Altered mitochondrial genome content signals worse pathology and prognosis in prostate cancer

Kalsbeek, Anton M.F.; Chan, Eva; Grogan, Judith; Petersen, Desiree C.; Jaratlerdsiri, Weerachai; Gupta, Ruta; Lyons, Ruth J.; Haynes, Anne‐Maree; Horvath, Lisa G.; Kench, James G.; Stricker, Phillip D.; Hayes, Vanessa M.

doi:10.1002/pros.23440

Cited by 21 publications

(15 citation statements)

References 38 publications

(68 reference statements)

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“…To evaluate a correlation of clinical parameters and mtDNA mutation frequency a logistic regression analysis was performed (Supplementary Table 3). Overall mtDNA mutation load correlated significantly with increasing patient age (p = 0.04, likelihood-ratio test), in line with recent reports 9,20,21 and with lower free to total PSA ratios (fPSA%, p = 0.05, likelihood-ratio test, Supplementary Table 3). A low fPSA% value is a prognostic indicator of poor prognosis 22 .…”

Section: Resultssupporting

confidence: 88%

“…Deleterious mtDNA mutation load and OXPHOS capacity. While increasing numbers of potentially deleterious mtDNA mutations in cancer samples are reported [9][10][11][12]21,23 , their functional significance is rarely evaluated. We correlated the frequency and type of mtDNA mutations with functional data for each sample.…”

Section: Resultsmentioning

confidence: 99%

“…can guide future studies of tumorigenesis and progressionsupporting metabolic pathways. Metabolic alterations and high load of non-synonymous mtDNA mutations are accompanied by an increase in mtDNA content and mt-density, which is a characteristic of more aggressive PCa 21,50 . Confirming this hypothesis, a set of highly correlated metagenes extracted from the gene expression profile of PCa samples exhibiting a severe respiratory phenotype was able to predict significantly shorter survival.…”

Section: Discussionmentioning

confidence: 99%

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OXPHOS remodeling in high-grade prostate cancer involves mtDNA mutations and increased succinate oxidation

et al. 2020

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Rewiring of energy metabolism and adaptation of mitochondria are considered to impact on prostate cancer development and progression. Here, we report on mitochondrial respiration, DNA mutations and gene expression in paired benign/malignant human prostate tissue samples. Results reveal reduced respiratory capacities with NADH-pathway substrates glutamate and malate in malignant tissue and a significant metabolic shift towards higher succinate oxidation, particularly in high-grade tumors. The load of potentially deleterious mitochondrial-DNA mutations is higher in tumors and associated with unfavorable risk factors. High levels of potentially deleterious mutations in mitochondrial Complex I-encoding genes are associated with a 70% reduction in NADH-pathway capacity and compensation by increased succinate-pathway capacity. Structural analyses of these mutations reveal amino acid alterations leading to potentially deleterious effects on Complex I, supporting a causal relationship. A metagene signature extracted from the transcriptome of tumor samples exhibiting a severe mitochondrial phenotype enables identification of tumors with shorter survival times.

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Section: Resultssupporting

confidence: 88%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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OXPHOS remodeling in high-grade prostate cancer involves mtDNA mutations and increased succinate oxidation

et al. 2020

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“…Nevertheless, low mtDNA content was more prevalent in patients who received preoperative radiation therapy, which may be explained by the radiationinduced DNA damage in the mitochondrial genome combined by impaired enzyme synthesis. Although most studies revealed that high mtDNA content was associated with better outcome in cancer, some studies showed contrary data (18,(42)(43)(44)(45)(46)(47)(48)(49)(50)(51). Thus, the role of mtDNA in cancer prognosis remains controversial.…”

Section: Discussionmentioning

confidence: 99%

High Tumor Mitochondrial DNA Content Correlates With an Improved Patient's Outcome in WHO Grade III Meningioma

et al. 2020

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Background: Studies have shown mitochondrial genome content (mtDNA content) varies in many malignancies. However, its distribution and prognostic values in high-grade meningioma remain largely unknown. In this retrospective study, we sought to assess a putative correlation between the mtDNA content and clinical characteristics. Methods: Mitochondrial DNA was extracted from 87 World Health Organization grade III meningioma samples using a qPCR method. The distribution of mtDNA content in WHO grade III meningioma and its correlations with clinical variables were assessed. Furthermore, we prognostic values were also determined. Results: Mean mtDNA content was 617.7 (range, 0.8-3000). There was no mtDNA distribution difference based on the histological subtypes (P = 0.07). Tumors with preoperative radiation were associated with lower mtDNA content (P = 0.041), whereas no correlations with other clinical variables were observed. A high mtDNA content was associated with significantly better PFS (P = 0.044) and OS (P = 0.019). However, in patients who received postoperative radiotherapy, low mtDNA content was associated with better PFS (P = 0.028), while no difference in OS was observed (P = 0.272). Low mtDNA content was also associated with better OS and PFS in subgroups of patients with ER negative status (PFS, P = 0.002; OS, P = 0.002). Conclusions: Consistent with other tumors, high mtDNA content was associated with better outcome in WHO grade III meningioma in our cohort. However, for patients who received post-operative radiation therapy, low mtDNA content was associated with better PFS. These findings suggest that mtDNA content may further be explored as a potential biomarker for high-grade meningioma patients and for those who received postoperative radiation therapy.

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“…In human cells, mitochondrial ribosomes synthesize proteins encoded by 13 mitochondrial DNAencoded genes. Recent studies suggested reduced mitochondrial DNA content in PCa [60,61], so it is possible that PCa cells overexpress mitochondrial ribosomes to compensate the decrease of mitochondrial DNA content.…”

Section: Differentially Expressed Corum Protein Complexesmentioning

confidence: 99%

Quantitative Proteomic Analysis of Prostate Tissue Specimens Identifies Deregulated Protein Complexes in Primary Prostate Cancer

Zhou

Yan

Wang

et al. 2018

Preprint

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Prostate cancer (PCa) is the most frequently diagnosed non-skin cancer and a leading cause of mortality among males in developed countries. However, our understanding of the global changes of protein complexes within PCa tissue specimens remains very limited, although it has been well recognized that protein complexes carry out essentially all major processes in living organisms and that their deregulation drives the pathogenesis and progression of various diseases. By coupling tandem mass taggingsynchronous precursor selection-mass spectrometry/mass spectrometry/mass spectrometry (TMT-SPS-MS3) with differential expression and co-regulation analyses, the present study compared the differences between protein complexes in normal prostate, low-grade PCa, and high-grade PCa tissue specimens.Globally, a large downregulated putative protein-protein interaction (PPI) network was detected in both low-grade and high-grade PCa, yet a large upregulated putative PPI network was only detected in highgrade but not low-grade PCa, compared with normal controls. To identify specific protein complexes that are deregulated in PCa, quantified proteins were mapped to protein complexes in CORUM, a collection of experimentally verified mammalian protein complexes. Differential expression analysis suggested that mitochondrial ribosomes and the fibrillin-associated protein complex were significantly overexpressed, whereas the ITGA6-ITGB4-Laminin10/12 and the P2X7 receptor signaling complexes were significantly downregulated, in PCa compared with normal prostate. Moreover, differential co-regulation analysis indicated that the assembly levels of some nuclear protein complexes involved in RNA synthesis and processing were significantly increased in low-grade PCa, and those of mitochondrial complex I and its subcomplexes were significantly increased in high-grade PCa, compared with normal prostate. In summary, the study represents the first global and quantitative comparison of protein complexes in prostate tissue specimens. It is expected to enhance our understanding of the molecular mechanisms underlying PCa development and progression in human patients, as well as lead to the discovery of novel biomarkers and therapeutic targets for precision management of PCa.

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Altered mitochondrial genome content signals worse pathology and prognosis in prostate cancer

Cited by 21 publications

References 38 publications

OXPHOS remodeling in high-grade prostate cancer involves mtDNA mutations and increased succinate oxidation

OXPHOS remodeling in high-grade prostate cancer involves mtDNA mutations and increased succinate oxidation

High Tumor Mitochondrial DNA Content Correlates With an Improved Patient's Outcome in WHO Grade III Meningioma

Quantitative Proteomic Analysis of Prostate Tissue Specimens Identifies Deregulated Protein Complexes in Primary Prostate Cancer

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