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Harsanyi, S.;  Novakova, Z.V.;  Bevizova, K.;  Danisovic, L.;  Ziaran, S. Cell-Free DNA and Bladder Cancer. Encyclopedia. Available online: (accessed on 29 November 2023).
Harsanyi S,  Novakova ZV,  Bevizova K,  Danisovic L,  Ziaran S. Cell-Free DNA and Bladder Cancer. Encyclopedia. Available at: Accessed November 29, 2023.
Harsanyi, Stefan, Zuzana Varchulova Novakova, Katarina Bevizova, Lubos Danisovic, Stanislav Ziaran. "Cell-Free DNA and Bladder Cancer" Encyclopedia, (accessed November 29, 2023).
Harsanyi, S.,  Novakova, Z.V.,  Bevizova, K.,  Danisovic, L., & Ziaran, S.(2022, November 23). Cell-Free DNA and Bladder Cancer. In Encyclopedia.
Harsanyi, Stefan, et al. "Cell-Free DNA and Bladder Cancer." Encyclopedia. Web. 23 November, 2022.
Cell-Free DNA and Bladder Cancer

Bladder cancer (BC) is the 10th most frequent cancer in the world. The initial diagnosis and surveillance of BC require a combination of invasive and non-invasive methods, which are costly and suffer from several limitations. Cystoscopy with urine cytology and histological examination presents the standard diagnostic approach. Various biomarkers (e.g., proteins, genes, and RNAs) have been extensively studied in relation to BC.

bladder cancer biomarkers cell-free DNA DNA methylation non-coding RNA

1. Introduction

Bladder cancer (BC) is the 10th most common cancer worldwide, with over 573,000 new cases in 2020 [1]. Cellular origin in the urothelium accounts for more than 90% of all BCs [2]. These lesions range from benign, through small tumors, to aggressive and malignant neoplasms with lymphatic or vascular invasion, high recurrence rates with poor response to treatment, and bad prognosis [3][4][5].
The worldwide estimation of BC incidence for 2020 by The International Agency for Research on Cancer (IARC) reported that in males, BC is the seventh most frequent malignancy, while in females the frequency drops over three to four-fold, depending on the region. In the European Union, the age-standardized incidence rate is 20 for men and 4.6 for women as opposed to estimates from the year 2018, where the age-standardized incidence stood at 30.9 and 6.5, respectively [6][7][8]. According to the American Cancer Society (ACS), in the USA, approximately 90% of BC cases are patients older than 55 years and the average age at the time of diagnosis is 73 years. Additionally, BC is rated as the fourth most common malignancy in men, while the risk for women is 3.3-fold lower. The estimates for BC incidence in 2021 in the USA are 83.730 new cases (men—64.280, women—19.450) and 17.200 deaths (men—12.260, women—4.940), which points to a slight reduction in new cases in both men and women [9]. This phenomenon has also been observed in other countries [10][11][12]. However, discrepancies in worldwide reports of incidence and mortality are partially caused by different methodologies in data collection and analysis.
Tissue for histological or immunohistochemical examination is obtained by transurethral resection (TUR) of the papillary lesion or by multiple biopsies in the carcinoma in situ (Tis) stage. Later, the tumor tissue of individual patients is evaluated using the EORTC (European Organization for Research and Treatment of Cancer) scoring system for possible progression and recurrence [13][14]. According to the guidelines by the European Association of Urology (EAU), at the time of diagnosis, about 25% of patients present with muscle-invasive bladder cancer (MIBC), while the majority, about 75% of patients present with non-muscle invasive bladder cancer (NMIBC) [15][16]. These lesions are located in the mucosa (Ta, Tis) or submucosa (T1). The frequency of NMIBC is higher in younger patients (under 40) [17]. According to ACS, in the USA, approximately 50% of patients present with non-invasive or in situ cancers [18]. NMIBC has a one-to-five-year recurrence rate of 15–61% and an up to 17% chance of progression to MIBC within the first five years [19][20]. Additionally, even with combination treatment, the prognosis of patients remains unclear.
Etiopathogenesis of BC is not thoroughly explained, but many researchers consider this pathology similarly affected by environmental, mechanical, and genetic factors or rather, predisposition. Since the most common initial complaints of patients are macroscopic hematuria, dysuria, and symptoms similar, but unrelated to urinary tract infections (UTIs), researchers concluded that certain risk factors are in a causative relationship with BC [21]. These risk factors associated with BC include tobacco smoking, dietary factors, work-related exposure to chemicals (irritants, teratogens, mutagens), secondary cancer post-radiotherapy, chronic or frequent UTIs, or bladder schistosomiasis, and finally—race, gender, and genetic factors [22][23][24][25].
Diagnosing patients with NMIBC in the EU requires a combination of invasive (cystoscopy) and non-invasive methods (upper urinary tract imaging, and urine cytology). However, the management of patients from initial symptoms presentation to final diagnosis confirmed by tumor histology is a long process, and its speed and quality can positively or negatively affect patient prognosis. Patients undergoing regular preventive examinations are questioned on personal and family history, have their urine tested, undergo urinary cytology, and scheduled cystoscopies [26][27]. Urinary cytology, even if user-dependent is more sensitive for high-grade (HG) tumors and works best in conjunction with cystoscopy. On the other hand, patients not regularly examined tend to visit the physician with visible, often painless hematuria as their primary symptom. Irritative voiding and lower UTI symptoms are present to a lesser extent, especially present in the Tis stage. Imaging methods such as CT urography and ultrasonography (USG) are used to detect abnormalities in the urinary tract [28][29]. Magnetic resonance imaging (MRI) is also gaining interest in BC diagnostic process [30][31][32].
Due to the aforementioned limitations in the diagnosis, treatment, and management of BC patients, there is an urgent, long-standing need for better, more reliable, more precise examination methods that could provide a better understanding of individual cancer types, not only in the case of BC. Information about recurrence, progression, and prognosis is vital for the reliable stratification of patients and the future management of cancer as a whole. In this search for better predictive factors, various types of biomarkers are being studied for their association with BC [33][34]. Although, according to the EUA complex approaches such as the stratification of patients based on molecular classification, are promising but are not yet suitable for routine application [26][35].

2. Cell-Free DNA

Cell-free DNA (cfDNA) obtained from the liquid biopsy is fragmented DNA originating from deteriorating cancer cells [36]. Evaluation of alterations in DNA structure is gaining interest in the identification of cancer heterogeneity and patient prognosis. The method of real-time PCR was used to analyze quantitative changes in gene products [37]. However, nowadays the most frequent method for detecting alteration in cfDNA utilizes whole-genome sequencing, including digital PCR and next-generation sequencing (NGS) [38]. Sangster et al. proposed a theory of mutually exclusive gene mutations, where one gene contains a mutation, while the other does not, similarly in reverse [39]. This way they located two mutually exclusive pairs: KDM6A and KMT2D and also KDM6A and RB1.
The most common alteration is DNA mutation in genes associated with the processes of embryogenesis, proliferation, cell cycle regulation, and apoptosis. Genes with a substantial amount of research in association with BC are presented in Table 1.
Table 1. The most promising DNA markers.
The fibroblast growth factor receptor 3 gene (FGFR3) encodes for protein containing an extracellular domain with either 2 or 3 immunoglobulin (Ig)-like domains, a transmembrane domain, and a cytoplasmic tyrosine kinase domain that interacts with fibroblast growth factor and plays an important role in many important cellular processes, including regulation of proliferation, differentiation, apoptosis, angiogenesis), wound healing, and embryogenesis [46]. It was demonstrated that ectopic activation of FGFR3 is associated with several cancers, including multiple myeloma, cervical cancer, and BC [47][48][49]. In the case of BC, somatic mutations and gene overexpression are prevalent and may hold value as prognostic markers and as a tool for patient selection. Alterations affecting FGFR3 signaling were detected more frequently in the urinary bladder than in any other cancer type. Several forms of activation were described. The most common mechanism is missense point mutation which shows a strong relation to low-grade (LG) and low-stage cancer [50][51]. It was also shown that mutant FGFR3 affects the cell cycle regulation and led to changes in cell junctions and cell adherence to proteins occurring in the urothelial basement membrane and adjacent connective tissue, and induces alteration in expression of the extracellular matrix modulators, all functions predicted to provide a selective advantage to cells in the process of initial stages of cancer development [52]. Another form of FGFR3 activation is the formation of fusion proteins that can contribute to genomic instability [53]. However, the frequency of FGFR3-TACC3 fusion genes and their prognostic role are still unknown. FGFR3 overexpression seems to be a more suitable prognostic marker. Several studies demonstrated that stage Ta and T1 BC show overexpression of FGFR3 in 70–80% of Ta and 40–70% of T1 tumors [54][55][56]. More recently it has been shown that FGFR3 overexpression was also associated with reduced response to Bacillus Calmette-Guerin treatment and the expression of FGFR3 correlated with NMIBC stage, with more frequent overexpression in pTa tumors [57]. A recent study utilizing a 6-gene panel comprising 3 mutations (FGFR3, TERT, and HRAS) and 3 methylation analyses (OTX1, ONECUT2, and TWIST1) resulted in significant findings in the case of SN/SP/AUC as seen in Table 1, however, HRAS mutation did not prove significant [40].
PVRL4 gene (Nectin-4) encodes for a 510-amino acid protein (Nectin cell adhesion molecule) which contains 1 predicted transmembrane domain, followed by a 139-residue cytoplasmic sequence. It is expressed in the placenta, trachea, and human skin [58]. Recently it is considered a new prognostic biomarker for several types of cancer. Anti-nectin-4 antibody–drug-conjugate has great potential as a therapeutic agent for metastatic urothelial carcinoma [59]. It was also demonstrated that PVRL4 was also strongly expressed in NMIBC suggesting the assessment of anti-nectin-4 as a promising biomarker during the initial stages of the disease. In another experimental study, overexpression of PVRL4 in luminal BC cell lines was found, which correlated with the expression of GATA3 [41]. Current advances in monoclonal antibody treatment allowed for an anti-nectin-4 antibody (Enfortumab vedotin) to be approved for BC therapy, as moderate to strong overexpression of PVRL4 has been observed in 60% of BC patients [60].
Cyclin E gene (CCNE1) encodes for protein which has a pivotal role in cell cycle progression and differentiation [61]. Moreover, Keyomarsi et al. showed that breast cancers, and some other solid tumors, display significant quantitative and qualitative alterations in cyclin E protein production [62]. Rothman et al. demonstrated overexpression of CCNE1 in HG bladder tumors. There is also preliminary evidence that CCNE1 amplification is associated with frequent TP53 mutation and aggressive clinical outcomes [63]. A recent study reported a positive correlation between disease progression and copy-number variations (CNV) in CCNE1 combined with CDKN2A deletion [42].
Cyclin-dependent kinase inhibitor 2A (CDKN2A) encodes proteins that regulate two important cell cycle regulators—p53 and RB1. It produces a cyclin-dependent kinase inhibitor p16(INK4), and p14(ARF), which is essential for binding the p53-stabilizing protein MDM2 [64]. Several studies provided evidence that CDKN2A mutations are associated with cancer development. For instance, Chan et al. showed that pathogenic germline variants in CDKN2A significantly increase the risk of cutaneous melanoma and these alterations are also occasionally associated with a rare melanoma-astrocytoma syndrome and may lead to the development of malignant melanomas and neural system tumors, such as astrocytomas and meningiomas [65]. A large deletion in CDKN2A has been reported in neurofibromas, giant cell tumors of bone, and multiple primary cancers including sarcomas [66][67]. Loss of heterozygosity (LOH) in the 9p region belongs to typical processes in the initial stages of bladder cancer development [68]. Moreover, LOH of CDKN2A in combination with down-regulation of the p16 is in good correlation with progression in NMIBC [69]. CDKN2A homozygous deletion is also associated with invasiveness in FGFR3-mutated urothelial bladder carcinoma [70]. In a recent study, Verma et al. demonstrated that CDKN2A in combination with CTSV and FOXM1 has great potential to be a promising predictive marker of BC progression with 95.5% sensitivity and 100% specificity [43].
The telomerase reverse transcriptase gene (TERT) encodes a protein that acts as a safeguard of genomic integrity and is responsible for telomere maintenance. In cancer, telomerase activity is elevated and as a result, there is no induction of telomere shortening which enables cells to overcome replicative senescence and escape apoptosis, which belongs to crucial steps in cancer development [71]. TERT gene mutations are typical for various cancers, including melanoma, acute myeloid leukemia, and BC [72][73][74]. It was shown that mutations in the TERT promoter region are the most common somatic lesions in BC and may affect patient survival and disease recurrence through modification by a common polymorphism [75]. Carrasco et al. assessed the increased presence of TERT mutations as a potential biomarker of cancer aggressivity and progression [76]. Furthermore, Descostes et al. showed that TERT mutations in urine samples might be helpful for the early detection of recurrence in BC, especially in NMIBC. Overall sensitivity was 80.5% and specificity 89.8% [44].
Pleckstrin homology domain-containing S1 gene (PLEKHS1) encodes a protein with a function that still remains unclear. However, there are indications that PLEKHS1 may be after TERT function and is involved in cancer development. Interaction with the insulin-like growth factor (IGF) axis has been suggested, as PLEKHS1 was associated with mild blood glucose elevation, insulin resistance, and obesity [77]. Pignot et al. designed a two-phase study, where tissue from 154 and 181 bladder tumors was tested for PLEKHS1 mutation and its mRNA overexpression. Mutations occurred in 25.0% and 33.0% of NMIBC, while for MIBC it was 32.2% and 37.8%, respectively [78]. Dudley et al. discovered PLEKHS1 mutation in 46% of tested BC subjects [45]. Mutations of PLEKHS1 along with TERT promoter and GPR126 intron 6 have been found elevated in BC patients [79].


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