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Circulating Mitochondrial DNA is Linked to Progression and Prognosis of Epithelial Ovarian Cancer.

ABSTRACT: As peripheral blood contains fluctuated levels of circulating cell-free mitochondrial DNA (ccf mtDNA), we aimed to evaluate ccf mtDNA as a biomarker for diagnosis and prognosis of epithelial ovarian cancer (EOC). In the present study, we recruited 165 EOC patients and 60 healthy women. Quantitative RT-PCR was applied to amplify 79-bp and 230-bp fragments of the mitochondrial 16 s RNA gene in sera of these participants. MtDNA integrity was defined as the ratio of long to short mtDNA fragments. We observed that the levels of mtDNA79 and mtDNA230 were significantly increased (P?=?.0001), whereas the mtDNA integrity (P?=?.0001) was decreased in EOC patients compared with those in healthy controls. MtDNA79 showed a sensitivity of 90.3% and a specificity of 81.7% (AUC?=?0.900) to discriminate EOC from healthy controls. Moreover, the amounts of mtDNA79 (P?=?.0001, P?=?.012, P?=?.039) and mtDNA230 (P?=?.0001, P?=?.042) continuously raised from healthy controls over FIGO I-II to FIGO III and IV, with highest levels of mtDNA79 (P?=?.0001) and mtDNA230 (P?=?.0001) in FIGO III and IV. Increasing levels of mtDNA79 (P?=?.003, P?=?.0001) and mtDNA230 (P?=?.041, P?=?.0001) were also associated with lymph node metastasis and CA125 values. The higher levels of mtDNA79 (P?=?.0001; HR 3.2, 95%CI:1.6-6.3) and mtDNA230 (borderline P?=?.048, HR 0.9, 95%CI:0.9-1.0) also correlated with poor patients' overall survival, of which mtDNA79 could act as an independent factor for overall survival. Our data show a significant association of increasing levels of ccf mtDNA with EOC progress and poor prognosis.

SUBMITTER: Meng X

PROVIDER: S-EPMC6609736 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Circulating Mitochondrial DNA is Linked to Progression and Prognosis of Epithelial Ovarian Cancer.

Meng Xiaodan X Schwarzenbach Heidi H Yang Yifeng Y Müller Volkmar V Li Nan N Tian Dongmei D Shen Yan Y Gong Zhaohui Z

Translational oncology 20190702 9

As peripheral blood contains fluctuated levels of circulating cell-free mitochondrial DNA (ccf mtDNA), we aimed to evaluate ccf mtDNA as a biomarker for diagnosis and prognosis of epithelial ovarian cancer (EOC). In the present study, we recruited 165 EOC patients and 60 healthy women. Quantitative RT-PCR was applied to amplify 79-bp and 230-bp fragments of the mitochondrial 16 s RNA gene in sera of these participants. MtDNA integrity was defined as the ratio of long to short mtDNA fragments. We ...[more]

PMID: 31271962

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Project description:BACKGROUND:Mitochondria are the site of oxidative phosphorylation, a process which generates reactive oxygen species (ROS). Elevated ROS levels can lead to oxidative stress, a cellular state implicated in carcinogenesis. It is hypothesized that alternations in mitochondrial (MT) DNA, including heritable MT single nucleotide polymorphisms (MT-SNPs), have the potential to change the capacity of MT function, leading to increased oxidative stress and cancer risk. We investigated if common MT-SNPs and/or haplogroups and are associated with invasive serous ovarian cancer (OvCa) risk. METHODS:A panel of 64 MT-SNPs designed to tag all common variation in the European MT genome (minor allele frequency (MAF) >1%, r^2 >0.8) was genotyped in study participants of European descent using the Sequenom MassARRAY iPlex Gold® system (Sequenom Inc, CA, USA). Invasive serous OvCa cases (n?=?405) and frequency age-matched controls (n?=?445) were drawn from a population-based case-control study of OvCa in western Canada. Binary logistic regression was used to estimate the odds ratio (OR) and 95% confidence intervals (C.I.) for carriage of the minor versus major allele by case-control status. MitoTool was used to test the relationship between European haplogroup status and case-control status using Fisher's exact test. RESULTS:The most significant disease-SNP association was for rs2857285, a synonymous MT-SNP in ND4 (OR?=?4.84, 95% CI: 1.03-22.68, P?=?0.045). After adjustment for multiple testing using a Bonferroni correction of the Type 1 error this MT-SNP was not significant. No other MT-SNP had a P-value?<?0.05. European haplogroup status was not associated with case status. Most MT-SNPs (73%) genotyped had a MAF <5%. CONCLUSION:Common European MT-SNPs (MAF?>?5%) and haplogroups were not associated with invasive serous OvCa risk in this study; however, most European MT-SNPs have a low MAF (<5%), which we were underpowered to adequately assess. Larger studies are needed to clarify the role of low MAF MT-SNPs (MAF?<?5%) in invasive serous OvCa risk.

Project description:Epithelial ovarian cancer (EOC) is one of the malignancies in women, which has the highest mortality. However, the microlevel mechanism has not been discussed in detail. The expression profiles GSE27651, GSE38666, GSE40595, and GSE66957 including 188 tumor and 52 nontumor samples were downloaded from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) were filtered using R software, and we performed functional analysis using the clusterProfiler. Cytoscape software, the molecular complex detection plugin and database STRING analyzed DEGs to construct protein-protein interaction network. We identified 116 DEGs including 81 upregulated and 35 downregulated DEGs. Functional analysis revealed that they were significantly enriched in the extracellular region and biosynthesis of amino acids. We next identified four bioactive compounds (vorinostat, LY-294002,trichostatin A, and tanespimycin) based on ConnectivityMap. Then 114 nodes were obtained in protein-protein interaction. The three most relevant modules were detected. In addition, according to degree ≥ 10, 14 core genes including FOXM1, CXCR4, KPNA2, NANOG, UBE2C, KIF11, ZWINT, CDCA5, DLGAP5, KIF15, MCM2, MELK, SPP1, and TRIP13 were identified. Kaplan-Meier analysis, Oncomine, and Gene Expression Profiling Interactive Analysis showed that overexpression of FOXM1, SPP1, UBE2C, KIF11, ZWINT, CDCA5, UBE2C, and KIF15 was related to bad prognosis of EOC patients. CDCA5, FOXM1, KIF15, MCM2, and ZWINT were associated with stage. Receiver operating characteristic (ROC) curve showed that messenger RNA levels of these five genes exhibited better diagnostic efficiency for normal and tumor tissues. The Human Protein Atlas database was performed. The protein levels of these five genes were significantly higher in tumor tissues compared with normal tissues. Functional enrichment analysis suggested that all the hub genes played crucial roles in citrate cycle tricarboxylic acid cycle. Furthermore, the univariate and multivariate Cox proportional hazards regression showed that ZWINT was independent prognostic indictor among EOC patients. The genes and pathways discovered in the above studies may open a new direction for EOC treatment.

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Dataset Information

Circulating Mitochondrial DNA is Linked to Progression and Prognosis of Epithelial Ovarian Cancer.

Publications

Circulating Mitochondrial DNA is Linked to Progression and Prognosis of Epithelial Ovarian Cancer.

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