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Cancers
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Promising Biomarkers in Liquid Biopsy of Cancer
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Promising Biomarkers in Liquid Biopsy of Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Biomarkers".

Deadline for manuscript submissions: closed (31 January 2023) | Viewed by 34273

Special Issue Editor

Dr. Galatea Kallergi

E-Mail Website
Guest Editor
Department of Biology, University of Patras, 26504 Patras, Greece
Interests: signal transduction pathways in metastasis; liquid biopsy, detection and characterization of CTCs
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Targeted therapies have revolutionized the treatment of cancer. While these targets change during disease evolution or in response to therapy, it is extremely important to follow these alterations so that patients receive the appropriate treatment at each stage of the disease. Liquid biopsy (LB) can easily address this problem without painful interventions. LB is also an important tool for finding new therapeutic targets as well as prognostic factors for cancer patients. The main constituents of LB are circulating tumor cells (CTCs), ctDNA, exosomes, and microRNAs. Evaluation of one or more of these factors may provide useful information. Circulating tumor cells are important players in this field; however, they have not met expectations for their use in common clinical practice. This could possibly be attributed to the fact that most clinical trials focus on enumeration rather than characterization. Nevertheless, numerous studies have shown that specific CTC subtypes are much more important for prediction or prognosis compared to simple enumeration of total CTCs. On the other hand, the identification of specific mutations in ctDNA has also been shown to be a valuable predictive factor for specific treatments, such as EGFR targeted therapies. Exosomes and microRNAs are also involved in the detection of new biomarkers that can be easily evaluated in somatic fluids.

In this Special Issue we will focus on new biomarkers in every aspect of LB that can be used for prognosis, prediction to treatment or presenting new therapeutic targets.

Dr. Galatea Kallergi
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • biomarker
  • metastasis
  • CTCs
  • micro RNAs
  • exosomes
  • ctDNA
  • prognosis
  • prediction
  • therapy

Published Papers (15 papers)

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Research

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16 pages, 3818 KiB  
Article
Evaluation of Semen Self-Sampling Yield Predictors and CTC Isolation by Multi-Color Flow Cytometry for Liquid Biopsy of Localized Prostate Cancer
by Cesare Saitta, Ilaria De Simone, Vittorio Fasulo, Marinella Corbetta, Stefano Duga, Chiara Chiereghin, Federico Simone Colombo, Alessio Benetti, Roberto Contieri, Pier Paolo Avolio, Alessandro Uleri, Alberto Saita, Giorgio Ferruccio Guazzoni, Rodolfo Hurle, Piergiuseppe Colombo, Nicolò Maria Buffi, Paolo Casale, Giovanni Lughezzani, Rosanna Asselta, Giulia Soldà and Massimo Lazzeriadd Show full author list remove Hide full author list
Cancers 2023, 15(10), 2666; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15102666 - 09 May 2023
Viewed by 1370
Abstract
Liquid biopsy (LB) for prostate cancer (PCa) detection could represent an alternative to biopsy. Seminal fluid (SF) is a source of PCa-specific biomarkers, as 40% of ejaculate derives from the prostate. We tested the feasibility of an SF-based LB by evaluating the yield [...] Read more.
Liquid biopsy (LB) for prostate cancer (PCa) detection could represent an alternative to biopsy. Seminal fluid (SF) is a source of PCa-specific biomarkers, as 40% of ejaculate derives from the prostate. We tested the feasibility of an SF-based LB by evaluating the yield of semen self-sampling in a cohort of >750 patients with clinically localized PCa. The overall SF collection yield was 18.2% (39% when considering only compliant patients), with about a half of the patients (53.15%) not consenting to SF donation. Independent favorable predictors for SF collection were younger age and lower prostate volume. We implemented a protocol to enrich prostate-derived cells by multi-color flow cytometry and applied it on SF and urine samples from 100 patients. The number of prostate-enriched cells (SYTO-16+ PSMA+ CD45−) was variable, with higher numbers of cells isolated from SF than urine (p value < 0.001). Putative cancer cells (EpCAMhigh) were 2% of isolated cells in both specimens. The fraction of EpCAMhigh cells over prostate-enriched cells (PSMA+) significantly correlated with patient age in both semen and urine, but not with other clinical parameters, such as Gleason Score, ISUP, or TNM stage. Hence, enumeration of prostate-derived cells is not sufficient to guide PCa diagnosis; additional molecular analyses to detect patient-specific cancer lesions will be needed. Full article
(This article belongs to the Special Issue Promising Biomarkers in Liquid Biopsy of Cancer)
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15 pages, 3101 KiB  
Article
Small Extracellular Vesicles (sEVs) Biogenesis Molecular Players Are Associated with Clinical Outcome of Colorectal Cancer Patients
by Anastasia Kottorou, Foteinos-Ioannis Dimitrakopoulos, Georgia Diamantopoulou, Foteini Kalofonou, Michalis Stavropoulos, Konstantinos Thomopoulos, Thomas Makatsoris, Angelos Koutras and Haralabos Kalofonos
Cancers 2023, 15(6), 1685; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15061685 - 09 Mar 2023
Viewed by 1136
Abstract
A growing number of studies have shed light on the role of small extracellular vesicles (sEVs), including exosomes, in colorectal cancer (CRC). Available data regarding the clinical significance of molecular players in CRC, implicated in sEVs biogenesis, is limited. In this study, we [...] Read more.
A growing number of studies have shed light on the role of small extracellular vesicles (sEVs), including exosomes, in colorectal cancer (CRC). Available data regarding the clinical significance of molecular players in CRC, implicated in sEVs biogenesis, is limited. In this study, we assessed the expression of the most important genes which are implicated in sEVs biogenesis and their association with sEVs plasma levels, investigated with a double sandwich ELISA assay, as well as with the clinical outcome of patients with CRC. Our study shows that RAB27A, RAB27B, RAB2B, and RAB3B mRNA levels were lower in tumor tissues compared to tumor adjacent, non-malignant tissues (p < 0.001, p = 0.009, p = 0.011, and p < 0.001, respectively). In addition, high tumor expression of RAB27A, RAB27B, RAB9A, RAB11B, and STX1A was favorable of a 5-year survival (p = 0.038, p = 0.015, p = 0.008, p = 0.002, and p = 0.028, respectively). Furthermore, patients with adenomas had lower overall plasma sEVs concentrations, compared to healthy volunteers (p = 0.026), while no statistically significant differences were observed in the overall or tumor-derived plasma sEVs concentration (p = 0.885 and p = 0.330, respectively) of CRC patients. In conclusion, sEVs biogenesis has a potentially significant role in CRC, with RAB27A, RAB27B, RAB9A, RAB11B, and STX1A having a promising role in survival outcomes. Full article
(This article belongs to the Special Issue Promising Biomarkers in Liquid Biopsy of Cancer)
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15 pages, 991 KiB  
Article
Plasma Extracellular Vesicle Characteristics as Biomarkers of Resectability and Radicality of Surgical Resection in Pancreatic Cancer—A Prospective Cohort Study
by David Badovinac, Katja Goričar, Teja Lavrin, Hana Zavrtanik, Vita Dolžan, Metka Lenassi and Aleš Tomažič
Cancers 2023, 15(3), 605; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15030605 - 18 Jan 2023
Viewed by 1188
Abstract
Due to possible diagnostic misjudgment of tumor resectability, patients with pancreatic ductal adenocarcinoma (PDAC) might be exposed to non-radical resection or unnecessary laparotomy. With small extracellular vesicles (sEV) obtained by liquid biopsy, we aimed to evaluate their potential as biomarkers of tumor resectability, [...] Read more.
Due to possible diagnostic misjudgment of tumor resectability, patients with pancreatic ductal adenocarcinoma (PDAC) might be exposed to non-radical resection or unnecessary laparotomy. With small extracellular vesicles (sEV) obtained by liquid biopsy, we aimed to evaluate their potential as biomarkers of tumor resectability, radicality of resection and overall survival (OS). Our prospective study included 83 PDAC patients undergoing surgery with curative intent followed-up longitudinally. sEV were isolated from plasma, and their concentration and size were determined. Fifty patients underwent PDAC resection, and thirty-three had no resection. Preoperatively, patients undergoing resection had higher sEV concentrations than those without resection (p = 0.023). Resection was predicted at the cutoff value of 1.88 × 109/mL for preoperative sEV concentration (p = 0.023) and the cutoff value of 194.8 nm for preoperative mean diameter (p = 0.057). Furthermore, patients with R0 resection demonstrated higher preoperative plasma sEV concentrations than patients with R1/R2 resection (p = 0.014). If sEV concentration was above 1.88 × 109/mL or if the mean diameter was below 194.8 nm, patients had significantly longer OS (p = 0.018 and p = 0.030, respectively). Our proof-of-principle study identified preoperative sEV characteristics as putative biomarkers of feasibility and radicality of PDAC resection that also enable discrimination of patients with worse OS. Liquid biopsy with sEV could aid in PDAC patient stratification and treatment optimization in the future. Full article
(This article belongs to the Special Issue Promising Biomarkers in Liquid Biopsy of Cancer)
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14 pages, 2821 KiB  
Article
Serum-Exosome-Derived miRNAs Serve as Promising Biomarkers for HCC Diagnosis
by Tao Rui, Xiaobing Zhang, Jufeng Guo, Aizhai Xiang, Ning Tang, Jian Liu and Zonglei Mao
Cancers 2023, 15(1), 205; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15010205 - 29 Dec 2022
Cited by 9 | Viewed by 2296
Abstract
Background: Serum exosomes are emerging as key liquid biopsy biomarkers for the early diagnosis of cancer. However, the proportion and distribution of small RNA (sRNA) species from serum exosomes of hepatocellular carcinoma (HCC) patients remain unclear. Effective and reliable biomarkers for HCC diagnosis [...] Read more.
Background: Serum exosomes are emerging as key liquid biopsy biomarkers for the early diagnosis of cancer. However, the proportion and distribution of small RNA (sRNA) species from serum exosomes of hepatocellular carcinoma (HCC) patients remain unclear. Effective and reliable biomarkers for HCC diagnosis should be explored. Methods: In this study, we aimed to use sRNA sequencing to profile the sRNAs of serum exosomes in HCC and non-tumor donors. The serum exosomes of 124 HCC patients and 46 non-tumor donors were enrolled for detecting the values of the potential biomarkers for the diagnosis of HCC. Results: We found that miRNAs accounted for the maximal percentage of all types of sRNAs both in the serum exosomes of HCC patients and non-tumor donors. This indicated that the serum-exosome-derived microRNAs (miRNAs) were the most valuable as potential biomarkers in HCC diagnosis. Then, miRNAs were set as research candidates. In our Chinese cohorts, three serum-exosome-derived miRNAs (miR-122-5p, let-7d-5p, and miR-425-5p) could be promising biomarkers for distinguishing HCC patients from non-tumor donors. In addition, they were preferred for the early diagnosis of HCC. We also presented the base distribution of some novel serum-exosome-derived miRNAs and described the potential values as biomarkers. Conclusions: The results suggested that the serum-exosome-derived miRNAs were the most crucial sRNA species and they highlighted the potential of serum-exosome-derived miRNAs as promising biomarkers for HCC diagnosis. Full article
(This article belongs to the Special Issue Promising Biomarkers in Liquid Biopsy of Cancer)
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21 pages, 1877 KiB  
Article
Targeted Sequencing of Plasma-Derived vs. Urinary cfDNA from Patients with Triple-Negative Breast Cancer
by Henrike Herzog, Senol Dogan, Bahriye Aktas and Ivonne Nel
Cancers 2022, 14(17), 4101; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14174101 - 24 Aug 2022
Cited by 6 | Viewed by 1946
Abstract
In breast cancer, the genetic profiling of circulating cell-free DNA (cfDNA) from blood plasma was shown to have good potential for clinical use. In contrast, only a few studies were performed investigating urinary cfDNA. In this pilot study, we analyzed plasma-derived and matching [...] Read more.
In breast cancer, the genetic profiling of circulating cell-free DNA (cfDNA) from blood plasma was shown to have good potential for clinical use. In contrast, only a few studies were performed investigating urinary cfDNA. In this pilot study, we analyzed plasma-derived and matching urinary cfDNA samples obtained from 15 presurgical triple-negative breast cancer patients. We used a targeted next-generation sequencing approach to identify and compare genetic alterations in both body fluids. The cfDNA concentration was higher in urine compared to plasma, but there was no significant correlation between matched samples. Bioinformatical analysis revealed a total of 3339 somatic breast-cancer-related variants (VAF ≥ 3%), whereof 1222 vs. 2117 variants were found in plasma-derived vs. urinary cfDNA, respectively. Further, 431 shared variants were found in both body fluids. Throughout the cohort, the recovery rate of plasma-derived mutations in matching urinary cfDNA was 47% and even 63% for pathogenic variants only. The most frequently occurring pathogenic and likely pathogenic mutated genes were NF1, CHEK2, KMT2C and PTEN in both body fluids. Notably, a pathogenic CHEK2 (T519M) variant was found in all 30 samples. Taken together, our results indicated that body fluids appear to be valuable sources bearing complementary information regarding the genetic tumor profile. Full article
(This article belongs to the Special Issue Promising Biomarkers in Liquid Biopsy of Cancer)
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11 pages, 1450 KiB  
Article
Detection of ESR1 Mutations in Primary Tumors and Plasma Cell-Free DNA in High-Grade Serous Ovarian Carcinoma Patients
by Dimitra Stergiopoulou, Athina Markou, Lydia Giannopoulou, Paul Buderath, Ioanna Balgkouranidou, Nikolaos Xenidis, Stylianos Kakolyris, Sabine Kasimir-Bauer and Evi Lianidou
Cancers 2022, 14(15), 3790; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14153790 - 04 Aug 2022
Cited by 3 | Viewed by 2128
Abstract
ESR1 mutations have been recently associated with resistance to endocrine therapy in metastatic breast cancer and their detection has led to the development and current evaluation of novel, highly promising therapeutic strategies. In ovarian cancer there have been just a few reports on [...] Read more.
ESR1 mutations have been recently associated with resistance to endocrine therapy in metastatic breast cancer and their detection has led to the development and current evaluation of novel, highly promising therapeutic strategies. In ovarian cancer there have been just a few reports on the presence of ESR1 mutations. The aim of our study was to evaluate the frequency and the clinical relevance of ESR1 mutations in high-grade serous ovarian cancer (HGSOC). Drop-off droplet digital PCR (ddPCR) was first used to screen for ESR1 mutations in 60 primary tumors (FFPEs) from HGSOC patients and in 80 plasma cell-free DNA (cfDNA) samples from advanced and metastatic ovarian cancer patients. We further used our recently developed ESR1-NAPA assay to identify individual ESR1 mutations in drop-off ddPCR-positive samples. We report for the first time the presence of ESR1 mutations in 15% of FFPEs and in 13.8% of plasma cfDNA samples from advanced and metastatic ovarian cancer patients. To define the clinical significance of this finding, our results should be further validated in a large and well-defined cohort of ovarian cancer patients. Full article
(This article belongs to the Special Issue Promising Biomarkers in Liquid Biopsy of Cancer)
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12 pages, 1263 KiB  
Article
miRNAs in Serum Exosomes for Differential Diagnosis of Brain Metastases
by Silvia Catelan, Debora Olioso, Alessandra Santangelo, Chiara Scapoli, Anna Tamanini, Giampietro Pinna, Francesco Sala, Giuseppe Lippi, Antonio Nicolato, Giulio Cabrini and Maria Cristina Dechecchi
Cancers 2022, 14(14), 3493; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14143493 - 18 Jul 2022
Cited by 9 | Viewed by 1661
Abstract
Circulating miRNAs are increasingly studied and proposed as tumor markers with the aim of investigating their role in monitoring the response to therapy as well as the natural evolution of primary or secondary brain tumors. This study aimed to evaluate the modulation of [...] Read more.
Circulating miRNAs are increasingly studied and proposed as tumor markers with the aim of investigating their role in monitoring the response to therapy as well as the natural evolution of primary or secondary brain tumors. This study aimed to evaluate the modulation of the expression of three miRNAs, miR-21, miR-222 and miR-124-3p, in the serum exosomes of patients with high-grade gliomas (HGGs) and brain metastases (BMs) to verify their usefulness in the differential diagnosis of brain masses; then, it focused on their variations following the surgical and/or radiosurgical treatment of the BMs. A total of 105 patients with BMs from primary lung or breast cancer, or melanoma underwent neurosurgery or radiosurgery treatment, and 91 patients with HGGs were enrolled, along with 30 healthy controls. A significant increase in miR-21 expression in serum exosomes was observed in both HGGs and BMs compared with healthy controls; on the other hand, miR-124-3p was significantly decreased in BMs, and it was increased in HGGs. After the surgical or radiosurgical treatment of patients with BMs, a significant reduction in miR-21 was noted with both types of treatments. This study identified a signature of exosomal miRNAs that could be useful as a noninvasive complementary analysis both in the differential diagnosis of BMs from glial tumors and in providing information on tumor evolution over time. Full article
(This article belongs to the Special Issue Promising Biomarkers in Liquid Biopsy of Cancer)
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17 pages, 879 KiB  
Article
In Early Breast Cancer, the Ratios of Neutrophils, Platelets and Monocytes to Lymphocytes Significantly Correlate with the Presence of Subsets of Circulating Tumor Cells but Not with Disseminated Tumor Cells
by Sabine Kasimir-Bauer, Ebru Karaaslan, Olaf Hars, Oliver Hoffmann and Rainer Kimmig
Cancers 2022, 14(14), 3299; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14143299 - 06 Jul 2022
Cited by 4 | Viewed by 2183
Abstract
Circulating tumor cells (CTCs) crosstalk with different blood cells before a few of them settle down as disseminated tumor cells (DTCs). We evaluated the correlation between CTC subtypes, DTCs and the neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR) and monocyte [...] Read more.
Circulating tumor cells (CTCs) crosstalk with different blood cells before a few of them settle down as disseminated tumor cells (DTCs). We evaluated the correlation between CTC subtypes, DTCs and the neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR) and monocyte to lymphocyte ratio (MLR) for better prognostication of 171 early staged diagnosed breast cancer (BC) patients. —Clinical data and blood values before treatment were retrospectively recorded, representing the 75% percentile, resulting in 3.13 for NLR, 222.3 for PLR and 0.39 for MLR, respectively. DTCs were analyzed by immunocytochemistry using the pan-cytokeratin antibodyA45-B/B3. CTCs were determined applying the AdnaTests BreastCancerDetect and EMT (Epithelial Mesenchymal Transition) Detect. —Reduced lymphocyte (p = 0.007) and monocyte counts (p = 0.012), an elevated NLR (p = 0.003) and PLR (p = 0.001) significantly correlated with the presence of epithelial CTCs while a reduced MLR was related to EMT-CTCs (p = 0.045). PLR (p = 0.029) and MLR (p = 0.041) significantly related to lymph node involvement and monocyte counts significantly correlated with OS (p = 0.034). No correlations were found for NLR, PLR and MLR with DTCs, however, DTC-positive patients, harboring a lower PLR, had a significant shorter OS (p = 0.043). —Pro-inflammatory markers are closely related to different CTC subsets. This knowledge might improve risk prognostication of these patients. Full article
(This article belongs to the Special Issue Promising Biomarkers in Liquid Biopsy of Cancer)
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13 pages, 2004 KiB  
Article
PARP-1 Expression and BRCA1 Mutations in Breast Cancer Patients’ CTCs
by Thodoris Sklias, Vasileios Vardas, Evangelia Pantazaka, Athina Christopoulou, Vassilis Georgoulias, Athanasios Kotsakis, Yiannis Vasilopoulos and Galatea Kallergi
Cancers 2022, 14(7), 1731; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14071731 - 29 Mar 2022
Cited by 6 | Viewed by 2549
Abstract
BRCA1 and PARP are involved in DNA damage repair pathways. BRCA1 mutations have been linked to higher likelihood of triple negative breast cancer (TNBC). The aim of the study was to determine PARP-1 expression and BRCA1 mutations in circulating tumor cells (CTCs) of [...] Read more.
BRCA1 and PARP are involved in DNA damage repair pathways. BRCA1 mutations have been linked to higher likelihood of triple negative breast cancer (TNBC). The aim of the study was to determine PARP-1 expression and BRCA1 mutations in circulating tumor cells (CTCs) of BC patients. Fifty patients were enrolled: 23 luminal and 27 TNBC. PARP expression in CTCs was identified by immunofluorescence. Genotyping was performed by PCR-Sanger sequencing in the same samples. PARP-1 expression was higher in luminal (61%) and early BC (54%), compared to TNBC (41%) and metastatic (33%) patients. In addition, PARP-1 distribution was mostly cytoplasmic in luminal patients (p = 0.024), whereas it was mostly nuclear in TNBC patients. In cytokeratin (CK)-positive patients, those with the CK+PARP+ phenotype had longer overall survival (OS, log-rank p = 0.046). Overall, nine mutations were detected; M1 and M2 were completely new and M4, M7 and M8 were characterized as pathogenic. M7 and M8 were predominantly found in metastatic TNBC patients (p = 0.014 and p = 0.002). Thus, PARP-1 expression and increased mutagenic burden in TNBC patients’ CTCs, could be used as an indicator to stratify patients regarding therapeutic approaches. Full article
(This article belongs to the Special Issue Promising Biomarkers in Liquid Biopsy of Cancer)
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15 pages, 2364 KiB  
Article
Rational Development of Liquid Biopsy Analysis in Renal Cell Carcinoma
by Kate I. Glennon, Mahafarin Maralani, Narges Abdian, Antoine Paccard, Laura Montermini, Alice Jisoo Nam, Madeleine Arseneault, Alfredo Staffa, Pouria Jandaghi, Brian Meehan, Fadi Brimo, Simon Tanguay, Janusz Rak and Yasser Riazalhosseini
Cancers 2021, 13(22), 5825; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13225825 - 20 Nov 2021
Cited by 6 | Viewed by 3263
Abstract
Renal cell carcinoma (RCC) is known for its variable clinical behavior and outcome, including heterogeneity in developing relapse or metastasis. Recent data highlighted the potential of somatic mutations as promising biomarkers for risk stratification in RCC. Likewise, the analysis of circulating tumor DNA [...] Read more.
Renal cell carcinoma (RCC) is known for its variable clinical behavior and outcome, including heterogeneity in developing relapse or metastasis. Recent data highlighted the potential of somatic mutations as promising biomarkers for risk stratification in RCC. Likewise, the analysis of circulating tumor DNA (ctDNA) for such informative somatic mutations (liquid biopsy) is considered an important advance for precision oncology in RCC, allowing to monitor molecular disease evolution in real time. However, our knowledge about the utility of ctDNA analysis in RCC is limited, in part due to the lack of RCC-appropriate assays for ctDNA analysis. Here, by interrogating different blood compartments in xenograft models, we identified plasma cell-free (cf) DNA and extracellular vesicles (ev) DNA enriched for RCC-associated ctDNA. Additionally, we developed sensitive targeted sequencing and bioinformatics workflows capable of detecting somatic mutations in RCC-relevant genes with allele frequencies ≥ 0.5%. Applying this assay to patient-matched tumor and liquid biopsies, we captured tumor mutations in cf- and ev-DNA fractions isolated from the blood, highlighting the potentials of both fractions for ctDNA analysis. Overall, our study presents an RCC-appropriate sequencing assay and workflow for ctDNA analysis and provides a proof of principle as to the feasibility of detecting tumor-specific mutations in liquid biopsy in RCC patients. Full article
(This article belongs to the Special Issue Promising Biomarkers in Liquid Biopsy of Cancer)
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15 pages, 1385 KiB  
Article
Clinical Significance of Plasma CD9-Positive Exosomes in HIV Seronegative and Seropositive Lung Cancer Patients
by Foteinos-Ioannis Dimitrakopoulos, Anastasia E. Kottorou, Kristen Rodgers, John Timothy Sherwood, Georgia-Angeliki Koliou, Beverly Lee, Andrew Yang, Julie Renee Brahmer, Stephen B. Baylin, Stephen C. Yang, Hajime Orita, Alicia Hulbert and Malcolm V. Brock
Cancers 2021, 13(20), 5193; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13205193 - 16 Oct 2021
Cited by 5 | Viewed by 3183
Abstract
Recently, the role of exosomes in the progression of both cancer and HIV (human immunodeficiency virus) has been described. This study investigates the clinical significance of CD9-positive plasma exosomes in lung cancer patients, healthy individuals, and HIV-positive patients with or without lung cancer. [...] Read more.
Recently, the role of exosomes in the progression of both cancer and HIV (human immunodeficiency virus) has been described. This study investigates the clinical significance of CD9-positive plasma exosomes in lung cancer patients, healthy individuals, and HIV-positive patients with or without lung cancer. Using a verified with transmission electron microscopy double-sandwich ELISA technique, plasma-derived exosomes were isolated and quantified from 210 lung cancer patients (including 44 metastatic patients with progressive disease after chemotherapy), 49 healthy controls, 20 patients with pulmonary granulomas, 19 HIV+ patients with lung cancer, 31 HIV+ patients without cancer, and 3 HIV+ patients with pulmonary granulomas. Plasma exosome concentrations differed between healthy controls, patients with immunocompetent pulmonary granulomas and patients with lung cancer even after chemotherapy (p < 0.001). Lung cancer patients after chemotherapy had lower exosome concentrations compared to patients with untreated lung cancer or granuloma (p < 0.001 for both). HIV+ patients without lung cancer had significantly higher exosome concentrations compared to HIV+ patients with lung cancer (p = 0.016). Although exosome concentrations differed between all different lung cancer histologies and healthy controls (p < 0.001 for all histologies), adjusted statistical significance was oµy retained for patients with granulomas and SCLC (Small-cell lung cancer, p < 0.001). HIV-induced immunodeficient patients with or without lung cancer had lower plasma exosomes compared to immunocompetent granuloma and lung cancer patients (p < 0.001). Finally, higher plasma exosomes were associated both on univariate (p = 0.044), and multivariate analysis (p = 0.040) with a better 3-year survival in stage II and III NSCLC (Non-small-cell lung carcinoma) patients. In conclusion, our study shows that CD9-positive plasma exosomes are associated with both lung cancer and HIV, prior chemotherapy, as well as with survival, suggesting a possible prognostic value. Full article
(This article belongs to the Special Issue Promising Biomarkers in Liquid Biopsy of Cancer)
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15 pages, 1774 KiB  
Article
USP44 Promoter Methylation in Plasma Cell-Free DNA in Prostate Cancer
by Dora Londra, Sophia Mastoraki, Evangelos Bournakis, Martha Zavridou, Anastasios Thanos, Theodoros Rampias and Evi S. Lianidou
Cancers 2021, 13(18), 4607; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13184607 - 14 Sep 2021
Cited by 7 | Viewed by 2502
Abstract
Liquid biopsy provides real-time monitoring of tumor evolution and response to therapy through analysis of circulating tumor cells (CTCs) and plasma-circulating tumor DNA (ctDNA). USP44 is a critical gene which plays an important role in cell proliferation; however, its accurate role in other [...] Read more.
Liquid biopsy provides real-time monitoring of tumor evolution and response to therapy through analysis of circulating tumor cells (CTCs) and plasma-circulating tumor DNA (ctDNA). USP44 is a critical gene which plays an important role in cell proliferation; however, its accurate role in other cellular networks is under research. USP44 promoter methylation has been so far reported in colorectal neoplasia and metastatic breast cancer. In this study, we examined for the first time USP44 promoter methylation in plasma cell-free DNA (cfDNA) of patients with prostate cancer (early stage n = 32, metastatic n = 39) and 10 healthy donors (HD). USP44 promoter methylation was detected in plasma cell-free DNA by a newly developed highly specific and sensitive real-time MSP method. Our findings indicate that USP44 promoter is methylated in plasma cell-free DNA of metastatic prostate cancer patients and that detection of USP44 promoter methylation is significantly associated with overall survival (OS) (p = 0.008). We report for the first time that detection of USP44 promoter methylation in plasma cell free DNA provides significant prognostic information in metastatic prostate cancer. Full article
(This article belongs to the Special Issue Promising Biomarkers in Liquid Biopsy of Cancer)
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32 pages, 847 KiB  
Review
Liquid Biopsies in Lung Cancer
by Marcel Kemper, Carolin Krekeler, Kerstin Menck, Georg Lenz, Georg Evers, Arik Bernard Schulze and Annalen Bleckmann
Cancers 2023, 15(5), 1430; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15051430 - 23 Feb 2023
Cited by 8 | Viewed by 2919
Abstract
As lung cancer has the highest cancer-specific mortality rates worldwide, there is an urgent need for new therapeutic and diagnostic approaches to detect early-stage tumors and to monitor their response to the therapy. In addition to the well-established tissue biopsy analysis, liquid-biopsy-based assays [...] Read more.
As lung cancer has the highest cancer-specific mortality rates worldwide, there is an urgent need for new therapeutic and diagnostic approaches to detect early-stage tumors and to monitor their response to the therapy. In addition to the well-established tissue biopsy analysis, liquid-biopsy-based assays may evolve as an important diagnostic tool. The analysis of circulating tumor DNA (ctDNA) is the most established method, followed by other methods such as the analysis of circulating tumor cells (CTCs), microRNAs (miRNAs), and extracellular vesicles (EVs). Both PCR- and NGS-based assays are used for the mutational assessment of lung cancer, including the most frequent driver mutations. However, ctDNA analysis might also play a role in monitoring the efficacy of immunotherapy and its recent accomplishments in the landscape of state-of-the-art lung cancer therapy. Despite the promising aspects of liquid-biopsy-based assays, there are some limitations regarding their sensitivity (risk of false-negative results) and specificity (interpretation of false-positive results). Hence, further studies are needed to evaluate the usefulness of liquid biopsies for lung cancer. Liquid-biopsy-based assays might be integrated into the diagnostic guidelines for lung cancer as a tool to complement conventional tissue sampling. Full article
(This article belongs to the Special Issue Promising Biomarkers in Liquid Biopsy of Cancer)
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20 pages, 2159 KiB  
Review
Extracellular Vesicles in Liquid Biopsies as Biomarkers for Solid Tumors
by Barnabas Irmer, Suganja Chandrabalan, Lukas Maas, Annalen Bleckmann and Kerstin Menck
Cancers 2023, 15(4), 1307; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15041307 - 18 Feb 2023
Cited by 20 | Viewed by 2616
Abstract
Extracellular vesicles (EVs) are secreted by all living cells and are ubiquitous in every human body fluid. They are quite heterogeneous with regard to biogenesis, size, and composition, yet always reflect their parental cells with their cell-of-origin specific cargo loading. Since numerous studies [...] Read more.
Extracellular vesicles (EVs) are secreted by all living cells and are ubiquitous in every human body fluid. They are quite heterogeneous with regard to biogenesis, size, and composition, yet always reflect their parental cells with their cell-of-origin specific cargo loading. Since numerous studies have demonstrated that EV-associated proteins, nucleic acids, lipids, and metabolites can represent malignant phenotypes in cancer patients, EVs are increasingly being discussed as valuable carriers of cancer biomarkers in liquid biopsy samples. However, the lack of standardized and clinically feasible protocols for EV purification and characterization still limits the applicability of EV-based cancer biomarker analysis. This review first provides an overview of current EV isolation and characterization techniques that can be used to exploit patient-derived body fluids for biomarker quantification assays. Secondly, it outlines promising tumor-specific EV biomarkers relevant for cancer diagnosis, disease monitoring, and the prediction of cancer progression and therapy resistance. Finally, we summarize the advantages and current limitations of using EVs in liquid biopsy with a prospective view on strategies for the ongoing clinical implementation of EV-based biomarker screenings. Full article
(This article belongs to the Special Issue Promising Biomarkers in Liquid Biopsy of Cancer)
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26 pages, 1229 KiB  
Review
Circulating Long Non-Coding RNAs Could Be the Potential Prognostic Biomarker for Liquid Biopsy for the Clinical Management of Oral Squamous Cell Carcinoma
by Ruma Dey Ghosh and Sudhriti Guha Majumder
Cancers 2022, 14(22), 5590; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14225590 - 14 Nov 2022
Cited by 6 | Viewed by 1553
Abstract
Long non-coding RNA (lncRNA) have little or no coding potential. These transcripts are longer than 200 nucleotides. Since lncRNAs are master regulators of almost all biological processes, recent evidence proves that aberrantly expressed lncRNAs are pathogenic for oral squamous cell carcinoma (OSCC) and [...] Read more.
Long non-coding RNA (lncRNA) have little or no coding potential. These transcripts are longer than 200 nucleotides. Since lncRNAs are master regulators of almost all biological processes, recent evidence proves that aberrantly expressed lncRNAs are pathogenic for oral squamous cell carcinoma (OSCC) and other diseases. LncRNAs influence chromatin modifications, transcriptional modifications, post-transcriptional modifications, genomic imprinting, cell proliferation, invasion, metastasis, and apoptosis. Consequently, they have an impact on the disease transformation, progression, and morbidity in OSCC. Therefore, circulating lncRNAs could be the potential cancer biomarker for the better clinical management (diagnosis, prognosis, and monitoring) of OSCC to provide advanced treatment strategies and clinical decisions. In this review, we report and discuss the recent understandings and perceptions of dysregulated lncRNAs with a focus on their clinical significance in OSCC-disease monitoring and treatment. Evidence clearly indicates that a specific lncRNA expression signature could act as an indicator for the early prediction of diagnosis and prognosis for the initiation, progression, recurrence, metastasis and other clinical prognostic-factors (overall survival, disease-free survival, etc.) in OSCC. The present review demonstrates the current knowledge that all potential lncRNA expression signatures are molecular biomarkers for the early prediction of prognosis in OSCC. Finally, the review provides information about the clinical significance, challenges and limitations of the clinical usage of circulating lncRNAs in a liquid biopsy method in early, pre-symptomatic, sub-clinical, accurate OSCC prognostication. More studies on lncRNA are required to unveil the biology of the inherent mechanisms involved in the process of the development of differential prognostic outcomes in OSCC. Full article
(This article belongs to the Special Issue Promising Biomarkers in Liquid Biopsy of Cancer)
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