Cancers

Editorial

Jump to: Research, Review, Other

2 pages, 173 KiB

Open AccessEditorial

Cell-Free DNA: Unveiling the Future of Cancer Diagnostics and Monitoring

by Edoardo Francini, Pier Vitale Nuzzo and Giuseppe Nicolò Fanelli

Cancers 2024, 16(3), 662; https://doi.org/10.3390/cancers16030662 - 4 Feb 2024

Viewed by 1633

Abstract

As we conclude this Special Issue of 21 published articles dedicated to cell-free DNA (cfDNA) as a prognostic and predictive biomarker in solid cancers, we find ourselves gazing at a vibrant landscape of research on cfDNA [...] Full article

(This article belongs to the Special Issue Cell-Free DNA as Prognostic and Predictive Biomarker in Solid Cancers)

Research

Jump to: Editorial, Review, Other

15 pages, 2395 KiB

Open AccessArticle

Quantitative ctDNA Detection in Hepatoblastoma: Implications for Precision Medicine

by Smadar Kahana-Edwin, James Torpy, Lucy E. Cain, Anna Mullins, Geoffrey McCowage, Sarah E. Woodfield, Sanjeev A. Vasudevan, Dan P. T. Shea, Andre E. Minoche, Andres F. Espinoza, Sarah Kummerfeld, Leonard D. Goldstein and Jonathan Karpelowsky

Cancers 2024, 16(1), 12; https://doi.org/10.3390/cancers16010012 - 19 Dec 2023

Cited by 1 | Viewed by 2212

Abstract

Hepatoblastoma is characterized by driver mutations in CTNNB1, making it an attractive biomarker for a liquid biopsy approach utilizing circulating tumor DNA (ctDNA). This prospective observational study sought to ascertain the feasibility of ctDNA detection in patients with hepatoblastoma and explore its [...] Read more.

Hepatoblastoma is characterized by driver mutations in CTNNB1, making it an attractive biomarker for a liquid biopsy approach utilizing circulating tumor DNA (ctDNA). This prospective observational study sought to ascertain the feasibility of ctDNA detection in patients with hepatoblastoma and explore its associations with established clinical indicators and biomarkers, including serum Alpha-fetoprotein (AFP). We obtained 38 plasma samples and 17 tumor samples from 20 patients with hepatoblastoma. These samples were collected at various stages: 10 at initial diagnosis, 17 during neoadjuvant chemotherapy, 6 post-operatively, and 5 at disease recurrence. Utilizing a bespoke sequencing assay we developed called QUENCH, we identified single nucleotide variants and deletions in CTNNB1 ctDNA. Our study demonstrated the capability to quantitate ctDNA down to a variant allele frequency of 0.3%, achieving a sensitivity of 90% for patients at initial diagnosis, and a specificity of 100% at the patient level. Notably, ctDNA positivity correlated with tumor burden, and ctDNA levels exhibited associations with macroscopic residual disease and treatment response. Our findings provide evidence for the utility of quantitative ctDNA detection in hepatoblastoma management. Given the distinct detection targets, ctDNA and AFP-based stratification and monitoring approaches could synergize to enhance clinical decision-making. Further research is needed to elucidate the interplay between ctDNA and AFP and determine the optimal clinical applications for both methods in risk stratification and residual disease detection. Full article

(This article belongs to the Special Issue Cell-Free DNA as Prognostic and Predictive Biomarker in Solid Cancers)

► Show Figures

Graphical abstract

27 pages, 2842 KiB

Open AccessArticle

Evaluating Stacked Methylation Markers for Blood-Based Multicancer Detection

by Karen Funderburk, Sara R. Bang-Christensen, Brendan F. Miller, Hua Tan, Gennady Margolin, Hanna M. Petrykowska, Catherine Baugher, S. Katie Farney, Sara A. Grimm, Nader Jameel, David O. Holland, Naomi S. Altman and Laura Elnitski

Cancers 2023, 15(19), 4826; https://doi.org/10.3390/cancers15194826 - 1 Oct 2023

Cited by 1 | Viewed by 1714

Abstract

The ability to detect several types of cancer using a non-invasive, blood-based test holds the potential to revolutionize oncology screening. We mined tumor methylation array data from the Cancer Genome Atlas (TCGA) covering 14 cancer types and identified two novel, broadly-occurring methylation markers [...] Read more.

The ability to detect several types of cancer using a non-invasive, blood-based test holds the potential to revolutionize oncology screening. We mined tumor methylation array data from the Cancer Genome Atlas (TCGA) covering 14 cancer types and identified two novel, broadly-occurring methylation markers at TLX1 and GALR1. To evaluate their performance as a generalized blood-based screening approach, along with our previously reported methylation biomarker, ZNF154, we rigorously assessed each marker individually or combined. Utilizing TCGA methylation data and applying logistic regression models within each individual cancer type, we found that the three-marker combination significantly increased the average area under the ROC curve (AUC) across the 14 tumor types compared to single markers (p = 1.158 × 10⁻¹⁰; Friedman test). Furthermore, we simulated dilutions of tumor DNA into healthy blood cell DNA and demonstrated increased AUC of combined markers across all dilution levels. Finally, we evaluated assay performance in bisulfite sequenced DNA from patient tumors and plasma, including early-stage samples. When combining all three markers, the assay correctly identified nine out of nine lung cancer plasma samples. In patient plasma from hepatocellular carcinoma, ZNF154 alone yielded the highest combined sensitivity and specificity values averaging 68% and 72%, whereas multiple markers could achieve higher sensitivity or specificity, but not both. Altogether, this study presents a comprehensive pipeline for the identification, testing, and validation of multi-cancer methylation biomarkers with a considerable potential for detecting a broad range of cancer types in patient blood samples. Full article

(This article belongs to the Special Issue Cell-Free DNA as Prognostic and Predictive Biomarker in Solid Cancers)

► Show Figures

Graphical abstract

12 pages, 3115 KiB

Open AccessArticle

Accurate Detection of Urothelial Bladder Cancer Using Targeted Deep Sequencing of Urine DNA

by Dongin Lee, Wookjae Lee, Hwang-Phill Kim, Myong Kim, Hyun Kyu Ahn, Duhee Bang and Kwang Hyun Kim

Cancers 2023, 15(10), 2868; https://doi.org/10.3390/cancers15102868 - 22 May 2023

Cited by 4 | Viewed by 2301

Abstract

Patients with hematuria are commonly given an invasive cystoscopy test to detect bladder cancer (BC). To avoid the risks associated with cystoscopy, several urine-based methods for BC detection have been developed, the most prominent of which is the deep sequencing of urine DNA. [...] Read more.

Patients with hematuria are commonly given an invasive cystoscopy test to detect bladder cancer (BC). To avoid the risks associated with cystoscopy, several urine-based methods for BC detection have been developed, the most prominent of which is the deep sequencing of urine DNA. However, the current methods for urine-based BC detection have significant levels of false-positive signals. In this study, we report on uAL100, a method to precisely detect BC tumor DNA in the urine without tumor samples. Using urine samples from 43 patients with BC and 21 healthy donors, uAL100 detected BC with 83.7% sensitivity and 100% specificity. The mutations identified in the urine DNA by uAL100 for BC detection were highly associated with BC tumorigenesis and progression. We suggest that uAL100 has improved accuracy compared to other urine-based methods for early BC detection and can reduce unnecessary cystoscopy tests for patients with hematuria. Full article

(This article belongs to the Special Issue Cell-Free DNA as Prognostic and Predictive Biomarker in Solid Cancers)

► Show Figures

Figure 1

10 pages, 1736 KiB

Open AccessArticle

Practical Utility of Liquid Biopsies for Evaluating Genomic Alterations in Castration-Resistant Prostate Cancer

by Seung-Hwan Jeong, Dongsoo Kyung, Hyeong Dong Yuk, Chang Wook Jeong, Wookjae Lee, Jung-Ki Yoon, Hwang-Phill Kim, Duhee Bang, Tae-You Kim, Yoojoo Lim and Cheol Kwak

Cancers 2023, 15(10), 2847; https://doi.org/10.3390/cancers15102847 - 20 May 2023

Cited by 5 | Viewed by 2261

Abstract

Traditional tissue-based assessments of genomic alterations in castration-resistant prostate cancer (CRPC) can be challenging. To evaluate the real-world clinical utility of liquid biopsies for the evaluation of genomic alterations in CRPC, we preemptively collected available plasma samples and archival tissue samples from patients [...] Read more.

Traditional tissue-based assessments of genomic alterations in castration-resistant prostate cancer (CRPC) can be challenging. To evaluate the real-world clinical utility of liquid biopsies for the evaluation of genomic alterations in CRPC, we preemptively collected available plasma samples and archival tissue samples from patients that were being treated for clinically confirmed CRPC. The cell-free DNA (cfDNA) and tumor tissue DNA were analyzed using the AlphaLiquid^®100-HRR panel. Plasma samples from a total of 87 patients were included in this study. Somatic mutations from cfDNA were detected in 78 (89.7%) patients, regardless of the presence of overt metastasis or concomitant treatment given at the time of plasma sample collection. Twenty-three patients were found to have known deleterious somatic or germline mutations in HRR genes from their cfDNA. Archival tissue samples from 33 (37.9%) patients were available for comparative analysis. Tissue sequencing was able to yield an NGS result in only 51.5% of the tissue samples. The general sensitivity of cfDNA for detecting somatic mutations in tissues was 71.8%, but important somatic/germline mutations in HRR genes were found to have a higher concordance (100%). Liquid biopsies can be a reasonable substitute for tissue biopsies in CRPC patients when evaluating genomic alterations. Full article

(This article belongs to the Special Issue Cell-Free DNA as Prognostic and Predictive Biomarker in Solid Cancers)

► Show Figures

Figure 1

19 pages, 3369 KiB

Open AccessArticle

p53/TP53 Status Assessment in Gastroesophageal Adenocarcinoma

by Elisa Boldrin, Maria Assunta Piano, Francesco Bernaudo, Rita Alfieri, Maria Raffaella Biasin, Isabella Monia Montagner, Alice Volpato, Genny Mattara, Francesco Lamacchia, Giovanna Magni, Antonio Rosato, Antonio Scapinello, Pierluigi Pilati and Matteo Curtarello

Cancers 2023, 15(10), 2783; https://doi.org/10.3390/cancers15102783 - 16 May 2023

Cited by 1 | Viewed by 2423

Abstract

Chromosomal instability (CIN) is very frequent in gastroesophageal adenocarcinoma (GEA) and it is characterized by TP53 deletions/mutations resulting in p53 nuclear accumulation, as revealed by immunohistochemistry (IHC), which considers the cases with “high” staining levels to be positive. Aiming to improve aberrant TP53 [...] Read more.

Chromosomal instability (CIN) is very frequent in gastroesophageal adenocarcinoma (GEA) and it is characterized by TP53 deletions/mutations resulting in p53 nuclear accumulation, as revealed by immunohistochemistry (IHC), which considers the cases with “high” staining levels to be positive. Aiming to improve aberrant TP53 detection, droplet digital PCR (ddPCR) was used to evaluate TP53 deletion in formalin-fixed, paraffin-embedded DNA (FFPE-DNA) and cell-free DNA (cfDNA). To further investigate the mutational TP53 profile, next-generation sequencing (NGS) was performed in a subset of FFPE samples. After combining “low” and “high” IHC staining level groups, the proportion of deletion events was significantly higher compared to the “intermediate” group (72.9% vs. 47.5%, p-value = 0.002). The ddPCR TP53 deletion assay was feasible for cfDNA but only had good agreement (72.7%, Cohen’s kappa = 0.48) with the assay performed with FFPE-DNA of the “low-level” group. NGS analysis confirmed that, in the “low-level” group, a high percentage (66.7%) of cases were aberrant, with disruptive mutations that probably led to p53 loss. Data suggested that p53 IHC alone underestimates the CIN phenotype in GEA and that molecular analysis in both solid and liquid biopsies could be integrated with it; in particular, in cases of completely negative staining. Full article

(This article belongs to the Special Issue Cell-Free DNA as Prognostic and Predictive Biomarker in Solid Cancers)

► Show Figures

Figure 1

14 pages, 1101 KiB

Open AccessArticle

Clinical Potential of Circulating Cell-Free DNA (cfDNA) for Longitudinally Monitoring Clinical Outcomes in the First-Line Setting of Non-Small-Cell Lung Cancer (NSCLC): A Real-World Prospective Study

by Valerio Gristina, Nadia Barraco, Maria La Mantia, Luisa Castellana, Lavinia Insalaco, Marco Bono, Alessandro Perez, Delia Sardo, Sara Inguglia, Federica Iacono, Sofia Cutaia, Tancredi Didier Bazan Russo, Edoardo Francini, Lorena Incorvaia, Giuseppe Badalamenti, Antonio Russo, Antonio Galvano and Viviana Bazan

Cancers 2022, 14(23), 6013; https://doi.org/10.3390/cancers14236013 - 6 Dec 2022

Cited by 20 | Viewed by 2296

Abstract

Background: Despite the increasing implementation of targeted and immunotherapy-based treatments, the prognosis of patients with advanced NSCLC remains dismal. We prospectively evaluated longitudinal plasma cfDNA kinetics as an early marker of therapeutic efficacy in patients with advanced NSCLC undergoing standard first-line treatments. Methods: [...] Read more.

Background: Despite the increasing implementation of targeted and immunotherapy-based treatments, the prognosis of patients with advanced NSCLC remains dismal. We prospectively evaluated longitudinal plasma cfDNA kinetics as an early marker of therapeutic efficacy in patients with advanced NSCLC undergoing standard first-line treatments. Methods: From February 2020 to May 2022, treatment-naïve patients with advanced NSCLC were consecutively enrolled at the Medical Oncology Unit of the Paolo Giaccone University Hospital, Palermo (Italy). We quantified cfDNA in terms of ng/μL using a Qubit^TM dsDNA HS Assay Kit. The agreement between the cfDNA and radiologic response was evaluated from baseline (T0) to the radiologic evaluation (T1). Results: A total of 315 liquid biopsy samples were collected from 63 patients at baseline, with a total of 235 paired plasma samples from 47 patients at disease re-evaluation. A fair concordance was observed between early and durable radiographic and cfDNA response (Cohen’s kappa coefficient = 0.001); 11 and 18 patients receiving TKI (Pearson’s chi-squared test = 4.278; Cohen’s kappa coefficient = 0.039) and IO treatments (Pearson’s chi-squared test = 7.481; Cohen’s kappa coefficient = 0.006) showed a significant and durable association between cfDNA dynamics and the first radiologic evaluation, whereas among the 18 patients undergoing CT, no significant correlation was observed (Pearson’s chi-squared test = 0.720; Cohen’s kappa coefficient = 0.396). The ECOG-PS 2 patients presented with the mean baseline cfDNA levels 2.6-fold higher than those with ECOG-PS 0–1 (1.71 vs. 0.65 ng/µL; p = 0.105). Conclusions: Our real-world study demonstrates that quantitative changes in cfDNA values correlated with responses to therapy and relapse of disease in treatment-naïve patients with advanced NSCLC undergoing TKI- and IO-based treatments. Full article

(This article belongs to the Special Issue Cell-Free DNA as Prognostic and Predictive Biomarker in Solid Cancers)

► Show Figures

Figure 1

11 pages, 433 KiB

Open AccessArticle

The Clinical Impact of Methylated Homeobox A9 ctDNA in Patients with Non-Resectable Biliary Tract Cancer Treated with Erlotinib and Bevacizumab

by Line Bechsgaard Andersen, Marit Sofie Kjær Mahler, Rikke Fredslund Andersen, Lars Henrik Jensen and Louise Raunkilde

Cancers 2022, 14(19), 4598; https://doi.org/10.3390/cancers14194598 - 22 Sep 2022

Cited by 7 | Viewed by 1641

Abstract

Methylated homeobox A9 (meth-HOXA9) is tumor specific and has been suggested as a prognostic biomarker in several types of cancer. ctDNA measured as meth-HOXA9 may be a valuable biomarker in the decision-making process about last-line treatment of biliary tract cancer (BTC). The aim [...] Read more.

Methylated homeobox A9 (meth-HOXA9) is tumor specific and has been suggested as a prognostic biomarker in several types of cancer. ctDNA measured as meth-HOXA9 may be a valuable biomarker in the decision-making process about last-line treatment of biliary tract cancer (BTC). The aim of the study was to investigate the clinical impact of meth-HOXA9 in plasma from patients receiving erlotinib and bevacizumab for late-stage BTC and to investigate the treatment effect and adverse events. Droplet digital PCR was applied to detect meth-HOXA9 in 39 patients. Response rates were registered according to RECIST (1.1) and adverse events according to Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE (4.0)). Endpoints were progression-free survival (PFS), overall survival (OS), response rate, and toxicity. A significant difference in PFS and OS between patients with increasing and non-increasing meth-HOXA9 was detected after one treatment cycle, hazard ratio (HR) 12.4 (p < 0.0001) and HR 2.75 (p = 0.04), respectively. The most common adverse events of erlotinib were fatigue, pain, and rash, and those of bevacizumab were bleeding and wounds. This study found meth-HOXA9 to be negatively associated with survival in patients with late-stage BTC. Hence, meth-HOXA9 may guide early discontinuation of ineffective treatment. Full article

(This article belongs to the Special Issue Cell-Free DNA as Prognostic and Predictive Biomarker in Solid Cancers)

► Show Figures

Figure 1

17 pages, 2659 KiB

Open AccessArticle

Genomic Aberrations in Circulating Tumor DNAs from Palbociclib-Treated Metastatic Breast Cancer Patients Reveal a Novel Resistance Mechanism

by Maysa Abu-Khalaf, Chun Wang, Zhenchao Zhang, Rui Luo, Weelic Chong, Daniel P. Silver, Frederick Fellin, Rebecca Jaslow, AnaMaria Lopez, Terrence Cescon, Wei Jiang, Ronald Myers, Qiang Wei, Bingshan Li, Massimo Cristofanilli and Hushan Yang

Cancers 2022, 14(12), 2872; https://doi.org/10.3390/cancers14122872 - 10 Jun 2022

Cited by 1 | Viewed by 2790

Abstract

Previously undescribed molecular mechanisms of resistance will emerge with the increased use of cyclin-dependent kinase 4/6 inhibitors in clinical settings. To identify genomic aberrations in circulating tumor DNA associated with treatment resistance in palbociclib-treated metastatic breast cancer (MBC) patients, we collected 35 pre- [...] Read more.

Previously undescribed molecular mechanisms of resistance will emerge with the increased use of cyclin-dependent kinase 4/6 inhibitors in clinical settings. To identify genomic aberrations in circulating tumor DNA associated with treatment resistance in palbociclib-treated metastatic breast cancer (MBC) patients, we collected 35 pre- and post-treatment blood samples from 16 patients with estrogen receptor-positive (ER⁺) MBC, including 9 with inflammatory breast cancer (IBC). Circulating cell-free DNAs (cfDNAs) were isolated for sequencing using a targeted panel of 91 genes. Our data showed that FBXW7 and CDK6 were more frequently altered in IBC than in non-IBC, whereas conversely, PIK3CA was more frequently altered in non-IBC than in IBC. The cfDNA samples collected at follow-up harbored more mutations than baseline samples. By analyzing paired samples, we observed a higher percentage of patients with mutations in RB1, CCNE1, FBXW7, EZH2, and ARID1A, but a lower proportion of patients with mutated TSC2 at the post-treatment stage when they developed progression. Moreover, acquisition of CCNE1 mutations or loss of TSC2 mutations after treatment initiation conferred an unfavorable prognosis. These data provide insights into the relevance of novel genomic alterations in cfDNA to palbociclib resistance in MBC patients. Future large-scale prospective studies are warranted to confirm our findings. Full article

(This article belongs to the Special Issue Cell-Free DNA as Prognostic and Predictive Biomarker in Solid Cancers)

► Show Figures

Figure 1

14 pages, 2557 KiB

Open AccessArticle

Early Assessment of Chemotherapy Response in Advanced Non-Small Cell Lung Cancer with Circulating Tumor DNA

by Stephanie J. Yaung, Corinna Woestmann, Christine Ju, Xiaoju Max Ma, Sandeep Gattam, Yiyong Zhou, Liu Xi, Subrata Pal, Aarthi Balasubramanyam, Nalin Tikoo, Claus Peter Heussel, Michael Thomas, Mark Kriegsmann, Michael Meister, Marc A. Schneider, Felix J. Herth, Birgit Wehnl, Maximilian Diehn, Ash A. Alizadeh, John F. Palma and Thomas Muley Show full author list Hide full author list

Cancers 2022, 14(10), 2479; https://doi.org/10.3390/cancers14102479 - 18 May 2022

Cited by 3 | Viewed by 9187

Abstract

Monitoring treatment efficacy early during therapy could enable a change in treatment to improve patient outcomes. We report an early assessment of response to treatment in advanced NSCLC using a plasma-only strategy to measure changes in ctDNA levels after one cycle of chemotherapy. [...] Read more.

Monitoring treatment efficacy early during therapy could enable a change in treatment to improve patient outcomes. We report an early assessment of response to treatment in advanced NSCLC using a plasma-only strategy to measure changes in ctDNA levels after one cycle of chemotherapy. Plasma samples were collected from 92 patients with Stage IIIB-IV NSCLC treated with first-line chemo- or chemoradiation therapies in an observational, prospective study. Retrospective ctDNA analysis was performed using next-generation sequencing with a targeted 198-kb panel designed for lung cancer surveillance and monitoring. We assessed whether changes in ctDNA levels after one or two cycles of treatment were associated with clinical outcomes. Subjects with ≤50% decrease in ctDNA level after one cycle of chemotherapy had a lower 6-month progression-free survival rate (33% vs. 58%, HR 2.3, 95% CI 1.2 to 4.2, log-rank p = 0.009) and a lower 12-month overall survival rate (25% vs. 70%, HR 4.3, 95% CI 2.2 to 9.7, log-rank p < 0.001). Subjects with ≤50% decrease in ctDNA level after two cycles of chemotherapy also had shorter survival. Using non-invasive liquid biopsies to measure early changes in ctDNA levels in response to chemotherapy may help identify non-responders before standard-of-care imaging in advanced NSCLC. Full article

(This article belongs to the Special Issue Cell-Free DNA as Prognostic and Predictive Biomarker in Solid Cancers)

► Show Figures

Figure 1

13 pages, 1472 KiB

Open AccessArticle

Baseline Plasma Tumor DNA (ctDNA) Correlates with PSA Kinetics in Metastatic Castration-Resistant Prostate Cancer (mCRPC) Treated with Abiraterone or Enzalutamide

by Vincenza Conteduca, Chiara Casadei, Emanuela Scarpi, Nicole Brighi, Giuseppe Schepisi, Cristian Lolli, Giorgia Gurioli, Ilaria Toma, Giulia Poti, Alberto Farolfi and Ugo De Giorgi

Cancers 2022, 14(9), 2219; https://doi.org/10.3390/cancers14092219 - 29 Apr 2022

Cited by 5 | Viewed by 2473

Abstract

Background: Baseline high circulating tumor DNA (ctDNA) fraction in plasma and androgen receptor (AR) copy number (CN) gain identify mCRPC patients with worse outcomes. This study aimed to assess if ctDNA associates with PSA kinetics. Methods: In this prospective biomarker study, we evaluate [...] Read more.

Background: Baseline high circulating tumor DNA (ctDNA) fraction in plasma and androgen receptor (AR) copy number (CN) gain identify mCRPC patients with worse outcomes. This study aimed to assess if ctDNA associates with PSA kinetics. Methods: In this prospective biomarker study, we evaluate ctDNA fraction and AR CN from plasma samples. We divided patients into high and low ctDNA level and in AR gain and AR normal. Results: 220 baseline samples were collected from mCRPC treated with abiraterone (n = 140) or enzalutamide (n = 80). A lower rate of PSA decline ≥ 50% was observed in patients with high ctDNA (p = 0.017) and AR gain (p = 0.0003). Combining ctDNA fraction and AR CN, we found a different median PSA progression-free survival (PFS) among four groups: (1) low ctDNA/AR normal, (2) high ctDNA/AR normal, (3) low ctDNA/AR gain, and (4) high ctDNA/AR gain (11.4 vs. 5.0 vs. 4.8 vs. 3.7 months, p < 0.0001). In a multivariable analysis, high ctDNA, AR gain, PSA DT, PSA DT velocity remained independent predictors of PSA PFS. Conclusions: Elevated ctDNA levels and AR gain are negatively and independently correlated with PSA kinetics in mCRPC men treated with abiraterone or enzalutamide. Full article

(This article belongs to the Special Issue Cell-Free DNA as Prognostic and Predictive Biomarker in Solid Cancers)

► Show Figures

Graphical abstract

15 pages, 3309 KiB

Open AccessArticle

Machine-Learning-Based Clinical Biomarker Using Cell-Free DNA for Hepatocellular Carcinoma (HCC)

by Taehee Lee, Piper A. Rawding, Jiyoon Bu, Sunghee Hyun, Woosun Rou, Hongjae Jeon, Seokhyun Kim, Byungseok Lee, Luke J. Kubiatowicz, Dawon Kim, Seungpyo Hong and Hyuksoo Eun

Cancers 2022, 14(9), 2061; https://doi.org/10.3390/cancers14092061 - 20 Apr 2022

Cited by 17 | Viewed by 4859

Abstract

(1) Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Although various serum enzymes have been utilized for the diagnosis and prognosis of HCC, the currently available biomarkers lack the sensitivity needed to detect HCC at early stages [...] Read more.

(1) Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Although various serum enzymes have been utilized for the diagnosis and prognosis of HCC, the currently available biomarkers lack the sensitivity needed to detect HCC at early stages and accurately predict treatment responses. (2) Methods: We utilized our highly sensitive cell-free DNA (cfDNA) detection system, in combination with a machine learning algorithm, to provide a platform for improved diagnosis and prognosis of HCC. (3) Results: cfDNA, specifically alpha-fetoprotein (AFP) expression in captured cfDNA, demonstrated the highest accuracy for diagnosing malignancies among the serum/plasma biomarkers used in this study, including AFP, aspartate aminotransferase, alanine aminotransferase, albumin, alkaline phosphatase, and bilirubin. The diagnostic/prognostic capability of cfDNA was further improved by establishing a cfDNA score (cfD_HCC), which integrated the total plasma cfDNA levels and cfAFP-DNA expression into a single score using machine learning algorithms. (4) Conclusion: The cfD_HCC score demonstrated significantly improved accuracy in determining the pathological features of HCC and predicting patients’ survival outcomes compared to the other biomarkers. The results presented herein reveal that our cfDNA capture/analysis platform is a promising approach to effectively utilize cfDNA as a biomarker for the diagnosis and prognosis of HCC. Full article

(This article belongs to the Special Issue Cell-Free DNA as Prognostic and Predictive Biomarker in Solid Cancers)

► Show Figures

Figure 1

14 pages, 1856 KiB

Open AccessArticle

Application of an Ultrasensitive NGS-Based Blood Test for the Diagnosis of Early-Stage Lung Cancer: Sensitivity, a Hurdle Still Difficult to Overcome

by Malaïka Van der Linden, Bram Van Gaever, Lennart Raman, Karim Vermaelen, Ingel Demedts, Veerle Surmont, Ulrike Himpe, Yolande Lievens, Liesbeth Ferdinande, Franceska Dedeurwaerdere, Joni Van der Meulen, Kathleen Claes, Björn Menten and Jo Van Dorpe

Cancers 2022, 14(8), 2031; https://doi.org/10.3390/cancers14082031 - 18 Apr 2022

Cited by 4 | Viewed by 2634

Abstract

Diagnosis of lung cancer requires histological examination of a tissue sample, which in turn requires an invasive procedure that cannot always be obtained. Circulating tumor DNA can be reliably detected in blood samples of advanced-stage lung cancer patients and might also be a [...] Read more.

Diagnosis of lung cancer requires histological examination of a tissue sample, which in turn requires an invasive procedure that cannot always be obtained. Circulating tumor DNA can be reliably detected in blood samples of advanced-stage lung cancer patients and might also be a minimally invasive alternative for early-stage lung cancer detection. We wanted to explore the potential of targeted deep sequencing as a test for the diagnosis of early-stage lung cancer in combination with imaging. Mutation detection on cell-free DNA from pretreatment plasma samples of 51 patients with operable non-small cell lung cancer was performed and results were compared with 12 control patients undergoing surgery for a non-malignant lung lesion. By using a variant allele frequency threshold of 1%, somatic variants were detected in 23.5% of patients with a median variant allele fraction of 3.65%. By using this threshold, we could almost perfectly discriminate early-stage lung cancer patients from controls. Our study results are discussed in the light of those from other studies. Notwithstanding the potential of today’s techniques for the use of liquid biopsy-based cell-free DNA analysis, sensitivity of this application for early-stage lung cancer detection is currently limited by a biological background of somatic variants with low variant allele fraction. Full article

(This article belongs to the Special Issue Cell-Free DNA as Prognostic and Predictive Biomarker in Solid Cancers)

► Show Figures

Figure 1

15 pages, 877 KiB

Open AccessArticle

Detection of Cancer Mutations by Urine Liquid Biopsy as a Potential Tool in the Clinical Management of Bladder Cancer Patients

by Nurul Khalida Ibrahim, Ahmed Eraky, Jan Eggers, Tim Alexander Steiert, Susanne Sebens, Klaus-Peter Jünemann, Alexander Hendricks, Corinna Bang, Martin Stanulla, Andre Franke, Claudius Hamann, Christoph Röcken, Norbert Arnold, Laura Hinze and Michael Forster

Cancers 2022, 14(4), 969; https://doi.org/10.3390/cancers14040969 - 15 Feb 2022

Cited by 2 | Viewed by 3691

Abstract

The standard diagnostic and follow-up examination for bladder cancer is diagnostic cystoscopy, an invasive test that requires compliance for a long period. Urine cytology and recent biomarkers come short of replacing cystoscopy. Urine liquid biopsy promises to solve this problem and potentially allows [...] Read more.

The standard diagnostic and follow-up examination for bladder cancer is diagnostic cystoscopy, an invasive test that requires compliance for a long period. Urine cytology and recent biomarkers come short of replacing cystoscopy. Urine liquid biopsy promises to solve this problem and potentially allows early detection, evaluation of treatment efficacy, and surveillance. A previous study reached 52–68% sensitivity using small-panel sequencing but could increase sensitivity to 68–83% by adding aneuploidy and promoter mutation detection. Here, we explore whether a large 127-gene panel alone is sufficient to detect tumor mutations in urine from bladder cancer patients. We recruited twelve bladder cancer patients, obtained preoperative and postoperative urine samples, and successfully analyzed samples from eleven patients. In ten patients, we found at least one mutation in bladder-cancer-associated genes, i.e., a promising sensitivity of 91%. In total, we identified 114 variants, of which 90 were predicted as nonbenign, 30% were associated with cancer, and 13% were actionable according to the CIViC database. Sanger sequencing of the patients’ formalin-fixed, paraffin-embedded (FFPE) tumor tissues confirmed the findings. We concluded that incorporating urine liquid biopsy is a promising strategy in the management of bladder cancer patients. Full article

(This article belongs to the Special Issue Cell-Free DNA as Prognostic and Predictive Biomarker in Solid Cancers)

► Show Figures

Graphical abstract

13 pages, 1914 KiB

Open AccessArticle

Aberrant Methylation of SLIT2 Gene in Plasma Cell-Free DNA of Non-Small Cell Lung Cancer Patients

by Yujin Kim, Bo Bin Lee, Dongho Kim, Sang-Won Um, Joungho Han, Young Mog Shim and Duk-Hwan Kim

Cancers 2022, 14(2), 296; https://doi.org/10.3390/cancers14020296 - 7 Jan 2022

Cited by 6 | Viewed by 2254

Abstract

This study aimed to understand aberrant methylation of SLITs genes as a biomarker for the early detection and prognosis prediction of non-small cell lung cancer (NSCLC). Methylation levels of SLITs were determined using the Infinium HumanMethylation450 BeadChip or pyrosequencing. Five CpGs at the [...] Read more.

This study aimed to understand aberrant methylation of SLITs genes as a biomarker for the early detection and prognosis prediction of non-small cell lung cancer (NSCLC). Methylation levels of SLITs were determined using the Infinium HumanMethylation450 BeadChip or pyrosequencing. Five CpGs at the CpG island of SLIT1, SLIT2 or SLIT3 genes were significantly (Bonferroni corrected p < 0.05) hypermethylated in tumor tissues obtained from 42 NSCLC patients than in matched normal tissues. Methylation levels of these CpGs did not differ significantly between bronchial washings obtained from 76 NSCLC patients and 60 cancer-free patients. However, methylation levels of SLIT2 gene were significantly higher in plasma cell-free DNA of 72 NSCLC patients than in that of 61 cancer-free patients (p = 0.001, Wilcoxon rank sum test). Prediction of NSCLC using SLIT2 methylation was achieved with a sensitivity of 73.7% and a specificity of 61.9% in a plasma test dataset (N = 40). A Cox proportional hazards model showed that SLIT2 hypermethylation in plasma cell-free DNA was significantly associated with poor recurrence-free survival (hazards ratio = 2.19, 95% confidence interval = 1.21–4.36, p = 0.01). The present study suggests that aberrant methylation of SLIT2 in plasma cell-free DNA is a valuable biomarker for the early detection of NSCLC and prediction of recurrence-free survival. However, further research is needed with larger sample size to confirm results. Full article

(This article belongs to the Special Issue Cell-Free DNA as Prognostic and Predictive Biomarker in Solid Cancers)

► Show Figures

Figure 1

12 pages, 961 KiB

Open AccessArticle

Circulating Cell-Free DNA as Biomarker of Taxane Resistance in Metastatic Castration-Resistant Prostate Cancer

by Edoardo Francini, Fang-Shu Ou, Justin Rhoades, Eric G. Wolfe, Edward P. O’Connor, Gavin Ha, Gregory Gydush, Kaitlin M. Kelleher, Rupal S. Bhatt, Steven P. Balk, Christopher J. Sweeney, Viktor A. Adalsteinsson, Mary-Ellen Taplin and Atish D. Choudhury

Cancers 2021, 13(16), 4055; https://doi.org/10.3390/cancers13164055 - 12 Aug 2021

Cited by 1 | Viewed by 2214

Abstract

There are no biomarkers predictive of resistance to docetaxel or cabazitaxel validated for patients with metastatic castration-resistant prostate cancer (mCRPC). We assessed the association between ABCB1 amplification and primary resistance to docetaxel or cabazitaxel for patients with mCRPC, using circulating cell-free DNA (cfDNA). [...] Read more.

There are no biomarkers predictive of resistance to docetaxel or cabazitaxel validated for patients with metastatic castration-resistant prostate cancer (mCRPC). We assessed the association between ABCB1 amplification and primary resistance to docetaxel or cabazitaxel for patients with mCRPC, using circulating cell-free DNA (cfDNA). Patients with ≥1 plasma sample drawn within 12 months before starting docetaxel (cohort A) or cabazitaxel (cohort B) for mCRPC were identified from the Dana–Farber Cancer Institute IRB approved database. Sparse whole genome sequencing was performed on the selected cfDNA samples and tumor fractions were estimated using the computational tool ichorCNA. We evaluated the association between ABCB1 amplification or other copy number alterations and primary resistance to docetaxel or cabazitaxel. Of the selected 176 patients, 45 samples in cohort A and 21 samples in cohort B had sufficient tumor content. No significant association was found between ABCB1 amplification and primary resistance to docetaxel (p = 0.58; odds ratio (OR) = 1.49) or cabazitaxel (p = 0.97; OR = 1.06). No significant association was found between exploratory biomarkers and primary resistance to docetaxel or cabazitaxel. In this study, ABCB1 amplification did not predict primary resistance to docetaxel or cabazitaxel for mCRPC. Future studies including ABCB1 amplification in a suite of putative biomarkers and a larger cohort may aid in drawing definitive conclusions. Full article

(This article belongs to the Special Issue Cell-Free DNA as Prognostic and Predictive Biomarker in Solid Cancers)

► Show Figures

Figure 1

Review

Jump to: Editorial, Research, Other

16 pages, 476 KiB

Open AccessReview

The Evolution of Affordable Technologies in Liquid Biopsy Diagnostics: The Key to Clinical Implementation

by George Alexandrou, Katerina-Theresa Mantikas, Rebecca Allsopp, Calista Adele Yapeter, Myesha Jahin, Taryn Melnick, Simak Ali, R. Charles Coombes, Christofer Toumazou, Jacqueline A. Shaw and Melpomeni Kalofonou

Cancers 2023, 15(22), 5434; https://doi.org/10.3390/cancers15225434 - 16 Nov 2023

Cited by 5 | Viewed by 2104

Abstract

Cancer remains a leading cause of death worldwide, despite many advances in diagnosis and treatment. Precision medicine has been a key area of focus, with research providing insights and progress in helping to lower cancer mortality through better patient stratification for therapies and [...] Read more.

Cancer remains a leading cause of death worldwide, despite many advances in diagnosis and treatment. Precision medicine has been a key area of focus, with research providing insights and progress in helping to lower cancer mortality through better patient stratification for therapies and more precise diagnostic techniques. However, unequal access to cancer care is still a global concern, with many patients having limited access to diagnostic tests and treatment regimens. Noninvasive liquid biopsy (LB) technology can determine tumour-specific molecular alterations in peripheral samples. This allows clinicians to infer knowledge at a DNA or cellular level, which can be used to screen individuals with high cancer risk, personalize treatments, monitor treatment response, and detect metastasis early. As scientific understanding of cancer pathology increases, LB technologies that utilize circulating tumour DNA (ctDNA) and circulating tumour cells (CTCs) have evolved over the course of research. These technologies incorporate tumour-specific markers into molecular testing platforms. For clinical translation and maximum patient benefit at a wider scale, the accuracy, accessibility, and affordability of LB tests need to be prioritized and compared with gold standard methodologies in current use. In this review, we highlight the range of technologies in LB diagnostics and discuss the future prospects of LB through the anticipated evolution of current technologies and the integration of emerging and novel ones. This could potentially allow a more cost-effective model of cancer care to be widely adopted. Full article

(This article belongs to the Special Issue Cell-Free DNA as Prognostic and Predictive Biomarker in Solid Cancers)

► Show Figures

Figure 1

26 pages, 1033 KiB

Open AccessReview

Circulating Cell-Free DNA in Renal Cell Carcinoma: The New Era of Precision Medicine

by Edoardo Francini, Giuseppe Nicolò Fanelli, Filippo Pederzoli, Sandor Spisak, Erika Minonne, Massimiliano Raffo, Hubert Pakula, Viktoria Tisza, Cristian Scatena, Antonio Giuseppe Naccarato, Massimo Loda and Pier Vitale Nuzzo

Cancers 2022, 14(18), 4359; https://doi.org/10.3390/cancers14184359 - 7 Sep 2022

Cited by 11 | Viewed by 3659

Abstract

Tumor biopsy is still the gold standard for diagnosing and prognosis renal cell carcinoma (RCC). However, its invasiveness, costs, and inability to accurately picture tumor heterogeneity represent major limitations to this procedure. Analysis of circulating cell-free DNA (cfDNA) is a non-invasive cost-effective technique [...] Read more.

Tumor biopsy is still the gold standard for diagnosing and prognosis renal cell carcinoma (RCC). However, its invasiveness, costs, and inability to accurately picture tumor heterogeneity represent major limitations to this procedure. Analysis of circulating cell-free DNA (cfDNA) is a non-invasive cost-effective technique that has the potential to ease cancer detection and prognosis. In particular, a growing body of evidence suggests that cfDNA could be a complementary tool to identify and prognosticate RCC while providing contemporary mutational profiling of the tumor. Further, recent research highlighted the role of cfDNA methylation profiling as a novel method for cancer detection and tissue-origin identification. This review synthesizes current knowledge on the diagnostic, prognostic, and predictive applications of cfDNA in RCC, with a specific focus on the potential role of cell-free methylated DNA (cfMeDNA). Full article

(This article belongs to the Special Issue Cell-Free DNA as Prognostic and Predictive Biomarker in Solid Cancers)

► Show Figures

Figure 1

20 pages, 794 KiB

Open AccessReview

Extracellular Nucleic Acids in the Diagnosis and Progression of Colorectal Cancer

by Jakub Styk, Gergely Buglyó, Ondrej Pös, Ádám Csók, Beáta Soltész, Peter Lukasz, Vanda Repiská, Bálint Nagy and Tomáš Szemes

Cancers 2022, 14(15), 3712; https://doi.org/10.3390/cancers14153712 - 29 Jul 2022

Cited by 5 | Viewed by 3240

Abstract

Colorectal cancer (CRC) is the 3rd most common malignant neoplasm worldwide, with more than two million new cases diagnosed yearly. Despite increasing efforts in screening, many cases are still diagnosed at a late stage, when mortality is high. This paper briefly reviews known [...] Read more.

Colorectal cancer (CRC) is the 3rd most common malignant neoplasm worldwide, with more than two million new cases diagnosed yearly. Despite increasing efforts in screening, many cases are still diagnosed at a late stage, when mortality is high. This paper briefly reviews known genetic causes of CRC (distinguishing between sporadic and familial forms) and discusses potential and confirmed nucleic acid biomarkers obtainable from liquid biopsies, classified by their molecular features, focusing on clinical relevance. We comment on advantageous aspects such as better patient compliance due to blood sampling being minimally invasive, the possibility to monitor mutation characteristics of sporadic and hereditary CRC in a disease showing genetic heterogeneity, and using up- or down-regulated circulating RNA markers to reveal metastasis or disease recurrence. Current difficulties and thoughts on some possible future directions are also discussed. We explore current evidence in the field pointing towards the introduction of personalized CRC management. Full article

(This article belongs to the Special Issue Cell-Free DNA as Prognostic and Predictive Biomarker in Solid Cancers)

► Show Figures

Figure 1

20 pages, 373 KiB

Open AccessReview

The Promise of Circulating Tumor DNA in Head and Neck Cancer

by Sukhkaran S. Aulakh, Dustin A. Silverman, Kurtis Young, Steven K. Dennis and Andrew C. Birkeland

Cancers 2022, 14(12), 2968; https://doi.org/10.3390/cancers14122968 - 16 Jun 2022

Cited by 20 | Viewed by 3637

Abstract

As the seventh most common cancer globally, head and neck cancers (HNC) exert considerable disease burden, with an estimated 277,597 deaths worldwide in 2020 alone. Traditional risk factors for HNC include tobacco, alcohol, and betel nut; more recently, human papillomavirus has emerged as [...] Read more.

As the seventh most common cancer globally, head and neck cancers (HNC) exert considerable disease burden, with an estimated 277,597 deaths worldwide in 2020 alone. Traditional risk factors for HNC include tobacco, alcohol, and betel nut; more recently, human papillomavirus has emerged as a distinct driver of disease. Currently, limitations of cancer screening and surveillance methods often lead to identifying HNC in more advanced stages, with associated poor outcomes. Liquid biopsies, in particular circulating tumor DNA (ctDNA), offer the potential for enhancing screening, early diagnosis, and surveillance in HNC patients, with potential improvements in HNC patient outcomes. In this review, we examine current methodologies for detecting ctDNA and highlight current research illustrating viral and non-viral ctDNA biomarker utilities in HNC screening, diagnosis, treatment response, and prognosis. We also summarize current challenges and future directions for ctDNA testing in HNC patients. Full article

(This article belongs to the Special Issue Cell-Free DNA as Prognostic and Predictive Biomarker in Solid Cancers)

14 pages, 1101 KiB

Open AccessReview

Transcending Blood—Opportunities for Alternate Liquid Biopsies in Oncology

by Bonnita Werner, Kristina Warton and Caroline E. Ford

Cancers 2022, 14(5), 1309; https://doi.org/10.3390/cancers14051309 - 3 Mar 2022

Cited by 15 | Viewed by 2808

Abstract

Cell-free DNA (cfDNA) is a useful molecular biomarker in oncology research and treatment, but while research into its properties in blood has flourished, there remains much to be discovered about cfDNA in other body fluids. The cfDNA from saliva, sputum, cerebrospinal fluid, urine, [...] Read more.

Cell-free DNA (cfDNA) is a useful molecular biomarker in oncology research and treatment, but while research into its properties in blood has flourished, there remains much to be discovered about cfDNA in other body fluids. The cfDNA from saliva, sputum, cerebrospinal fluid, urine, faeces, pleural effusions, and ascites has unique advantages over blood, and has potential as an alternative ‘liquid biopsy’ template. This review summarises the state of current knowledge and identifies the gaps in our understanding of non-blood liquid biopsies; where their advantages lie, where caution is needed, where they might fit clinically, and where research should focus in order to accelerate clinical implementation. An emphasis is placed on ascites and pleural effusions, being pathological fluids directly associated with cancer. We conclude that non-blood fluids are viable sources of cfDNA in situations where solid tissue biopsies are inaccessible, or only accessible from dated archived specimens. In addition, we show that due to the abundance of cfDNA in non-blood fluids, they can outperform blood in many circumstances. We demonstrate multiple instances in which DNA from various sources can provide additional information, and thus we advocate for analysing non-blood sources as a complement to blood and/or tissue. Further research into these fluids will highlight opportunities to improve patient outcomes across cancer types. Full article

(This article belongs to the Special Issue Cell-Free DNA as Prognostic and Predictive Biomarker in Solid Cancers)

► Show Figures

Figure 1

Other

Jump to: Editorial, Research, Review

18 pages, 1050 KiB

Open AccessSystematic Review

Cell-Free Circulating (Tumor) DNA before Surgery as a Prognostic Factor in Non-Metastatic Colorectal Cancer: A Systematic Review

by Suzanna J. Schraa, Karlijn L. van Rooijen, Miriam Koopman, Geraldine R. Vink and Remond J. A. Fijneman

Cancers 2022, 14(9), 2218; https://doi.org/10.3390/cancers14092218 - 29 Apr 2022

Cited by 19 | Viewed by 3346

Abstract

Identification of non-metastatic colorectal cancer (CRC) patients with a high risk of recurrence after tumor resection is important to select patients who might benefit from adjuvant treatment. Cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA) analyses after surgery are promising biomarkers to predict [...] Read more.

Identification of non-metastatic colorectal cancer (CRC) patients with a high risk of recurrence after tumor resection is important to select patients who might benefit from adjuvant treatment. Cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA) analyses after surgery are promising biomarkers to predict recurrence in these patients. However, these analyses face several challenges and do not allow guidance of neoadjuvant treatment, which might become a novel standard option in colon cancer treatment. The prognostic value of cfDNA/ctDNA before surgery is unclear. This systematic review aims to provide an overview of publications in which the prognostic value of presurgery cfDNA/ctDNA in non-metastatic CRC patients was studied and is performed according to PRISMA guidelines. A total of 29 out of 1233 articles were included and categorized into three groups that reflect the type of approach: measurement of cfDNA, ctDNA somatic alterations, and ctDNA methylation. Overall, a clear association between presurgery cfDNA/ctDNA and the outcome was not observed, but large studies that primarily focus on the prognostic value of presurgery cfDNA/ctDNA are lacking. Designing and performing studies that focus on the value of presurgery cfDNA/ctDNA is needed, in addition to standardization in the reporting of cfDNA/ctDNA results according to existing guidelines to improve comparability and interpretation among studies. Full article

(This article belongs to the Special Issue Cell-Free DNA as Prognostic and Predictive Biomarker in Solid Cancers)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Cell-Free DNA as Prognostic and Predictive Biomarker in Solid Cancers

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Published Papers (22 papers)

Editorial

Research

Review

Other

Further Information

Guidelines

MDPI Initiatives

Follow MDPI