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- Hindawi Publishing Corporation
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- Copyright © 2021 Ming Yu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Abstract
Hindawi Journal of Oncology Volume 2021, Article ID 6627241, 10 pages https://doi.org/10.1155/2021/6627241 ReviewArticle Can Circulating Cell-Free DNA or Circulating Tumor DNA Be a Promising Marker in Ovarian Cancer? Ming Yu , Yu Zhu, Lichen Teng, Jialin Cui, and Yajuan Su Department of Clinical Laboratory, Harbin Medical University Cancer Hospital, Harbin, China Correspondence should be addressed to Yajuan Su; suyajuan1977@sina.com Received 29 October 2020; Revised 24 March 2021; Accepted 31 March 2021; Published 12 April 2021 Academic Editor: Yuan Seng Wu Copyright © 2021 Ming Yu et al. *is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In recent years, the studies on ovarian cancer have made great progress, but the morbidity and mortality of patients with ovarian cancer are still very high. Due to the lack of effective early screening and detecting tools, 70% of ovarian cancer patients are diagnosed at an advanced stage. *e overall survival rate of ovarian cancer patients treated with surgical combined with chemotherapy has not been significantly improved, and they usually relapse or resist chemotherapy. *erefore, a novel tumor marker is beneficial for the diagnosis and prognosis of patients with ovarian cancer. As the index of “liquid biopsy,” circulating cell-free DNA/circulating tumor DNA (cfDNA/ctDNA) has attracted a lot of attention. It has more remarkable advantages than traditional methods and gives a wide range of clinical applications in kinds of solid tumors. *is review attempts to illuminate the important value of cfDNA/ctDNA in ovarian cancer, including diagnosis, monitoring, and prognosis. Meanwhile, we will present future directions and challenges for detection of cfDNA/ctDNA. and immunotherapy; advances have been made in the 1. Introduction clinical treatment of ovarian cancer with bevacizumab Ovarian cancer is the most lethal malignancy of female (a recombinant human monoclonal IgG1 antibody that acts reproductive system, while epithelial ovarian cancer is the by inhibiting the biological activity of human vascular en- most common type. Although the incidence of ovarian dothelial growth factor) or the poly ADP-ribose polymerase cancer is less than cervical cancer and uterine body cancer, (PARP) inhibitor olaparib [3]. Although they have initial the death rate of ovarian cancer ranks first in gynecological treatment response and are sensitive to chemotherapy, most tumors, which generates a threat to women’s health and life. of them tend to recur and produce resistance to chemo- Because of the complicated characteristics of ovarian cancer therapy drugs [4]; the 5-year survival rate is less than 30%. and the tumor being just located in the pelvic cavity, early *erefore, early diagnosis is very important to monitor ovarian cancer patients often have no obvious symptoms therapy response and improve prognosis of patients. and signs; as a result, only about 25% patients can be di- Imaging examination and serum tumor markers are agnosed before they get worse [1]. *e main treatment widely employed as diagnostic technologies in clinical de- principle of ovarian cancer is surgery, supplemented of tection of ovarian cancer; unfortunately, these methods have chemotherapy. Surgery is the preferred option for ovarian not researched the standards of high sensitivity and speci- cancer, which can stage tumors, develop treatment plan, and ficity for early diagnosis; mortality did not significantly differ judge the prognosis. Chemotherapy also contributes to the between screened women and those with no screening [5]. treatment of ovarian cancer; it is divided into neoadjuvant Transvaginal ultrasound has limited ability to distinguish chemotherapy, postoperative chemotherapy, and post- between benign and malignant lesions, and it is difficult to relapse chemotherapy. For most patients, the main che- find small tumors [6]. *e detection of serum cancer antigen motherapy regimen is a combination of platinum and 125 (CA125) has low sensitivity, which makes it difficult to paclitaxel [2]. In addition, there are targeted radiotherapy detect early lesions. Meanwhile, it also has poor specificity, 2 Journal of Oncology The presence of cfDNA in serum The changes of cfDNA in The presence of nucleic of patients with systemic lupus serum were detected in acids in plasma of human erythematosus various types of cancers 1948 1960 1977 –2021 1999 1996 1994 Early detection and diagnosis The presence of gene The presence of The presence of gene Therapy responses monitoring methylation micrisatellite altrenation mutation Recurrence prediction Drug resistance assessment Prognosis judgement Figure 1: *e development history of cfDNA/ctDNA is detected in many diseases and cancers. *e detection can involve the concentration and integrity, mutation, methylation of cfDNA/ctDNA, and so on. Analyses of cfDNA/ctDNA can be used to early detection and diagnosis, therapy responses monitoring, recurrence prediction, drug resistance assessment, and prognosis judgment. because it can be detected in other nonmalignant diseases, about cfDNA. In 1994, the N-ras gene point mutation was which is likely to result in false positive [7]. Histopatho- confirmed in cfDNA of patients with myelodysplastic logical biopsy [8] is also one of the diagnostic tools for syndrome or acute myelogenous leukemia [15]. Subse- ovarian cancer, which has been regarded as the gold stan- quently, it was reported that microsatellite alterations dard. However, it is time-consuming and costly; in addition, [16, 17] and gene methylation [18, 19] were also presented in there is difficulty in sampling and it can make patients cfDNA from cancer patients, and cfDNA could be used as a painful and risky; moreover, the tissue samples cannot be marker for early diagnosis, evaluation of cancer therapeutic applied repeatedly. Based on the above, it is particularly effect, and judgment of prognosis (Figure 1). necessary to find a non-invasive, repeatedly, early tumor marker with high sensitivity and specificity for detection and diagnosis of ovarian cancer. 2.2. e Sources and Characteristics of cfDNA/ctDNA. For healthy individuals, circulating DNA in plasma comes from *e detection of cfDNA/ctDNA is called “liquid biopsy,” which is an emerging technology. *e detection method is apoptotic cells [20]. Circulating DNA is released through physiological processes and may be cleared by its own non-invasive and safe, the operation is simple and conve- nient, requiring only a small amount of blood to complete system; for instance, macrophages in the blood remove free material from damaged or dead cells, which is normal the detection, and the sample can be repeatedly collected. CfDNA/CtDNA can carry the same genetic changes and metabolism. When tumor occurs, somatic cell apoptosis is also a source of circulating DNA, because the trapezoidal epigenetic information as tumor issues [9], such as point pattern of plasma or serum DNA is similar to that of ap- mutations, copy number variations, promoter methylation, microsatellite instability, and loss of heterozygosity. It can optotic cells [21]. Beside the DNA release by apoptotic tu- mors cells, it also includes the DNA release by necrotic overcome tumor heterogeneity [10], reflect the tumor load of human body [11], and then dynamically and timely reflect tumor cells; as a result, necrosis is an important cause of the presence of DNA fragments. Similarly, the tumor cells se- the patients’ conditions. *ese features make cfDNA/ctDNA a promising biomarker. cretion can also release DNA [22]. Only a small part of circulating DNA from tumor cells, thus, is called ctDNA. In addition, fetal DNA fragment released into the maternal 2. CfDNA/CtDNA circulation during pregnancy is the source of cfDNA [23]. 2.1. eDevelopmentHistoryofcfDNA/ctDNA. CfDNA is a And cfDNA may be derived from leukolysis, infection, kind of free DNA that exists outside the cells and can be trauma, and empyrosis [24, 25]. *e exact mechanism of cfDNA released from cells into circulation is still unclear, but detected in blood, urine, and other body fluids. Mendel and Metais [12] first discovered the presence of cfDNA in human it is certain that cfDNA cannot be a single source, but multiple sources. CfDNA from different sources can interact blood in 1948. About 20 years later, Tan [13] detected cfDNA in the serum of patients with systemic lupus erythematosus. with each other, creating cascades that releasing DNA into *en, Leon [14] found the changes of cfDNA are reflected in the loop (Figure 2). various types of cancer. *e levels of cfDNA increased in the Agarose gel electrophoresis showed that the purified serum of cancer patients and then decreased after treatment. DNA in plasma was double-stranded DNA and composed If the levels of cfDNA remained high, it might indicate a lack fragments can be up to 21 kb [26]. *e concentration of of response to chemotherapy. And the increasing levels of circulating DNA in plasma from healthy people is very low, 6.6–5.0 ng/ml, and the average length of cfDNA is 176 bp [20]. cfDNA might be a sign of recurrence of tumor or poor prognosis. Since then, there were more and more studies But the concentration of circulating DNA is significantly Journal of Oncology 3 diagnosis of ovarian cancer. Stamenkovic experiment [36] Apoptosis found that the correlated co-efficiency between the values of cfDNA concentration and cfDNA integrity were 0.86 and Necrosis 0.71. *e area under curve (AUC) of cfDNA concentration was 0.81, and the AUC of cfDNA integrity was 0.60. However, the AUC of combined detection was 0.84, Active secretion achieving the best diagnostic effect. Similarly, Yu experiment Figure 2: *e sources of cfDNA/ctDNA. *e circulating DNA in [37] found that diagnostic value of AUC for cfDNA con- the blood stream comes from tumour cells, which may have centration was 0.86 and for cfDNA integrity was 0.72. When mechanisms (apoptosis, necrosis, and active secretion). combined detection of them, the diagnostic value was 0.90. According, the joint effect of diagnosis is superior to single increased in malignant tumors and moderately increased in detection; the combined testing of cfDNA concentration and benign diseases [27]. *e plasma DNA fragments of cancer cfDNA integrity was favorable to diagnosis for ovarian patients are longer than those of noncancer patients [28]. cancer. *e reasons for the differences of the experimental However, the length of ctDNA is shorter than cfDNA (133–144bp results might be related to a variety of factors. Only when a vs 167 bp) [29]. *e difference of cfDNA levels may be related to uniform standard is achieved can cfDNA/ctDNA be better tumor type, stage, tumor load, and other factors [30]. In order to applied to clinical practice. Consequently, further studies are better apply cfDNA/ctDNA to clinical practice, the biological needed to analyze the factors that may influence the diag- characteristics of them still need to be continuously explored. nostic sensitivity and specificity of ovarian cancer and to *ey provide a sufficient and powerful basis for the follow-up validate the diagnostic efficiency of using cfDNA alone or in research and contribute to the study of its clinical application. combination with traditional methods. TP53 mutation is the most common in high-grade se- rous ovarian cancer, accounting for more than 95% of so- 2.3. e Clinical Applications of cfDNA/ctDNA in Ovarian matic mutations [70]. Detection of TP53 mutations in Cancer. CfDNA/CtDNA plays an important role in ovarian cfDNA/ctDNA has been reported [38–40]. *e studies cancer management; hence, we use PubMed database to showed that there were the same TP53 mutations in ovarian collect relevant articles about the clinical applications of cancer tissues and matched blood samples. Tumor-derived cfDNA/ctDNA in ovarian cancer. An overview of the re- DNA mutations could be detected in the plasma of some search studies on ctDNA/ctDNA in ovarian cancer is ovarian cancer patients, especially those with advanced summarized (Table 1). ovarian cancer patients. *erefore, detection of TP53 mu- tations in cfDNA/ctDNA could assist in the diagnosis of 2.4. eDiagnosticValueofcfDNA/ctDNAinOvarianCancer. ovarian cancer and determine the malignant degree of In recent years, many researchers have studied the value of ovarian cancer. However, the diagnostic performance has not been reported; different methods and different detection cfDNA in the early detection and diagnosis of ovarian cancer. For example, Shao et al. [31] found the levels of techniques lead to different results. It is needed to test the sensitivity and specificity about diagnosis of ovarian cancer. cfDNA in the ovarian cancer group were significantly higher than those in the benign ovarian disease group and the Meanwhile, it is needed to determine whether other ovarian healthy control group. It was in accordance with result of cancer-related mutations are appropriate for diagnosis. *e Kamat AA′ research [32]. Shao et al. [31] also found that studies of gene mutations have great potential for diagnosing levels of cfDNA were significantly increased in ovarian ovarian cancer. cancer patients with stage 3–4 compared with those in Changes of DNA methylation have been revealed to be ovarian cancer patients with stage 1–2. *e area under the an early event in tumorigenesis [71]. Circulating DNA methylation may be a potential marker for early diagnosis of receiver operating characteristic (ROC) curve was 0.917, and the sensitivity and specific were 88.9% and 89.5%, respec- the ovarian cancer [41]. *ere were several methylation changes in tissues and corresponding plasma samples of tively. *e detection of cfDNA was more sensitive and specific than traditional tumor markers, and the diagnostic ovarian cancer. For example, Dvorska´ D et al. [42] showed that, in the tissues of malignant ovarian cancer patients, the performance can be further improved when combined de- tection of these biomarkers. Capizzi et al [33] found the methylation levels of CDH1 gene were higher than those of quantitative detection of cfDNA can separate malignant healthy controls, and the difference was statistically signif- ovarian cancer from benign ovarian disease and healthy icant. Methylation of CDH1 gene was also highly expressed people with 77% sensitivity and 96% specificity. Pereira et al. in the corresponding plasma samples. Wu et al. [43] verified [34] found ctDNA was detected in 93.8% of ovarian cancer that abnormal methylation of RASSF2A has a frequency of patients and significantly correlated with serum CA125 and 51.1% in the tissues of patients with epithelial ovarian cancer and 36% in plasma, but has not been detected in benign computed tomography (CT) examination. But detection of ctDNA was more sensitive. However, Zhou meta-analysis tumors or healthy individuals. Swamy et al. [44] detected the hypermethylation of RASSF1A and BRCA1 in ctDNA of found that even though the quantitative detection of cfDNA had a high specificity of 0.90, its sensitivity was low to 0.70 ovarian carcinoma. *e rates of methylation were 31.9% and 56.9%, respectively. *is suggested that the methylation [35]. In conclusion, the quantitative analysis of cfDNA has unsatisfactory sensitivity but acceptable specificity for the pattern of gene in tumor tissues DNA is similar to that in 4 Journal of Oncology Table 1: An overview of the research studies on ctDNA/ctDNA in ovarian cancer is summarized. Author Year Application Sample Method Target Shao et al. [31] 2015 Diagnosis Serum bDNA technique *e levels of cfDNA Kamat et al. [32] 2006 Diagnosis Plasma Real-time PCR *e levels of cfDNA Diagnosis/therapy Capizzi et al. [33] 2008 Plasma Real-time PCR *e levels of cfDNA response Pereira et al. [34] 2015 Diagnosis Serum Droplet digital PCR *e levels of ctDNA Peripheral *e levels and integrity of Zhou et al. [35] 2016 Diagnosis Quantitative real-time PCR blood cfDNA Peripheral *e levels and integrity of Stamenkovic et al. [36] 2020 Diagnosis Quantitative real-time PCR blood cfDNA Peripheral *e levels and integrity of Yu et al. [37] 2019 Diagnosis Quantitative real-time PCR blood cfDNA Otsukaet al. [38] 2004 Diagnosis Plasma F-SSCP TP53 mutations Park et al. [39] 2018 Diagnosis Plasma Digital PCR TP53 mutations Peripheral Swisher et al. [40] 2005 Diagnosis Ligase detection reaction TP53 mutations blood Peripheral BRCA1 and RASSF1A Battagli et al. [41] 2004 Diagnosis MSP blood methylation Dvorska´ et al. [42] 2019 Diagnosis Plasma MSP Gene methylation Wu et al. [43] 2014 Diagnosis Serum MSP RASSFA methylation RASS1A and BRCA1 Sandeep et al. [44] 2019 Diagnosis Plasma MSP methylation Peripheral Qualitative detection Li et al. [45] 2019 Diagnosis NGS blood (methylation) Wang et al. [46] 2017 Diagnosis Serum MSP OPCML methylation Liggett et al. [47] 2011 Diagnosis Serum NGS DNA methylation Widschwendter et al. 2017 Diagnosis Serum Bisulfite sequencing DNA methylation [48] Low-coverage whole-genome Vanderstichele [49] 2017 Diagnosis Plasma Chromosomal instability sequencing Cheng et al. [50] 2009 *erapy response Plasma Quantitative PCR *e levels of cfDNA Kamat et al. [51] 2006 *erapy response Plasma Real-time PCR *e levels of cfDNA Hufnagl et al. [52] 2020 *erapy response Plasma Quantitative RT-PCR *e levels of cfDNA Arend et al. [53] 2018 *erapy response Plasma NGS Mutations Vitale et al. [54] 2020 *erapy response Serum NGS TP53 mutations Kim et al. [55] 2019 *erapy response Plasma Digital PCR TP53 mutations Parkinson et al. [56] 2016 *erapy response Plasma Microfluidic digital PCR TP53 mutations Harris et al. [57] 2016 *erapy response Plasma Quantitative PCR Chromosomal rearrangements Morikawa et al. [58] 2018 *erapy response Plasma Droplet digital PCR PIK3CA and KRAS mutations Christie et al. [59] 2017 *erapy response Plasma NGS BRCA1/2 germline mutations *erapy response/ Steffensen et al. [60] 2014 Plasma Real-time PCR *e levels of cfDNA prognosis Ratajska et al. [61] 2017 *erapy response Plasma NGS BRCA1/2 mutations BRCA1 and BRCA2 reversion Weigelt et al. [62] 2017 *erapy response Plasma NGS mutations Kamat et al. [63] 2010 Prognosis Plasma Real-time PCR *e levels of cfDNA No et al. [64] 2012 Prognosis Serum Quantitative real-time PCR *e levels of cfDNA Phallen et al. [65] 2017 Prognosis Plasma TES-seq Genomic mutations Dobrzyckaet al. [66] 2011 Prognosis Plasma PCR-RFLP KRAS and TP53 mutations Peripheral Zhuang et al. [67] 2017 Prognosis Meta-analysis KRAS mutation blood Giannopoulou et al. 2018 Prognosis Plasma Real-time MSP ESR1 methylation [68] Giannopoulou et al. 2017 Prognosis Plasma Real-time MSP RASSF1A methylation [69] Journal of Oncology 5 before and after chemotherapy of ovarian cancer patients, cfDNA/ctDNA of ovarian cancer; aberrant methylation of cfDNA/ctDNA may be valuable markers in ovarian cancer. which was related to the situation of patients after che- motherapy. Kamat et al. [51] thought that the levels of Furthermore, compared with quantitative detection, quali- tative detection of DNA methylation has better diagnostic cfDNA increase is related to the apoptosis index of tumor value [45]. Wang et al. [46] showed no significant difference cells. However, as the DNA was quickly cleared, cfDNA in CA125 level between patients with early epithelial ovarian gradually declined. It showed that the levels of cfDNA were cancer and healthy controls by one-way ANOVA analysis. significantly associated with tumor burden. As tumor However, the OPCML methylation level of cfDNA was burden increased, so did cfDNA. In a word, the concen- significantly different in early epithelial ovarian cancer pa- tration of cfDNA increased in cancer patients and decreased tients compared with healthy controls. Hence, this supports after effective treatment. *e variations of cfDNA concen- the idea that specific methylation could identify epithelial tration in cancer patients can dynamically reflect the de- velopment and progression of ovarian cancer. *e changes ovarian cancer from healthy individuals and the detection of cfDNA methylation was more sensitive and specific than of cfDNA levels have a statistically significant correlation with the response to treatment, but correlation was not traditional markers. Liggett et al. [47] found methylation differences of cfDNA in RASSF1A, CALCA, and EP300 could demonstrated with carcinoma antigen 15–3 (CA15-3), distinguish malignant ovarian tumors from control group, carcinoma antigen 19–9 (CA19-9) [52]. Similarly, ctDNA with a sensitivity of 90.0% and specificity of 86.7%. Widsch- could also be applied to evaluate treatment response dy- wendter et al. [48] revealed that the methylation pattern of namically [35], because the concentration of ctDNA cannot ctDNA, which distinguished high-grade serous ovarian cancer be detected after six months of initial treatment. It suggested patients from benign patients and healthy women, had a that patients might respond well to treatment. Accordingly, cfDNA/ctDNA could serve as a meaningful biomarker to sensitivity of 41.4% and a specificity of 90.7%. *us, abnormal methylation of cfDNA/ctDNA can be used to early diagnose monitor disease progression and therapeutic response, meanwhile, becoming a tool for reflecting tumor load. ovarian cancer, which has good prospects for clinical appli- cation. But, the sensitivity and sensitivity of diagnosis are Monitoring changes of cfDNA levels may have benefit for the ovarian cancer patients. different. Analyzing the causes of the differences is helpful to improve the diagnostic efficiency; it is needed to further study Analyzing status of gene mutations and methylation and confirm the diagnostic value of cfDNA methylation. changes in cfDNA/ctDNA is also helpful for understanding Chromosomal instability is also an important sign in patients’ respond to treatment. Arend et al [53] indicated ovarian cancer and can be detected in cfDNA. Although that 38 genetic variations were detected in six genes in tumor there were few reports about chromosome instability, pre- DNA before the neoadjuvant chemotherapy. And there were liminary study has shown that it is useful for the diagnosis of 59 mutations in the nineteen genes in cfDNA. After the neoadjuvant chemotherapy, 33 of the 38 variations in tumor ovarian cancer and has potential in clinical research. Van- derstichele et al. [49] demonstrated that the measurements DNA remained unchanged, while only 6 of the 59 mutations were present in cfDNA. *erefore, detection of cfDNA gene of chromosomal instability in cfDNA from ovarian cancer patients were highest, compared to the benign patients and variations may better reflect the response to chemotherapy healthy controls. Especially in high-grade serous ovarian in patients with high-grade serous ovarian cancer. But, this cancer, the AUC of cfDNA detection was 0.94, the specificity still requires a larger number of cases to expand the tests and was 99.6%, and the sensitivity was 2–5 times higher than that determine the role of cfDNA mutations in ovarian carci- of CA125 and malignant index risk. *us, chromosomal noma. TP53 mutation is a characteristic marker for high- instability in cfDNA can be suitable for diagnosis of ovarian grade serous ovarian cancer and might reflect the conditions cancer with high sensitivity and specificity. of patients. After chemotherapy, TP53 mutations in serum ctDNA were not detect, but reappeared as the disease progresses [54]. Kim YM’s experimental results manifested that TP53 mutant allele fraction in ctDNA significantly 2.5. eMoniteringValueofcfDNA/ctDNAinOvarianCancer decreased after therapy, and no significant difference in the 2.5.1. Response to erapy. As a widely used of marker rate of descent compared with CA125 [55]. However, the during treatment and follow-up, CA125 performed poorly result of Parkinson CA′ research demonstrated that ctDNA in clinical application [72]. Conversely, it was reported that responded to treatment earlier than CA125. And patients cfDNA/ctDNA might play an important role in reflecting with TP53 mutation allele fraction in ctDNA decreased by therapeutic response of cancer patients. Shao et al. found the less than 60% were associated with adverse reactions [56]. levels of cfDNA increased significantly the first day after *erefore, TP53 mutations in ctDNA may be a potential surgery, but as time went on, the levels of cfDNA gradually marker to monitor therapeutic response in ovarian cancer, declined [31]. Cheng et al. [50] showed that, during the first and have crucial research value. After chemotherapy, methylation levels of ctDNA decreased significantly [47]. and second weeks of radiation therapy, the levels of cfDNA in eleven of cancer patients increased eightfold over a period After surgery, specific chromosomal rearrangements in cfDNA were not detected in 5/8 patients [57], which suggests of time, and then decreased at the end of the treatment. However, the levels of cfDNA in the other two cancer pa- a good response to treatment. *erefore, methylation tients decreased during treatment. Capizzi et al. [34] verified changes and specific chromosomal rearrangements might that cfDNA levels could significantly differentiate between play an important role in reflecting the therapeutic effect. 6 Journal of Oncology to the targeted therapy of the PARP1 inhibitors [61]. *e *ey had potential in monitoring the disease progression. But, because of the lack of research, there are few reports study about the BRCA1/2 mutations is a breakthrough and provides a better insight into response to chemotherapy. But about their response for ovarian cancer treatment; the role of them should be further demonstrated by a large number of reversion mutations tend to lead to a high incidence of experiments. As a consequence, the analysis of cfDNA/ clinically acquired drug resistance. *e BRCA1/BRCA2 ctDNA can assess the tumor load and better reflect the reversion mutations in cfDNA were found by sequencing response to treatment, so as to make a treatment plan and analysis from 21% of therapy-resistant of ovarian cancer provide reference for subsequent treatment. Current studies patients [62]. *e acquisition of BRCA1/2 reversion mu- support the increasing important value of cfDNA/ctDNA as tations was closely related to resistance to therapy and may a new monitoring tool for patients during therapy. be beneficial to predict the chemotherapy response of ovarian cancer, guiding the treatment of ovarian cancer. However, its specific mechanism is unclear. It is needed to 2.5.2. Recurrence and Metastasis. Although most ovarian further study and verify the role of BRCA1/BRCA2 reversion cancer patients have good respond to treatment, advanced mutations in ovarian cancer. ovarian cancer patients tend to relapse after 1 to 2 years of treatment. It is related to the patients’ age, histological type, tumor stage, and other factors. And ovarian cancer is prone 2.6. ePrognosticValueofcfDNA/ctDNAinOvarianCancer. to metastasis; 70% malignant tumors spread to pelvic and Ovarian cancer patients had a poor overall prognosis. De- abdominal organs. *e evaluation of recurrence and me- spite the fact that there were major breakthroughs in surgery tastasis mainly relies on CA125 and CT, but CA125 and CT and chemotherapy, the survival of ovarian cancer patients cannot monitor dynamically and timely the situation of did not improve significantly. 5-year survival rate of ad- ovarian cancer patients after recurrence, and the detection of vanced ovarian cancer patients was significantly lower than metastatic lesions is also limited. However, the use of cfDNA that of early ovarian cancer patients. *erefore, tumor is promising for monitoring the recurrence and metastasis in markers are urgently needed to assess the prognosis of ovarian cancer patients. During tumor recurrence, the levels of ovarian cancer patients. Quantitative analysis of cfDNA/ PIK3A-H1047 R in cfDNA increased again, and it had a ctDNA is reported to be beneficial in evaluating the prog- correlation with metastasis [58]. Parkinson et al. indicated that nosis of ovarian cancer. When the levels of cfDNA exceed a patients with relapsed ovarian cancer have higher levels of certain range, the risk of death increases, which is related to ctDNA than those with newly diagnosed ovarian cancer pa- the decreased survival rate of ovarian cancer patients [63]. tients [56]. Vitale et al. [54] demonstrated that TP53 mutation *e concentration of RAB25 in cfDNA was correlated with was present in the serum circulating cell-free tumor DNA of overall survival and progression-free survival. *e low levels relapsed high-grade serous ovarian cancer patients. After of RAB25 predicted better PFS and OS [64]; it was a chemotherapy, TP53 mutation reduced to undetectable level prognostic indicator for epithelial ovarian cancer. CfDNA in ctDNA, but increased again as the disease progressed, TP53 also showed prognostic importance for chemoresistant mutation can be used as an indicator of disease monitoring ovarian cancer patients. Patients with high levels of cfDNA and to judge recurrence. When patients with high-grade se- had poor PFS and OS [60]. Hence, monitoring the changes rous ovarian cancer recurred, an unbiased analysis of cfDNA of cfDNA levels can help adjust therapeutic regimens and could detect the BRCA1/2 reversion mutations [59]. Gifford observe the state of ovarian cancer patients. et al. [73] expound that hMLH1 methylation increased in the Detection of mutations in cfDNA/ctDNA also has im- plasma DNA after chemotherapy, which indicated that the portant value for the prognosis of ovarian cancer. *e ovarian cancer patients relapsed. Hence, the changes of cfDNA frequency of somatic mutations in plasma from patients can reflect the situation of ovarian cancer patients. In sum- with stage 1 or 2 ovarian cancer was 68%. As the tumor stage mary, the detection of cfDNA/ctDNA concentration is helpful increased, so did the mutant allele fraction in ctDNA. Pa- for the monitoring of metastasis and recurrence of tumor, and tients with high ctDNA levels had poor PFS and OS [65]. the gene mutations and methylation changes of cfDNA/ One-third of ovarian cancer patients have tumor-specific ctDNA also have great significance for development and TP53 mutation in plasma, which have low survival rate. progress of tumor. Monitoring the changes of cfDNA/ctDNA Circulating tumor DNA was an independent predictor of is positive to ovarian cancer. low survival in multivariate analysis [40]. Serous ovarian cancer patients with TP53 antibodies had poor overall survival [66]. Meanwhile, the TP53 mutation in ctDNA from 2.5.3. Resistance to Chemotherapy. Resistance to chemo- therapy is common among patients during the development high-grade serous ovarian cancer patients is associated with stage. *ree months after chemotherapy, the high TP53 and progression of the diseases; cfDNA/ctDNA in the mutation allele fraction in ctDNA indicated the poor pro- treatment of chemotherapy resistant ovarian cancer has an gression [55]. *ere was a more significant prognostic effect important effect. Steffensen et al. [60] proved that the use of than CA125. Hence, detection of TP53 mutation in cfDNA/ bevacizumab contributes to treatment of multi-resistance ctDNA is valuable for judging prognosis of ovarian cancer. epithelial ovarian cancer. Depending on the levels of cfDNA, In addition, analysis of TP53 mutation in the plasma DNA treatment could be guided; it could be applied as an assistive marker. *e BRCA1/2 mutations could be detected in the can determine the degree of malignant ovarian cancer and is helpful for postoperative follow-up [38]. *e frequency of ctDNA from ovarian cancer patients, which responded well Journal of Oncology 7 KRAS mutation was particularly high in ovarian mucinous medical field and has a broad application prospect. CfDNA/ carcinoma, and KRAS mutation was associated with poor ctDNA has obvious advantages over traditional methods. It overall survival [66]. *e meta-analysis clarified the presence can not only be used for prenatal screening [74], analysis of of KRAS mutation in epithelial ovarian cancer, and the immune diseases [75, 76], but also have very important KRAS mutation in cfDNA was associated not only with poor clinical value in oncology. It has been reported in colorectal OS but also with poor PFS [67]. So, the detection of KRAS cancer, breast cancer, non-small cell lung cancer, and other mutation in cfDNA was beneficial to the prognosis of tumors [77–82]. *e value of cfDNA/ctDNA can be dem- ovarian cancer patients. *en, the researchers detected onstrated and utilized through diagnosis, monitoring of PI3CA and KRAS mutations in cfDNA from ovarian clear therapeutic response, recurrence and drug resistance, and cell carcinoma using ddPCR and found that patients with prognosis. CfDNA/ctDNA is a prospective marker that higher levels of PIK3CA-H1047 R and KRAS-G12D had provides important evidence for clinical research and shorter PFS [58]. *e changes of two indexes were more application. sensitive and rapid than CA125. Consequently, assessing the Although the development of “liquid biopsy” has status of mutations may provide important information for made tremendous progress, it still faces many challenges. the prognosis of patients with ovarian cancer. If cfDNA/ctDNA is to be used effectively in the clinic, In high-grade serous ovarian cancer patients, there was there are some problems to be solved. For instance, the ERS1 methylation in primary tumors and paired circulating exact source and mechanism of cfDNA/ctDNA are un- tumor DNA, and ESR1 methylation had a remarkable con- clear, which will affect subsequent research. *e problems sistency between primary tumors and paired circulating tumor of collection and treatment of samples, extraction of DNA. *e presence of ESR1 methylation in primary tumors cfDNA/ctDNA, and analysis of outcome will also interfere was associated with better OS, PFS, and clinicopathologic with the results of the experiment. Different experimental features, such as age and tumor rest; however, there was no subjects were selected and different test methods and correlation in ctDNA [68]. RASSF1A promoter methylation techniques were used, resulting in the different results. also was found in high-grade serous ovarian cancer patients. *e sensitivity and specificity of detection still need to be *e levels of RASSF1A promoter methylation in primary improved. *erefore, it still needs to make efforts to tumors were higher than those in adjacent morphologically develop standardized procedures for early application in tumor cell-free tissues, and RASSF1A promoter methylation clinical trials. was also detected in paired circulating tumor DNA. RASSF1A promoter methylation in primary tumors was related to 4. Conclusions tumor grade and regional lymph node metastasis. More- over, RASSF1A promoter methylation was positively as- Not only the detection of concentration and integrity but sociated with OS. Nevertheless, there was no significant also the genetic mutations and methylation changes have correlation between RASSF1A promoter methylation and been reported in cfDNA/ctDNA of ovarian cancer. As the clinicopathological characteristics or OS in adjacent tissues new tumor marker, cfDNA/ctDNA plays a key role in the and paired plasma samples [69]. Although methylation can clinical application. It can be used to screen and detect be detected in ctDNA, the role of methylation in ctDNA is tumors and evaluate prognosis, therapeutic effects, and unclear. Further researches are needed to understand response to chemotherapeutic drugs. However, the value of whether cfDNA/tDNA can predict disease outcomes and cfDNA/ctDNA still needs to be explored continually. In the evaluate the prognosis of ovarian cancer. Subsequently, the future, cfDNA/ctDNA has tremendous potential of devel- studies showed that methylation of RASSF1A and BRCA1 opment and broad prospects of clinical application. Further was evident in different stages and grades of ovarian cancer efforts are needed to bring cfDNA/ctDNA into clinical and might have potential as a prognostic marker in ovarian practice at an early date. cancer patients. *e presence of hMLH1 methylation in plasma DNA from relapsed ovarian cancer patients was Conflicts of Interest associated with poor OS and was independent of age, disease duration, and other factors. So, the changes of *e authors declare that they have no conflicts of interest. DNA methylation in cfDNA provided potential for prognosis of patients with ovarian cancer [73]. *ere are few studies about the prognostic value of cfDNA/ctDNA Authors’ Contributions methylation in ovarian cancer, and the mechanism by M Y, Y Z, LC T, JL C, and YJ S contributed to writing, review, which methylation occurs in the blood is unclear. In a and editing. All authors have read and agreed to the pub- word, further efforts are needed to screen specific lished version of the manuscript. methylation and confirm the significance of cfDNA/ ctDNA methylation in prognosis of ovarian cancer. Acknowledgments 3. Future Directions and Challenges *e study was supported by grants from the Natural Science With the continuous development and innovation of Foundation of Heilongjiang Province, China (No. technology, cfDNA has become a research focus in the H2018049). 8 Journal of Oncology [18] M. Esteller, M. Sanchez-Cespedes, R. Rosell, D Sidransky, References S. B Baylin, and J. G Herman, “Detection of aberrant pro- [1] L. A. Torre, B. Trabert, C. E. DeSantis et al., “Ovarian cancer moter hypermethylation of tumor suppressor genes in serum statistics, 2018,” CA: A Cancer Journal for Clinicians, vol. 68, DNA from non-small cell lung cancer patients,” Cancer Re- no. 4, pp. 284–296, 2018. search, vol. 59, no. 1, pp. 67–70, 1999. [2] G. Angius, P. 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Journal of Oncology – Hindawi Publishing Corporation
Published: Apr 12, 2021