates and number of mtSNVs. b Frequency and distribution of single-nucleotide variants (SNVs) within the mitochondrial genome. Mutation frequency normalized by dividing the number of mutations per locus of each patient by (length of the locus (kbp) × MCN). c Distribution of mtSNVs across the mitochondrial genome. mtSNVs were fairly evenly distributed across the genome (black bars) and recurrent mutation positions are indicated by the histogram
Fig. 2
Fig. 2
The difference in mitochondrial mutational frequency and copy number with age. a Association of nuclear (green) and mitochondrial (yellow) mutation SNV/Mbp rates with patient age. Mitochondrial mutation rate normalized by MCN. b Distribution of mtSNVs in EOPC (red) and LOPC (blue) patients. The histogram indicates presence and frequency of a mtSNV. The most recurrent mtSNV was at position 16093. c The fraction of patients by number of mtSNVs, EOPC (gray bars), LOPC (black bars). d Tumor mitochondrial copy number (MCN) for both patient age groups. EOPC: n = 164; LOPC: n = 220
Fig. 3
Fig. 3
Associations between mitochondrial and nuclear genome mutations. a Correlations of mitochondrial features with nuclear genome features. The size and color of the dot represents the Spearman correlation and the background shading represents the P-value. Nuclear features: SNVs, CTXs, INVs, kataegis data available for 172 patients; Chromothripsis: n = 159; CNAs: MYC, NKX3-1 (n = 203); CDH1, CDKN1B, CHD1, PTEN, RB1, TP53 (n = 194); Methylation: n = 104. Mitochondrial features: 216 patients. b Mutations in OHR are associated with CNAs in MYC. Heatmap showing those patients with CNA gains (red) in MYC and those with mtSNVs in OHR, CSB1, the control region and ATP6, mtSNV color represents the ∆HF. Since CSB1 is a subregion within OHR, mutations in CSB1 are also considered as OHR mtSNVs, similarly, mtSNVs in OHR are also within the control region (n = 203). The bar plot on the right shows the fraction of patients with or without a MYC CNA that have a specific mtSNV. c Kaplan–Meier plot of 165 patients with OHR and MYC mutations. Patients were grouped according to whether they had neither MYC CNAs nor OHR SNVs (black line), a MYC CNA or an OHR mtSNV (blue) or had both (red line). The group that had a CNA gain in MYC and an mtSNV in the OHR region had significantly worse outcomes than those without the mutations. Biochemical RFR Biochemical relapse-free rate
Fig. 4
Fig. 4
Clinical impact of mitochondrial mutations in prostate cancer. a The associations of biochemical recurrence (BCR) and 21 mitochondrial features: 19 mitochondrial genes or regions, MCN (median-dichotomized), and mtSNV count (0 vs. 1 + ) were calculated using Cox models in 165 LOPC patients. Hazard ratios (HRs) are shown in the middle panel and P-values from the log-rank test in the right panel. The change in the 10-year survival for patients with mutations in each mitochondrial region is indicated (left panel). The color of the bars indicate the average ∆HF for mtSNVs in that region; light-blue 20–40%, medium-blue 40–60%, dark-blue ≥60%. b Kaplan–Meier plots of mtSNVs occurring within HV1 and (c) OHR. d Kaplan–Meier plot of results of leave-one-out cross-validation predictions (P-value from log-rank test)
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Lozano R, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global burden of disease study 2010. Lancet. 2012;380:2095–2128. doi: 10.1016/S0140-6736(12)61728-0. - DOI - PubMed
    1. Barbieri CE, et al. The mutational landscape of prostate cancer. Eur. Urol. 2013;64:567–576. doi: 10.1016/j.eururo.2013.05.029. - DOI - PMC - PubMed
    1. Barbieri CE, et al. Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nat. Genet. 2012;44:685–689. doi: 10.1038/ng.2279. - DOI - PMC - PubMed
    1. Cancer Genome Atlas Research Network The molecular taxonomy of primary prostate cancer. Cell. 2015;163:1011–1025. doi: 10.1016/j.cell.2015.10.025. - DOI - PMC - PubMed
    1. Baca SC, et al. Punctuated evolution of prostate cancer genomes. Cell. 2013;153:666–677. doi: 10.1016/j.cell.2013.03.021. - DOI - PMC - PubMed

Publication types

Substances