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Limited clinical relevance of mitochondrial DNA mutation and gene expression analyses in ovarian cancer.

Bragoszewski P, Kupryjanczyk J, Bartnik E, Rachinger A, Ostrowski J - BMC Cancer (2008)

Bottom Line: Somatic mutations in the D-loop sequence were found in 57% of ovarian cancers.Univariate analysis showed no association between mitochondrial DNA mutation status or mitochondrial gene expression and any of the examined clinicopathologic parameters.These discrepancies in the clinical utility of mitochondrial molecular tests in ovarian cancer require additional large, well-designed validation studies.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Gastroenterology and Hepatology, Medical Center for Postgraduate Education at the Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Roentgena 5, Warsaw, Poland. pwain@poczta.onet.pl

ABSTRACT

Background: In recent years, numerous studies have investigated somatic mutations in mitochondrial DNA in various tumours. The observed high mutation rates might reflect mitochondrial deregulation; consequently, mutation analyses could be clinically relevant. The purpose of this study was to determine if mutations in the mitochondrial D-loop region and/or the level of mitochondrial gene expression could influence the clinical course of human ovarian carcinomas.

Methods: We sequenced a 1320-base-pair DNA fragment of the mitochondrial genome (position 16,000-750) in 54 cancer samples and in 44 corresponding germline control samples. In addition, six transcripts (MT-ATP6, MT-CO1, MT-CYB, MT-ND1, MT-ND6, and MT-RNR1) were quantified in 62 cancer tissues by real-time RT-PCR.

Results: Somatic mutations in the D-loop sequence were found in 57% of ovarian cancers. Univariate analysis showed no association between mitochondrial DNA mutation status or mitochondrial gene expression and any of the examined clinicopathologic parameters. A multivariate logistic regression model revealed that the expression of the mitochondrial gene RNR1 might be used as a predictor of tumour sensitivity to chemotherapy.

Conclusion: In contrast to many previously published papers, our study indicates rather limited clinical relevance of mitochondrial molecular analyses in ovarian carcinomas. These discrepancies in the clinical utility of mitochondrial molecular tests in ovarian cancer require additional large, well-designed validation studies.

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Related in: MedlinePlus

Relative mRNA expression of selected genes in specimens from patients with ovarian carcinomas. A. – samples divided according to mutational status of the mtDNA D-loop (W – wild type, n = 19; M – mutated, n = 25). B. – samples divided according to response to chemotherapy (S – sensitive, n = 32; R – resistant, n = 30). Data are presented as mRNA expression levels for selected genes normalized to the geometric mean of the RNA concentrations of three control genes, glyceraldehyde-3-phosphate dehydrogenase, ubiquitin C, and β-actin. The boxes show the upper and the lower quartiles; the median values are shown as a horizontal line in each box; the whiskers represent minimum and maximum of the data values. Data were analyzed with the Mann-Whitney U test.
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Figure 1: Relative mRNA expression of selected genes in specimens from patients with ovarian carcinomas. A. – samples divided according to mutational status of the mtDNA D-loop (W – wild type, n = 19; M – mutated, n = 25). B. – samples divided according to response to chemotherapy (S – sensitive, n = 32; R – resistant, n = 30). Data are presented as mRNA expression levels for selected genes normalized to the geometric mean of the RNA concentrations of three control genes, glyceraldehyde-3-phosphate dehydrogenase, ubiquitin C, and β-actin. The boxes show the upper and the lower quartiles; the median values are shown as a horizontal line in each box; the whiskers represent minimum and maximum of the data values. Data were analyzed with the Mann-Whitney U test.

Mentions: Total RNA was isolated, and six transcripts that encoded polypeptides (MT-ATP6, MT-CO1, MT-CYB, MT-ND1, and MT-ND6) and ribosomal 12S RNA (MT-RNR1) were quantified by real-time RT-PCR. Because it was not possible to obtain sample pairs of ovarian carcinoma and corresponding normal tissue, gene expression was studied only in 62 tumour samples. Analysis of the results with the Mann-Whitney U test revealed that mutations in the D-loop did not influence the expression of mitochondrial genes (Fig. 1A). Furthermore, the expression of all analyzed mitochondrial genes was equal in responders and non-responders to the therapy (Fig. 1B). However, when the probability of sensitivity to chemotherapy was evaluated with a multivariate logistic regression model, both clinical parameters (age, FIGO stage, and grade) and the expression of RNR1 appeared to be predictors of platinum sensitivity (Table 3).


Limited clinical relevance of mitochondrial DNA mutation and gene expression analyses in ovarian cancer.

Bragoszewski P, Kupryjanczyk J, Bartnik E, Rachinger A, Ostrowski J - BMC Cancer (2008)

Relative mRNA expression of selected genes in specimens from patients with ovarian carcinomas. A. – samples divided according to mutational status of the mtDNA D-loop (W – wild type, n = 19; M – mutated, n = 25). B. – samples divided according to response to chemotherapy (S – sensitive, n = 32; R – resistant, n = 30). Data are presented as mRNA expression levels for selected genes normalized to the geometric mean of the RNA concentrations of three control genes, glyceraldehyde-3-phosphate dehydrogenase, ubiquitin C, and β-actin. The boxes show the upper and the lower quartiles; the median values are shown as a horizontal line in each box; the whiskers represent minimum and maximum of the data values. Data were analyzed with the Mann-Whitney U test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2571110&req=5

Figure 1: Relative mRNA expression of selected genes in specimens from patients with ovarian carcinomas. A. – samples divided according to mutational status of the mtDNA D-loop (W – wild type, n = 19; M – mutated, n = 25). B. – samples divided according to response to chemotherapy (S – sensitive, n = 32; R – resistant, n = 30). Data are presented as mRNA expression levels for selected genes normalized to the geometric mean of the RNA concentrations of three control genes, glyceraldehyde-3-phosphate dehydrogenase, ubiquitin C, and β-actin. The boxes show the upper and the lower quartiles; the median values are shown as a horizontal line in each box; the whiskers represent minimum and maximum of the data values. Data were analyzed with the Mann-Whitney U test.
Mentions: Total RNA was isolated, and six transcripts that encoded polypeptides (MT-ATP6, MT-CO1, MT-CYB, MT-ND1, and MT-ND6) and ribosomal 12S RNA (MT-RNR1) were quantified by real-time RT-PCR. Because it was not possible to obtain sample pairs of ovarian carcinoma and corresponding normal tissue, gene expression was studied only in 62 tumour samples. Analysis of the results with the Mann-Whitney U test revealed that mutations in the D-loop did not influence the expression of mitochondrial genes (Fig. 1A). Furthermore, the expression of all analyzed mitochondrial genes was equal in responders and non-responders to the therapy (Fig. 1B). However, when the probability of sensitivity to chemotherapy was evaluated with a multivariate logistic regression model, both clinical parameters (age, FIGO stage, and grade) and the expression of RNR1 appeared to be predictors of platinum sensitivity (Table 3).

Bottom Line: Somatic mutations in the D-loop sequence were found in 57% of ovarian cancers.Univariate analysis showed no association between mitochondrial DNA mutation status or mitochondrial gene expression and any of the examined clinicopathologic parameters.These discrepancies in the clinical utility of mitochondrial molecular tests in ovarian cancer require additional large, well-designed validation studies.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Gastroenterology and Hepatology, Medical Center for Postgraduate Education at the Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Roentgena 5, Warsaw, Poland. pwain@poczta.onet.pl

ABSTRACT

Background: In recent years, numerous studies have investigated somatic mutations in mitochondrial DNA in various tumours. The observed high mutation rates might reflect mitochondrial deregulation; consequently, mutation analyses could be clinically relevant. The purpose of this study was to determine if mutations in the mitochondrial D-loop region and/or the level of mitochondrial gene expression could influence the clinical course of human ovarian carcinomas.

Methods: We sequenced a 1320-base-pair DNA fragment of the mitochondrial genome (position 16,000-750) in 54 cancer samples and in 44 corresponding germline control samples. In addition, six transcripts (MT-ATP6, MT-CO1, MT-CYB, MT-ND1, MT-ND6, and MT-RNR1) were quantified in 62 cancer tissues by real-time RT-PCR.

Results: Somatic mutations in the D-loop sequence were found in 57% of ovarian cancers. Univariate analysis showed no association between mitochondrial DNA mutation status or mitochondrial gene expression and any of the examined clinicopathologic parameters. A multivariate logistic regression model revealed that the expression of the mitochondrial gene RNR1 might be used as a predictor of tumour sensitivity to chemotherapy.

Conclusion: In contrast to many previously published papers, our study indicates rather limited clinical relevance of mitochondrial molecular analyses in ovarian carcinomas. These discrepancies in the clinical utility of mitochondrial molecular tests in ovarian cancer require additional large, well-designed validation studies.

Show MeSH
Related in: MedlinePlus