**2. Biomarkers used in the diagnosis of ovarian cancer**

Tumor biomarkers are molecules that are produced by cancer cells or cells around them, which can be measured in body fluids or in the blood during the diagnosis, screening or treatment of cancer. Molecules that can be used as tumor biomarkers can be counted as cytoplasmic proteins, enzymes, hormones, surface antigens, receptors, oncofetal antigens (reemerging proteins in cancer that is normally lost after birth), oncogenes or their products. An ideal tumor biomarker should be sensitive enough for early detection of small tumors while retaining the specificity of the identified cancer type. Unfortunately, however, today there is no known tumor biomarker carrying these features [4].

The features that should be found in an ideal tumor biomarker are given below [5]:


Potential biomarkers used in ovarian cancer are grouped as gene, protein, metabolite, and miRNA-based biomarkers according to their type [5].

The vast majority of ovarian tumors arise from the accumulation of genetic damage, but the specific genetic pathways that are involved in the development of epithelial, borderline, and malignant tumors are largely unknown. Considering the important relationship between genetic alterations and ovarian tumors, potential ovarian-cancer biomarkers can be found at gene-level (hereditary gene mutations, epigenetic changes, and gene expression) studies. The most common genes associated with epithelial ovarian cancer are shown in **Table 1** [6].

BRCA1, BRCA2, and Lynch syndrome genes show high penetrance and offer lifetime risks of 7–40% for ovarian cancer. Nowadays, the multigene panels used for clinical genetic testing


Molecular and cellular analyses of these tumor types may lead to earlier diagnosis of ovarian cancer and it is hoped better survival rates. Many factors play a role in the development of cancer, while genomic mutations and epigenetic changes are very important. For this reason, studies on mutations and epigenetic alterations may provide information about features such

Tumor biomarkers are molecules that are produced by cancer cells or cells around them, which can be measured in body fluids or in the blood during the diagnosis, screening or treatment of cancer. Molecules that can be used as tumor biomarkers can be counted as cytoplasmic proteins, enzymes, hormones, surface antigens, receptors, oncofetal antigens (reemerging proteins in cancer that is normally lost after birth), oncogenes or their products. An ideal tumor biomarker should be sensitive enough for early detection of small tumors while retaining the specificity of the identified cancer type. Unfortunately, however, today there is

The features that should be found in an ideal tumor biomarker are given below [5]:

• Must have high sensitivity, should not be detected in cases of physiological or benign

Potential biomarkers used in ovarian cancer are grouped as gene, protein, metabolite, and

The vast majority of ovarian tumors arise from the accumulation of genetic damage, but the specific genetic pathways that are involved in the development of epithelial, borderline, and malignant tumors are largely unknown. Considering the important relationship between genetic alterations and ovarian tumors, potential ovarian-cancer biomarkers can be found at gene-level (hereditary gene mutations, epigenetic changes, and gene expression) studies. The most common genes associated with epithelial ovarian cancer are shown in **Table 1** [6].

BRCA1, BRCA2, and Lynch syndrome genes show high penetrance and offer lifetime risks of 7–40% for ovarian cancer. Nowadays, the multigene panels used for clinical genetic testing

• It should have high specificity; it should be specific to only one type of tumor.

• The predictive and prognostic benefit of tumor biomarkers should be known.

• Levels should be proportional to tumor characteristics and size.

• Half-life should be short, frequent and serial monitoring is possible.

as early diagnosis, surveillance, and response to treatment.

158 Ovarian Cancer - From Pathogenesis to Treatment

no known tumor biomarker carrying these features [4].

• It should be cheap and easy to apply.

miRNA-based biomarkers according to their type [5].

• Can be used as a screening test. • Sample taking should be easy.

tumors.

**2. Biomarkers used in the diagnosis of ovarian cancer**


and circulating tumor DNA (ctDNA) will improve cancer diagnosis, treatment, and imaging. Liquid biopsy can be performed "real-time" and at every stage of cancer. Although, it has some potential disadvantages such as; still is not certain to use in cancer diagnosis, difficulties in analysis of data obtaining from high-throughput screening and lack of data verification through clinical trials; it has significant potential for clinical cancer diagnosis in future [8].

The Role of Circulating Biomarkers in the Early Diagnosis of Ovarian Cancer

http://dx.doi.org/10.5772/intechopen.75484

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Some cancer derived cells are detected in peripheral blood, and appear as solid tumor cells that have broken away into the circulation [9]. There are two main types of CTCs to explain this phenomenon. The majority are "Accidental CTCs", and these are CTCs that are passively pushed by external forces, such as tumor growth, mechanical forces during surgical operation or friction. The rest are CTCs which gain more plasticity and metastatic potential via the epithelial-mesenchymal transition (EMT) process [8]. These CTCs can stay in the non-divided form in the vein, can spread together, or settle into a new tissue to compose the metastatic deposit. Regardless of the CTC pathway, these cells carry important information about tumor

CTCs have been demonstrated to have prognostic value among patients with breast, colorectal, gastric, lung, and pancreatic cancers in previous meta-analyses. However, the value of CTCs in ovarian cancer still remains controversial. Some studies did not observe any correlation between CTC status and prognosis. In contrast, other studies demonstrated an association Zhou et al. has shown that the prognostic value of CTCs was not associated with disease stage but with an elevated CA-125, both of which are known to correlate with prognosis either directly or indirectly. It has also been known that the CTC status was significant in respect to the overall survival (OS), progression-free survival (PFS), and disease-free survival (DFS) in

CTCs can be detected in both metastatic patients and patients with early, localized tumors. There is a significant potential for CTCs in the clinical management of cancers such as ovarian cancer. CTCs may enable real-time monitoring of treatment efficacy, identification of new therapy targets, and detecting and understanding drug resistance mechanisms [11]. CTC imaging and separation from leukocytes is dependent on reliable cell-surface markers. Based on the precipitation of CTCs in the low-speed centrifuge, the leukocyte fractions can be distinguished via physical features as well. Lee et al. used a nanoroughened microfluidic platform and detected CTCs in the sera of nearly all female participants (53/54, 98.1%) with ovarian cancer [12]. They also showed that although there is no relationship between CTC count and PFS in patients with newly diagnosed epithelial ovarian cancer (EOC), in patients with recurrent disease and chemoresistance; a relationship was found between CTC-cluster positivity and diminished OS [12]. It has been postulated that CTCs could result in metastatic progression and recurrence by way of epithelial-mesenchymal-transition (EMT) or development of stem-like features and hence a reduced OS. Therefore, researchers have tried to identify therapy-resistant tumor cells and to overcome treatment failure by analyzing CTCs transcriptional profiles [13]. In this study, the authors analyzed 15 single CTCs from 3 ovarian cancer patients and found them to be positive for stem cell (CD44, ALDH1A1, Nanog, Oct4) and

**3.1. Circulating tumor cells (CTCs)**

ovarian cancer [10].

composition, metastasis, drug sensitivity, and treatment.

EMT markers (N-cadherin, vimentin, Snai2, CD117, CD146) [13].

b Total Number of PubMed ID (PMIDs) Supporting the Association.

c The Number of Associated Single Nucleotide Polymorphism (SNPs).

**Table 1.** The most common genes associated with epithelial ovarian cancer.

include the mild-penetrance genes (lifetime risks of 6–13%) such as BRIP1, RAD51C, and RAD51D. The common low-penetrance susceptibility genes make up the rest of the genetic risk. Besides, SNPs have approximately 1% risk which is shown by population-based genome-wide association studies (GWASs) [7]. Expression analyses of quantitative or semiquantitatively specific genes in serum or tumor tissue can potentially contribute to tumor recognition. In the last decade, analysis of gene expression has gained momentum due to improvements in microarray technology. This is because microarray technology enables analysis of tens or hundreds of gene expressions in a single piece of tissue. Gene expression profiling has focused on three main topics: the separation of tumor tissue by normal ovarian tissue, the identification of different subtypes of ovarian cancer, and the determination of cancer according to possible responses to treatment.

DNA methylation and histone modification are epigenetic mechanisms that play important roles in gene regulation, tumor formation, and progression. Measuring the rate of methylation in specific genes in the promoter region helps early detection of cancer, detection of disease progression, and prediction of therapeutic response. Identification of specific genes that change with epigenetic regulation is one of the areas that are actively studied in ovarian cancer. In this chapter, we want to focus on circulating biomarkers and other types of biomarkers will not be discussed.
