Circulating Cell Free DNA as the Diagnostic Marker for Ovarian Cancer: A Systematic Review and Meta-Analysis
http://journals.plos.org/plosone/article/asset?id=10.1371%2Fjournal.pone.0155495.PDF
Abstract
Background
Quantitative analyses of circulating cell-free DNA (cfDNA) are potential methods for the detec- tion of ovarian cancer. Many studies have evaluated these approaches, but the results were too inconsistent to be conclusive. This study is the first to systematically evaluate the accuracy of circulating cfDNA for the diagnosis of ovarian cancer by conducting meta-analysis.
Methods
We searched PubMed, Embase, Cochrane Library and the Chinese National Knowledge Infrastructure (CNKI) databases systematically for relevant literatures up to December 10, 2015. All analyses were conducted using Meta-DiSc1.4 and Stata 12.0 software. Sensitiv- ity, specificity and other measures of accuracy of circulating cfDNA for the diagnosis of ovar- ian cancer were pooled. Meta-regression was performed to identify the sources of heterogeneity.
Results
This meta-analysis included a total of 9 studies, including 462 ovarian cancer patients and 407 controls. The summary estimates for quantitative analysis of circulating cfDNA in ovar- ian cancer screen were as follows: sensitivity, 0.70 (95% confidence interval (CI), 0.65– 0.74); specificity, 0.90 (95% CI, 0.87–0.93); positive likelihood ratio, 6.60 (95% CI, 3.90– 11.17); negative likelihood ratio, 0.34 (95% CI, 0.25–0.47); diagnostic odds ratio, 26.05 (95% CI, 14.67–46.26); and area under the curve, 0.89 (95% CI, 0.83–0.95), respectively. There was no statistical significance for the evaluation of publication bias.
Conclusions
Current evidence suggests that quantitative analysis of cfDNA has unsatisfactory sensitivity but acceptable specificity for the diagnosis of ovarian cancer. Further large-scale prospective studies are required to validate the potential applicability of using circulating cfDNA alone or
Background
Quantitative analyses of circulating cell-free DNA (cfDNA) are potential methods for the detec- tion of ovarian cancer. Many studies have evaluated these approaches, but the results were too inconsistent to be conclusive. This study is the first to systematically evaluate the accuracy of circulating cfDNA for the diagnosis of ovarian cancer by conducting meta-analysis.
Methods
We searched PubMed, Embase, Cochrane Library and the Chinese National Knowledge Infrastructure (CNKI) databases systematically for relevant literatures up to December 10, 2015. All analyses were conducted using Meta-DiSc1.4 and Stata 12.0 software. Sensitiv- ity, specificity and other measures of accuracy of circulating cfDNA for the diagnosis of ovar- ian cancer were pooled. Meta-regression was performed to identify the sources of heterogeneity.
Results
This meta-analysis included a total of 9 studies, including 462 ovarian cancer patients and 407 controls. The summary estimates for quantitative analysis of circulating cfDNA in ovar- ian cancer screen were as follows: sensitivity, 0.70 (95% confidence interval (CI), 0.65– 0.74); specificity, 0.90 (95% CI, 0.87–0.93); positive likelihood ratio, 6.60 (95% CI, 3.90– 11.17); negative likelihood ratio, 0.34 (95% CI, 0.25–0.47); diagnostic odds ratio, 26.05 (95% CI, 14.67–46.26); and area under the curve, 0.89 (95% CI, 0.83–0.95), respectively. There was no statistical significance for the evaluation of publication bias.
Conclusions
Current evidence suggests that quantitative analysis of cfDNA has unsatisfactory sensitivity but acceptable specificity for the diagnosis of ovarian cancer. Further large-scale prospective studies are required to validate the potential applicability of using circulating cfDNA alone or
Citation: Zhou Q, Li W, Leng B, Zheng W, He Z, Zuo
M, et al. (2016) Circulating Cell Free DNA as the
Diagnostic Marker for Ovarian Cancer: A Systematic
Review and Meta-Analysis. PLoS ONE 11(6):
e0155495. doi:10.1371/journal.pone.0155495
Editor: Jeffrey Chalmers, The Ohio State University, UNITED STATES
Received: January 10, 2016 Accepted: April 30, 2016 Published: June 2, 2016
Copyright: © 2016 Zhou et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability Statement: All relevant data are within the paper and its Supporting Information files.
Funding: This study was supported by National Natural Science Foundation of China (No. 81401187) (Quan Zhou).
Competing Interests: The authors have declared that no competing interests exist.
Editor: Jeffrey Chalmers, The Ohio State University, UNITED STATES
Received: January 10, 2016 Accepted: April 30, 2016 Published: June 2, 2016
Copyright: © 2016 Zhou et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability Statement: All relevant data are within the paper and its Supporting Information files.
Funding: This study was supported by National Natural Science Foundation of China (No. 81401187) (Quan Zhou).
Competing Interests: The authors have declared that no competing interests exist.
PLOS ONE | DOI:10.1371/journal.pone.0155495 June 2, 2016 1 / 17
in combination with conventional markers as diagnostic biomarker for ovarian cancer and
explore potential factors that may influence the accuracy of ovarian cancer diagnosis.
Introduction
Cancer constitutes an enormous burden on society in developed and developing countries alike [1]. Ovarian cancer is the most lethal form of all gynecological malignancies and the fifth most common cause of cancer death in women [2]. Each year, more than 230,000 new cases are diagnosed and 151,900 women died from ovarian cancer in worldwide [1]. Its lethality may be due to the lack of specific symptoms and effective screening and early diagnostic methods to detect the disease. Over 75% of patients are at advanced stage of the disease (Stage III or IV) when being diagnosed, with only 5%-21% of 10-year survival rate [3]. Therefore, the develop- ment of sensitive and specific diagnostic methods or biomarkers for early detection of ovarian cancer is urgently needed.
Currently, histopathology examination is considered the gold standard for ovarian cancer diag- nosis, but it is time consuming, costly and difficult to obtain tumor samples, which limits its appli- cation in early diagnosis. Thus, bimanual pelvic examination, cancer antigen (CA) 125 and transvaginal sonography are widely employed as main diagnostic tools for early diagnosis of ovar- ian cancer [3–5]. Unfortunately, several high-quality studies have demonstrated that the bimanual pelvic examination lacks accuracy as a screening method for ovarian cancer [6–8]. CA125, a tumor-specific antigen, is frequently used to detect ovarian cancer and is elevated in 80% of women with advanced ovarian carcinomas [3]. However, it has low diagnostic sensitivity (50%-62% for early stage ovarian cancer) and limited specificity (73%-77%) [4, 9]. Transvaginal sonography is a useful preoperative examination for predicting the diagnosis of pelvic masses, but it requires a spe- cific device and its diagnostic accuracy is largely affected by the experience of the examiner [10]. Therefore, minimally invasive and highly accurate diagnostic methods for detection of ovarian can- cer are promptly needed, so as to better improve the prognosis of patients with the disease.
Circulating cell-free DNA (cfDNA) is a type of cell-free nucleic acids that is released by both normal and tumor cells into the circulation through cellular necrosis and apoptosis [11]. Recently, some studies report that quantitative analysis of circulating cfDNA is an emerging non-invasive blood biomarker that can be utilized to assess tumor progression and predict prognosis, diagnosis and response to treatment in several types of cancers including ovarian cancer [12–14]. In particular, significantly elevated cfDNA levels have been detected in ovarian cancer patients, compared with healthy subjects [15–24].Thus, the quantitative assay of plasma DNA has been proposed as a screening tool for ovarian cancer [16–24]. A good number of studies have reported the potential of using circulating cfDNA as a novel diagnostic marker for ovarian cancer [16–24]. However, many of the published studies contain inconsistent results, and there are not any previous meta-analyses in the literature which covered this research question. In the present study, we conducted the meta-analysis using data from multiple stud- ies to systematically evaluate the potential of using circulating cfDNA as non-invasive bio- markers in the diagnosis of ovarian cancer.
Materials and Methods
Search strategy
The meta-analysis was conducted following the criteria of Preferred Reporting Items for Sys- tematic Reviews and Meta Analyses (PRISMA) [25] (S1 Appendix). A comprehensive literature
Introduction
Cancer constitutes an enormous burden on society in developed and developing countries alike [1]. Ovarian cancer is the most lethal form of all gynecological malignancies and the fifth most common cause of cancer death in women [2]. Each year, more than 230,000 new cases are diagnosed and 151,900 women died from ovarian cancer in worldwide [1]. Its lethality may be due to the lack of specific symptoms and effective screening and early diagnostic methods to detect the disease. Over 75% of patients are at advanced stage of the disease (Stage III or IV) when being diagnosed, with only 5%-21% of 10-year survival rate [3]. Therefore, the develop- ment of sensitive and specific diagnostic methods or biomarkers for early detection of ovarian cancer is urgently needed.
Currently, histopathology examination is considered the gold standard for ovarian cancer diag- nosis, but it is time consuming, costly and difficult to obtain tumor samples, which limits its appli- cation in early diagnosis. Thus, bimanual pelvic examination, cancer antigen (CA) 125 and transvaginal sonography are widely employed as main diagnostic tools for early diagnosis of ovar- ian cancer [3–5]. Unfortunately, several high-quality studies have demonstrated that the bimanual pelvic examination lacks accuracy as a screening method for ovarian cancer [6–8]. CA125, a tumor-specific antigen, is frequently used to detect ovarian cancer and is elevated in 80% of women with advanced ovarian carcinomas [3]. However, it has low diagnostic sensitivity (50%-62% for early stage ovarian cancer) and limited specificity (73%-77%) [4, 9]. Transvaginal sonography is a useful preoperative examination for predicting the diagnosis of pelvic masses, but it requires a spe- cific device and its diagnostic accuracy is largely affected by the experience of the examiner [10]. Therefore, minimally invasive and highly accurate diagnostic methods for detection of ovarian can- cer are promptly needed, so as to better improve the prognosis of patients with the disease.
Circulating cell-free DNA (cfDNA) is a type of cell-free nucleic acids that is released by both normal and tumor cells into the circulation through cellular necrosis and apoptosis [11]. Recently, some studies report that quantitative analysis of circulating cfDNA is an emerging non-invasive blood biomarker that can be utilized to assess tumor progression and predict prognosis, diagnosis and response to treatment in several types of cancers including ovarian cancer [12–14]. In particular, significantly elevated cfDNA levels have been detected in ovarian cancer patients, compared with healthy subjects [15–24].Thus, the quantitative assay of plasma DNA has been proposed as a screening tool for ovarian cancer [16–24]. A good number of studies have reported the potential of using circulating cfDNA as a novel diagnostic marker for ovarian cancer [16–24]. However, many of the published studies contain inconsistent results, and there are not any previous meta-analyses in the literature which covered this research question. In the present study, we conducted the meta-analysis using data from multiple stud- ies to systematically evaluate the potential of using circulating cfDNA as non-invasive bio- markers in the diagnosis of ovarian cancer.
Materials and Methods
Search strategy
The meta-analysis was conducted following the criteria of Preferred Reporting Items for Sys- tematic Reviews and Meta Analyses (PRISMA) [25] (S1 Appendix). A comprehensive literature
Circulating Cf-DNA as the Diagnostic Marker for OC
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