Mutational load of the mitochondrial genome predicts pathological features and biochemical recurrence 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:10.18632/aging.101044

Cited by 31 publications

(34 citation statements)

References 36 publications

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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%

“…Sequencing of the mtDNA of our 50 paired samples identified 84 specific HP sites in the tumors and 33 in benign samples, corresponding to a tumor mtDNA HP rate of 1.6 versus 0.6 in the benign tissues. Recent studies of mtDNA NGS reported mutation frequencies ranging from 0.7 to 2.1 per tumor [9][10][11][12]20 (Supplementary Table 6). The landscape study of Hopkins et al, which included samples of 384 PCa patients, reported a rate of 0.8.…”

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: Discussionmentioning

confidence: 99%

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

et al. 2020

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“…In particular, we found no correlation between mtDNA content and: (i) tumor size ( P ‐value = 0.47); (ii) distance from the tumor for NAP samples ( P ‐value = 0.63); or (iii) difference between NAP and PCa in the same prostate ( P ‐value = 0.51) (Supplementary Figure S3A‐C); as well as (iv) patients age; or (v) PSA level at diagnosis in PCa ( P ‐values = 0.41 and 0.49, respectively); and NAP samples ( P ‐values = 0.61 and 0.13, respectively). Using published mtDNA variant data available for 112 of the 115 patients included in a previous study, we further found no significant associations between mtDNA content and either the total number of mtDNA variants or number of mtDNA replication D‐Loop region variants ( P ‐values = 0.724 and 0.566, respectively).…”

Section: Resultsmentioning

confidence: 61%

“…-C); as well as (iv) patients age; or (v) PSA level at diagnosis in PCa (P-values = 0.41 and 0.49, respectively); and NAP samples (P-values = 0.61 and 0.13, respectively). Using published mtDNA variant data available for 112of the 115 patients included in a previous study,9 we further found no significant associations between mtDNA content and either the total number of mtDNA variants or number of mtDNA replication D-Loop region variants (P-values = 0.724 and 0.566, respectively).…”

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confidence: 52%

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

et al. 2017

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Background Mitochondrial genome (mtDNA) content is depleted in many cancers. In prostate cancer, there is intra‐glandular as well as inter‐patient mtDNA copy number variation. In this study, we determine if mtDNA content can be used as a predictor for prostate cancer staging and outcomes. Methods Fresh prostate cancer biopsies from 115 patients were obtained at time of surgery. All cores underwent pathological review, followed by isolation of cancer and normal tissue. DNA was extracted and qPCR performed to quantify the total amount of mtDNA as a ratio to genomic DNA. Differences in mtDNA content were compared for prostate cancer pathology features and disease outcomes. Results We showed a significantly reduced mtDNA content in prostate cancer compared with normal adjacent prostate tissue (mean difference 1.73‐fold, P‐value <0.001). Prostate cancer with increased mtDNA content showed unfavorable pathologic characteristics including, higher disease stage (PT2 vs PT3 P‐value = 0.018), extracapsular extension (P‐value = 0.02) and a trend toward an increased Gleason score (P‐value = 0.064). No significant association was observed between changes in mtDNA content and biochemical recurrence (median follow up of 107 months). Conclusions Contrary to other cancer types, prostate cancer tissue shows no universally depleted mtDNA content. Rather, the change in mtDNA content is highly variable, mirroring known prostate cancer genome heterogeneity. Patients with high mtDNA content have an unfavorable pathology, while a high mtDNA content in normal adjacent prostate tissue is associated with worse prognosis.

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“…The European comparative cohort included Australian patients selected based on a treatment-naïve surgically removed tumor with a Gleason score !8, as previously described by the Australian Prostate Cancer Centre (APCR; Supplementary Table S1; ref. 15).…”

Section: Patient Description Genetic Ancestries and Ethicsmentioning

confidence: 99%

Whole-Genome Sequencing Reveals Elevated Tumor Mutational Burden and Initiating Driver Mutations in African Men with Treatment-Naïve, High-Risk Prostate Cancer

et al. 2018

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African American men are more likely than any other racial group to die from prostate cancer. The contribution of acquired genomic variation to this racial disparity is largely unknown, as genomic from Africa is lacking. Here we performed the first tumor-normal paired deep whole-genome sequencing for Africa. A direct study-matched comparison between African- and European-derived, treatment-naïve, high-risk prostate tumors for 15 cases allowed for further comparative analyses of existing data. Excluding a single hyper-mutated tumor with 55 mutations per megabase, we observed a 1.8-fold increase in small somatic variants in African- versus European-derived tumors (P-value = 1.02e-04), rising to 4-fold when compared with published tumor-matched data. Furthermore, we observed an increase in oncogenic driver mutations in African tumors (P-value = 2.92e-03); roughly 30% of impacted genes were novel to prostate cancer, and 79% of recurrent driver mutations appeared early in tumorigenesis. Although complex genomic rearrangements were less frequent in African tumors, we describe a uniquely hyper-duplicated tumor impacting 149 transposable elements. Comparable to African Americans, ERG fusions and PIK3CA mutations were absent and PTEN loss less frequent. CCND1 and MYC were frequently gained, with somatic copy number changes more likely to occur late in tumorigenesis. In addition to traditional prostate cancer gene pathways, genes regulating calcium ion-ATPase signal transduction were disrupted in African tumors. Although preliminary, our results suggest that further validation and investigation into the potential implications for elevated tumor mutational burden and tumor-initiating mutations in clinically unfavorable prostate cancer can improve patient outcomes in Africa.

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Mutational load of the mitochondrial genome predicts pathological features and biochemical recurrence in prostate cancer

Cited by 31 publications

References 36 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

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

Whole-Genome Sequencing Reveals Elevated Tumor Mutational Burden and Initiating Driver Mutations in African Men with Treatment-Naïve, High-Risk Prostate Cancer

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