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Biomedicines
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Advances in Liquid Biopsy from Technological Innovation to Therapeutic Intervention
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Advances in Liquid Biopsy from Technological Innovation to Therapeutic Intervention

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (28 February 2026) | Viewed by 15299

Special Issue Editors

Dr. Mohamed Kamal

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Guest Editor
Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA 90089, USA
Interests: cancer biology; metastasis; drug resistance; biomarkers; circulating tumor cells; cancer stem cells; liquid biopsy; early detection
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. James Hicks

E-Mail Website
Guest Editor
1. Convergent Science Institute in Cancer, University of Southern California, Los Angeles, CA 90089, USA
2. Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA
3. USC Norris Comprehensive Cancer, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
Interests: single cell genomics; cancer genomics; sequencing; cancer evolution; circulating tumor cells (CTCs); liquid biopsy; biomarkers
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Liquid biopsy is a minimally invasive alternative to traditional tissue biopsies capable of providing longitudinal monitoring of tumor progression and response to therapy. Liquid biopsies such as blood, urine, aqueous humor, and ascites through the analyses of cell-free nucleic acids (cfDNA, cfRNA), circulating tumor cells (CTCs), and extracellular vehicles (EVs) have shown great promise in cancer diagnosis, prognosis, and treatment monitoring. Recent advancements in assay development and the integration of artificial intelligence (AI) have significantly enhanced the sensitivity and specificity of liquid biopsy techniques. In addition to their value as a minimally invasive tool for longitudinal monitoring of cancer, liquid biopsies could also serve as a rich source of information for a better understanding of cellular and molecular mechanisms of metastasis leading to the discovery of new drug targets and biomarkers. On top of that, recent reports have showed that elimination of CTCs from patients’ circulation could hinder metastasis.

This Special Issue aims to capture the current state of the art in liquid biopsy research including the following topics:

  1. Technological innovations including AI-assisted models for the detection of rare circulating events and for patients’ classification.
  2. Liquid biopsy-based biomarkers for predicting tumor prognosis and monitoring response to treatment.
  3. Liquid biopsy in cancer screening programs at the population level and of high-risk groups for early detection of cancer and detection of the disease’s precursors.
  4. Patient Risk Stratification using liquid biopsy biomarkers.
  5. Studies providing better understanding of the Biology of metastasis.
  6. Therapeutic interventions through the elimination of circulating cancer-related events.

Dr. Mohamed Kamal
Prof. Dr. James Hicks
Guest Editors

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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. Biomedicines is an international peer-reviewed open access monthly 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 2600 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

  • liquid biopsy
  • biomarkers
  • circulating tumor cells

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Published Papers (9 papers)

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Research

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13 pages, 1084 KB  
Article
Circulating Plasma Cells as a Minimally Invasive Adjunct to Bone Marrow Aspirates for Genetic Analysis of ER Stress and Autophagy in Multiple Myeloma: A Feasibility Study
by A.-M. Joëlle Marivel, Therese M. Becker, Alexander James, Yafeng Ma, Nirupama D. Verma, Tara L. Roberts and Silvia Ling
Biomedicines 2026, 14(4), 737; https://doi.org/10.3390/biomedicines14040737 - 24 Mar 2026
Viewed by 547
Abstract
Background: Multiple myeloma (MM) is characterised by clonal expansion of plasma cells (PCs) in the bone marrow (BM). Disease assessment and monitoring typically rely on invasive, single-site procedures, such as BM biopsies (BMBs), which may inadequately capture intra- and extra-medullary spatial heterogeneity. Circulating [...] Read more.
Background: Multiple myeloma (MM) is characterised by clonal expansion of plasma cells (PCs) in the bone marrow (BM). Disease assessment and monitoring typically rely on invasive, single-site procedures, such as BM biopsies (BMBs), which may inadequately capture intra- and extra-medullary spatial heterogeneity. Circulating plasma cells (CPCs), enriched from peripheral blood (PB), may represent a minimally invasive alternative or adjunct for molecular profiling. Objectives: This study aimed to evaluate the feasibility of using CPCs, enriched from PB, for mRNA analysis in plasma cell dyscrasia, including MM. A secondary objective was to assess whether mRNA expression levels of the endoplasmic reticulum (ER) stress sensors X-box-binding protein 1 (uXBP1) and activating transcription factor 6 (ATF6), and the chaperone-mediated autophagy marker Lysosomal-Associated Membrane Protein 2 (LAMP2A) by droplet digital PCR (ddPCR), were associated with resistance to the second-generation proteasome inhibitor (PI) carfilzomib (Cfz). Methods: Multiple myeloma (MM) cell lines (H929 and U266) and their carfilzomib-adapted derivatives were used to establish and validate droplet digital PCR (ddPCR) assays targeting ER stress (uXBP1, ATF6) and autophagy-related (LAMP2A) transcripts. Solid tumour cell lines, including serum-starved HeLa cells, served as biological controls to support assay specificity and sensitivity. Total RNA was extracted and reverse-transcribed to complementary DNA prior to analysis. Transcript levels were normalised to those of β-actin or GAPDH, as appropriate. ddPCR was performed using the BioRad QX200 system, with results reported as the normalised transcript copy number per microlitre of reaction. Matched bone marrow aspirate (BMA) and peripheral blood (PB) samples were collected at a single clinical time point from adults undergoing investigation for plasma cell dyscrasia between January 2021 and December 2023. Samples were obtained as part of standard clinical care and/or during treatment with Bortezomib (Btz) or Cfz. Mononuclear cells were isolated by density gradient centrifugation, and CD138+ plasma cells were enriched by fluorescence-activated cell sorting. Enrichment purity was assessed qualitatively by immunofluorescence microscopy using CD138 and CD117 markers. Samples yielding fewer than 1000 CD138+ plasma cells were excluded, resulting in 10 evaluable matched patient pairs. Results: Carfilzomib-adapted MM cell lines demonstrated reduced levels of uXBP1, ATF6, and LAMP2A mRNA compared to treatment-naïve cells. In matched BM and PB samples, uXBP1 mRNA levels were consistently lower in circulating PCs than in BM-derived PCs, whereas ATF6 mRNA levels were concordant between compartments. LAMP2A mRNA levels exhibited marked inter-patient heterogeneity. Conclusions: This study demonstrates the feasibility of using CPCs as a minimally invasive source for mRNA-based biomarker assessment and highlights ddPCR as a sensitive platform for quantifying ER stress and chaperone-mediated autophagy related transcripts in CPCs. Cfz adaptation was associated with reduced levels of uXBP1 and LAMP2A mRNA in MM cell lines. Future prospective studies evaluating the clinical utility of ER stress and chaperone-mediated autophagy associated transcripts in CPCs as predictors of resistance to PI are warranted. Full article
(This article belongs to the Special Issue Advances in Liquid Biopsy from Technological Innovation to Therapeutic Intervention)
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18 pages, 3101 KB  
Article
New SPRi Biosensors for Simultaneous Detection of Tau Protein Isoforms—The Importance of the Ptau181/Total Tau Ratio in Alzheimer’s Disease
by Zuzanna Zielinska and Ewa Gorodkiewicz
Biomedicines 2026, 14(2), 351; https://doi.org/10.3390/biomedicines14020351 - 3 Feb 2026
Viewed by 824
Abstract
Background: Tau protein is a nonspecific marker of neurodegeneration, and its phosphorylated form, ptau-181, is specifically associated with Alzheimer’s disease (AD). Calculating the ratio of the phosphorylated form to total tau protein can help distinguish AD from other tauopathies or neurodegeneration, as [...] Read more.
Background: Tau protein is a nonspecific marker of neurodegeneration, and its phosphorylated form, ptau-181, is specifically associated with Alzheimer’s disease (AD). Calculating the ratio of the phosphorylated form to total tau protein can help distinguish AD from other tauopathies or neurodegeneration, as well as reduce the impact of individual differences in total tau protein levels. This also allows one to monitor and compare the dynamics of changes within the same patient. Methods: Two SPRi biosensors were constructed, sensitive to the proteins described (total tau and ptau-181) for plasma determinations. The use of these biosensors requires prior sensor validation, during which specific parameters of the analytical method are established. Tests of the optimal concentration of the receptor layer in which particular antibodies were immobilized showed that the optimal concentration for total tau protein determinations was 1000 ng/mL. For ptau-181, it was 90 ng/mL. Biosensor layer formation was confirmed by analysis over a wide angle range, which enabled the generation of SPR curves. The dynamic range of the sensors is 1–50 pg/mL for total tau and 1–100 pg/mL for ptau-181. The limits of detection are 0.18 pg/mL and 0.037 pg/mL, respectively. Low standard deviation (SD) and coefficient of variation (CV) values indicate the good precision and accuracy of the results obtained using the SPRi biosensors. Specificity testing confirmed that no interferents influenced the assay. The method is therefore suitable for analyzing biological materials, such as blood plasma. Results: Proteins were thus measured in the blood plasma of AD patients and controls. Statistical analysis revealed significant differences in the concentrations of tau and ptau-181 protein between the two groups. The calculated ptau/total tau ratio for both sample groups also demonstrated high statistical significance. Conclusions: This suggests that a high ratio may be characteristic of AD. However, more extensive analysis is needed to obtain cutoff values. The ROC curves indicate that both biosensors have good diagnostic utility, with lower specificity for total tau. Full article
(This article belongs to the Special Issue Advances in Liquid Biopsy from Technological Innovation to Therapeutic Intervention)
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19 pages, 5453 KB  
Article
Alzheimer’s Disease-Associated Molecular Abnormalities in White Matter Glia and Related Pathologies Detected in Unfractionated and O4-Selected Serum Exosomes Using a Liquid Biopsy Approach
by Suzanne M. de la Monte and Ming Tong
Biomedicines 2026, 14(1), 251; https://doi.org/10.3390/biomedicines14010251 - 22 Jan 2026
Cited by 1 | Viewed by 709
Abstract
Background/Objectives: White matter degeneration is a significant and early mediator of cognitive impairment in Alzheimer’s disease (AD), yet the critical pathologic features remain poorly understood, under-detected, and therapeutically untargeted. Herein, we characterize molecular features of white matter glial cells in AD brains [...] Read more.
Background/Objectives: White matter degeneration is a significant and early mediator of cognitive impairment in Alzheimer’s disease (AD), yet the critical pathologic features remain poorly understood, under-detected, and therapeutically untargeted. Herein, we characterize molecular features of white matter glial cells in AD brains and assess the utility of non-invasive approaches for detecting related abnormalities in extracellular vesicles (EVs) isolated from serum (SEV). In addition, results from unfractionated (SEV-T) and O4 sulfatide-selected SEVs were compared to determine whether white matter abnormalities were detected with greater sensitivity in oligodendrocyte-specific SEVs (SEV-O4). Methods: Oligodendrocyte glycoprotein and astrocyte mRNA levels were measured in postmortem human AD and control frontal lobe white matter by RT-PCR. Immunoreactivity to oligodendrocyte glycoproteins, astrocyte structural proteins, neurofilament light chain (NfL), and aspartyl-asparaginyl-β-hydroxylase (ASPH) was measured by ELISA in SEV-T and SEV-O4 from patients with moderate AD or normal aging. Results: AD brain pathology was associated with significantly reduced mRNA expression of multiple oligodendrocyte glycoproteins and increased mRNA expression of astrocytic structural genes. SEV analyses demonstrated significantly increased immunoreactivity to 2′,3′-cyclic nucleotide 3′ phosphodiesterase (CNPase), myelin-associated glycoprotein 1 (MAG1), astrocyte proteins, and ASPH, a potent activator of Notch and myelin-regulated homeostatic functions. There were no significant benefits of measuring SEV-O4 compared with SEV-T immunoreactivity. Conclusions: AD is associated with significant molecular abnormalities in oligodendrocyte and astrocyte function in brain tissue. The abnormalities detected in SEVs likely reflect oligodendrocyte injury and degeneration, as well as astrocytic activation. The findings suggest that low-invasive SEV approaches, including the novel analysis of ASPH upregulation, can be used to detect and monitor AD white matter degeneration. Full article
(This article belongs to the Special Issue Advances in Liquid Biopsy from Technological Innovation to Therapeutic Intervention)
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19 pages, 4559 KB  
Article
Genetic Variants and Soluble Isoforms of PD-1/PD-L1 as Novel Biomarkers for Pancreatic Ductal Adenocarcinoma (PDAC) Susceptibility and Prognosis
by Marwa Hassan, Walaa H. El-Maadawy, Yasmine Elhusseny, Fatma Elbatol Agamy, Sally A. Fahim and Mahmoud Balata
Biomedicines 2025, 13(9), 2246; https://doi.org/10.3390/biomedicines13092246 - 12 Sep 2025
Cited by 5 | Viewed by 1713
Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive neoplasm often diagnosed at advanced stages. Immune checkpoint molecules, particularly programmed cell death protein-1 (PD-1) and its ligand PD-L1, are pivotal in tumor immune evasion. Genetic polymorphisms in PD-1/PD-L1 and their soluble isoforms (sPD-1/sPD-L1) [...] Read more.
Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive neoplasm often diagnosed at advanced stages. Immune checkpoint molecules, particularly programmed cell death protein-1 (PD-1) and its ligand PD-L1, are pivotal in tumor immune evasion. Genetic polymorphisms in PD-1/PD-L1 and their soluble isoforms (sPD-1/sPD-L1) may influence individual susceptibility to cancer and disease progression. Therefore, this study was conducted to examine the correlation between PD-1/PD-L1 gene polymorphisms, serum levels of sPD-1/sPD-L1, and their association with PDAC susceptibility, severity, and prognostication. Methods: This case–control study was performed with 150 PDAC patients and 150 controls. Clinical and laboratory data, including tumor markers (CA19-9 and CEA), were recorded. Allele-specific PCR was utilized to genotype PD-1 (rs6749527 and rs7421861) and PD-L1 (rs2297136, and rs4143815). sPD-1/sPD-L1 were quantified with ELISA. Mapping of the Kaplan–Meier survival curve of mutant genes was performed. Results: The rs7421861 AG and GG and rs4143815 GG genotypes, together with their G-alleles, were linked to increased PDAC risk and greater tumor burden. In contrast, the rs2297136 GG genotype and G-allele conferred protection against PDAC development. Serum sPD-L1 levels, rather than sPD-1, were markedly elevated in PDAC patients, progressively increased with tumor grade, and correlated with tumor markers. Also, higher PD-L1 gene expression was associated with lower overall survival. Conclusions: PD-1/PD-L1 genetic variants, particularly rs7421861 and rs4143815, along with sPD-L1 levels, correlate with PDAC susceptibility and disease severity. These findings endorse the prospects of integrating immune checkpoint genetic variants and soluble biomarkers for early identification, risk stratification, prognostication, and personalized therapeutic strategies in PDAC management. Full article
(This article belongs to the Special Issue Advances in Liquid Biopsy from Technological Innovation to Therapeutic Intervention)
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26 pages, 1442 KB  
Article
The Association of Toll-like Receptor-9 Gene Single-Nucleotide Polymorphism and AK155(IL-26) Serum Levels with Chronic Obstructive Pulmonary Disease Exacerbation Risk: A Case-Controlled Study with Bioinformatics Analysis
by Entsar R. Mokhtar, Salwa I. Elshennawy, Heba Elhakeem, Rayyh A. M. Saleh, Sawsan Bakr Elsawy, Khadiga S. M. Salama, Maha Fathy Mohamed, Rania Hamid Bahi, Hayam H. Mansour, Sammar Ahmed Kasim Mahmoud, Marwa M. Hassan, Sara M. Elhadad, Hanaa Mohammed Eid El Sayed, Aliaa N. Mohamed and Nadia M. Hamdy
Biomedicines 2025, 13(3), 613; https://doi.org/10.3390/biomedicines13030613 - 3 Mar 2025
Cited by 2 | Viewed by 2842
Abstract
Background: A crucial challenge is the determination of chronic obstructive pulmonary disease (COPD) immune-related mechanisms, where one of the important components of the inflammatory axes in COPD is Toll-like receptor-9 (TLR9) and interleukin-26 AK155(IL-26). Aim: To examine the relation between TLR9 (T1237C) SNP [...] Read more.
Background: A crucial challenge is the determination of chronic obstructive pulmonary disease (COPD) immune-related mechanisms, where one of the important components of the inflammatory axes in COPD is Toll-like receptor-9 (TLR9) and interleukin-26 AK155(IL-26). Aim: To examine the relation between TLR9 (T1237C) SNP rs5743836 and serum levels of AK155(IL-26) with the exacerbation of COPD. Subjects: A total of 96 COPD patients sub-classified into two groups. Materials: DNA was purified from blood samples of stable COPD patients (n = 48) vs. exacerbated COPD patients (n = 48) as well as 42 age- and sex-matched healthy smokers and passive smokers as a control group. Methods: Genotyping for TLR9 rs5743836 (T1237C) polymorphism was performed using real time polymerase chain reaction (RT-PCR). AK155(IL-26) serum levels were determined using ELISA. Results: There is a significantly higher frequency of the mutant homozygous genotype (C/C) and the mutated C allele of TLR9 rs5743836 (T1237C) in COPD patients and in the exacerbated group when compared with the control group and stable COPD patients, respectively, with OR 31.98, 1.8 to 57.7, and OR 3.64, 0.98 to 13.36, respectively. For the mutated C allele, the OR was 3.57, 1.94 to 6.56, p = 0.001, OR 1.83, 1.02 to 3.27, p = 0.041, respectively. In the exacerbated COPD group, there was a significant association between TLR9 rs5743836 SNP and BMI and the lung vital function measures, CRP, and AK155(IL-26). The exacerbated COPD group has higher serum levels of AK155(IL-26) compared with the stable group or when compared with the control group (p = 0.001) for both. AK155(IL-26) serum levels have a positive significant correlation with CRP and BMI and a significant negative correlation with FEV1% and FEV1/FVC in exacerbated COPD patients. Conclusions: Our results demonstrated a relation linking TLR-9 rs5743836 (T1237C) expression and the risk of COPD development and its exacerbation, indicating that dysfunctional polymorphisms of the innate immune genes can affect COPD development and its exacerbation. AK155(IL-26) upregulation was related to decreased lung functionality, systematic inflammatory disease, and COPD exacerbation. Full article
(This article belongs to the Special Issue Advances in Liquid Biopsy from Technological Innovation to Therapeutic Intervention)
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20 pages, 2411 KB  
Article
Development of PowerMag System II for Isolation of Circulating Tumor Cells with Improved Purity
by Cheng-Rou Ho, Hui-Ju Tsai, Jin-Ru Wang, Chia-Te Wang, Chiuan-Chian Chiou, Ju-Chien Cheng, Sum-Fu Chiang and Ching-Ping Tseng
Biomedicines 2025, 13(2), 431; https://doi.org/10.3390/biomedicines13020431 - 11 Feb 2025
Cited by 2 | Viewed by 1816
Abstract
Background/Objectives: The PowerMag system (PM) is a platform for the isolation of circulating tumor cells (CTCs) by the depletion of CD45+-leukocytes. However, an EpCAM−CD45− cell population is present in large numbers in the cell filtrates collected by [...] Read more.
Background/Objectives: The PowerMag system (PM) is a platform for the isolation of circulating tumor cells (CTCs) by the depletion of CD45+-leukocytes. However, an EpCAM−CD45− cell population is present in large numbers in the cell filtrates collected by PM. This lowers the purity of the CTCs and negatively impacts their molecular characterization. The aims of this study are to characterize the cellular properties of the EpCAM−CD45− cells and to upgrade the system to improve CTC purity. Methods: A real-time RT-PCR assay, Liu’s stain analysis, and Annexin V (AnxV) binding assay were used to define the cellular properties of the EpCAM−CD45− cells. An upgraded system was developed to remove the EpCAM−CD45− cells and improve the CTC purity. Clinical blood samples were used to evaluate the performance of the system. Results: The EpCAM−CD45− cells were defined as apoptotic cells, which displayed apoptotic body-like morphology and elicited AnxV binding activity. AnxV beads developed in-house can effectively bind and remove EpCAM−CD45− cells from the cell filtrates. An improved generation of a CTCs isolation platform, designated as PM II, was developed by integration of AnxV beads into the workflow to remove the apoptotic cells. PM II recovered CTCs with improved CTC purity by effective removal of the background apoptotic cells. The improved performance of PM II allowed for direct profiling of cancer-related gene mutations by next-generation sequencing without cell picking and further purification. Conclusions: PM II holds great promise as a platform for isolating CTCs with improved purity and for exploring its application in cancer diagnosis and monitoring in a clinical setting. Full article
(This article belongs to the Special Issue Advances in Liquid Biopsy from Technological Innovation to Therapeutic Intervention)
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Review

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23 pages, 6897 KB  
Review
Where Does Liquid Biopsy Add Value in Thyroid Cancer? Biological Rationale, Technological Innovation, and Clinical Utility
by María Alonso-Chamorro, Ainhoa Palacios Mejorada and Garcilaso Riesco-Eizaguirre
Biomedicines 2026, 14(6), 1274; https://doi.org/10.3390/biomedicines14061274 - 2 Jun 2026
Viewed by 254
Abstract
Thyroid cancer comprises biologically diverse entities ranging from largely indolent differentiated thyroid cancer (DTC) to aggressive poorly differentiated/anaplastic thyroid cancer and medullary thyroid cancer, generating a need for minimally invasive biomarkers that can be repeatedly sampled. This review summarizes recent advances in liquid [...] Read more.
Thyroid cancer comprises biologically diverse entities ranging from largely indolent differentiated thyroid cancer (DTC) to aggressive poorly differentiated/anaplastic thyroid cancer and medullary thyroid cancer, generating a need for minimally invasive biomarkers that can be repeatedly sampled. This review summarizes recent advances in liquid biopsy for thyroid cancer, focusing on analytes and technologies spanning circulating tumor DNA (ctDNA)/cell-free DNA, circulating microRNAs (miRNAs), extracellular vesicles (EVs), and circulating tumor cells (CTCs). For ctDNA, we contrast qPCR/ddPCR and next-generation sequencing, tumor-informed versus tumor-agnostic strategies, the impact of low tumor fraction in DTC, clonal hematopoiesis confounding, and emerging methylation-based multi-cancer detection paradigms. For miRNAs, we highlight that bulk serum/plasma and EV-enriched compartments are not interchangeable and that regulated EV loading supports fraction-resolved biomarker development. We review recent translational EV-miRNA studies, including externally validated classifiers for metastatic disease and follicular-patterned/indeterminate nodules, and summarize the evolution of CTC research from enumeration to preoperative risk stratification and postoperative or radioiodine-related kinetics. We conclude with an indications-first framework that pairs analyte choice with clinical intent (preoperative diagnosis, initial risk stratification, response to treatment and minimal residual disease and identification of actionable alterations and resistance mechanisms) and prioritizes standardized workflows and prospective multicenter validation. Multi-analyte integration, epigenetic/fragmentomic cfDNA signals, and higher-resolution EV analytics are likely to accelerate clinical adoption, particularly in advanced thyroid cancer where circulating signal and therapeutic actionability are highest. Full article
(This article belongs to the Special Issue Advances in Liquid Biopsy from Technological Innovation to Therapeutic Intervention)
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29 pages, 1410 KB  
Review
Diet-Driven Epigenetic Alterations in Colorectal Cancer: From DNA Methylation and microRNA Expression to Liquid Biopsy Readouts
by Theodora Chindea, Alina-Teodora Nicu, Gheorghe Dănuț Cimponeriu, Bianca Galateanu, Ariana Hudita, Mirela Violeta Șerban, Remus Iulian Nica and Liliana Burlibasa
Biomedicines 2026, 14(2), 267; https://doi.org/10.3390/biomedicines14020267 - 24 Jan 2026
Viewed by 1306
Abstract
The escalating incidence of colorectal cancer (CRC), particularly the alarming rise in early-onset cases, necessitates a paradigm shift from a purely genetic perspective to a broader investigation of promising pathways. This review explores the “nutri-epigenetic” interface, positioning liquid biopsy as a critical technology [...] Read more.
The escalating incidence of colorectal cancer (CRC), particularly the alarming rise in early-onset cases, necessitates a paradigm shift from a purely genetic perspective to a broader investigation of promising pathways. This review explores the “nutri-epigenetic” interface, positioning liquid biopsy as a critical technology for translating dietary impacts into actionable clinical biomarkers. We contrast the molecular consequences of the Western dietary pattern, characterized by methyl-donor deficiency and pro-inflammatory metabolites, with the protective mechanisms of the Mediterranean diet. Mechanistically, we detail how Western-style diets drive a specific “epigenetic double-hit”: promoting global DNA hypomethylation (destabilizing LINE-1) while paradoxically inducing promoter hypermethylation of critical tumour suppressors (MLH1, APC, MGMT) and silencing tumour-suppressive microRNAs (miR-34b/c, miR-137) via methylation of their encoding genes. Conversely, we highlight the capacity of Mediterranean bioactive compounds (e.g., resveratrol, curcumin, butyrate) to inhibit DNA methyltransferases and restore epigenetic homeostasis. Bridging molecular biology and clinical utility, we demonstrate how these diet-sensitive signatures, specifically circulating methylated DNA and dysregulated microRNAs, can be captured via liquid biopsy. We propose that these circulating analytes serve as dynamic, accessible biomarkers for monitoring the molecular progression toward a carcinogenic state, thereby establishing a novel framework for personalized risk stratification and validating the efficacy of preventive nutritional strategies. Full article
(This article belongs to the Special Issue Advances in Liquid Biopsy from Technological Innovation to Therapeutic Intervention)
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18 pages, 310 KB  
Review
Agnostic Biomarkers and Molecular Signatures in Colorectal Cancer—Guiding Chemotherapy and Predicting Response
by Ilektra Kyrochristou, Georgios D. Lianos, Gerasimia D. Kyrochristou, Georgios Anagnostopoulos, Christina Bali, Stergios Boussios, Michail Mitsis, Dimitrios Schizas and Konstantinos Vlachos
Biomedicines 2025, 13(8), 2038; https://doi.org/10.3390/biomedicines13082038 - 21 Aug 2025
Cited by 8 | Viewed by 1882
Abstract
The concept of agnostic biomarkers—molecular modifications that guide therapy irrespective of tumor origin—has gained increasing relevance in oncology, including colorectal cancer (CRC). This review aims to critically evaluate the role of such biomarkers in CRC, highlighting their clinical significance as therapeutic targets and [...] Read more.
The concept of agnostic biomarkers—molecular modifications that guide therapy irrespective of tumor origin—has gained increasing relevance in oncology, including colorectal cancer (CRC). This review aims to critically evaluate the role of such biomarkers in CRC, highlighting their clinical significance as therapeutic targets and indicators of prognosis. Through a PubMed search using the terms “agnostic treatment AND colorectal cancer,” eight key studies were identified and qualitatively analyzed. We focus on several biomarkers commonly regarded as agnostic across tumor types, including BRAF V600E mutation, receptor tyrosine kinase (RTK) and PI3K fusions, the CpG island methylator phenotype (CIMP), high tumor mutational burden (TMB), and microsatellite instability (MSI). These markers are inspected for their prevalence in CRC, underlying pathophysiological mechanisms of cancer promotion, and predictive or prognostic implications. Moreover, we integrate findings from broader oncologic studies to contextualize the evolving role of agnostic biomarkers beyond organ-specific paradigms. Emerging evidence suggests that leveraging these molecular signatures may inform the use of targeted and immunotherapeutic agents as first-line options in select CRC populations. Collectively, agnostic biomarkers represent an auspicious avenue for personalizing CRC treatment, particularly in advanced-stage disease where traditional treatment options remain limited. Full article
(This article belongs to the Special Issue Advances in Liquid Biopsy from Technological Innovation to Therapeutic Intervention)
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