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31 2025

Blood Circulating Tumor DNA‐based Genomic Profiling and Serial Analysis in Patients With Advanced Biliary Tract Cancer

Abstract   Background/Aim: This study aimed to identify mutation profile similarities between tissue and circulating tumor DNA (ctDNA) and to explore driver mutations as potential prognostic or predictive biomarkers or druggable targets in patients with advanced biliary tract cancer (BTC).   Patients and Methods: We prospectively enrolled 18 patients with advanced BTC and analyzed next-generation sequencing data fr|om 60 ctDNA samples using AlphaLiquid® 100. This assay screens up to 118 genes for single-nucleotide variants (SNVs) and insertion or deletions (INDELs), 27 genes for copy number alterations (CNAs), and 10 genes for fusions. We examined the intra-patient tissue-ctDNA concordance and studied the association between ctDNA variant allele frequency (VAF) and survival.   Results: A total of seven gallbladder cancer cases, six intrahepatic cholangiocarcinoma cases, and five extrahepatic cholangiocarcinoma cases were observed. Among these cases, tumor tissues were available for 16 patients. Genetic alterations were detected in 88% (14/16) of tissue DNA samples and 89% (16/18) of samples with ctDNA at baseline. The most common genes altered in ctDNA were TP53 (n=11), ERBB3 (n=3), and KRAS (n=3). There was a 29% overlap in somatic SNVs/INDELs and a 60% overlap in CNAs between tissue DNA and ctDNA, while no fusion variant was detected. The sensitivity and positive predictive value of ctDNA for all types of somatic mutations were 47% and 43%, respectively. Among the 14 patients whose serial ctDNA was analyzed, 10 showed changes in ctDNA. A high pre-treatment VAF (>4.0%) was associated with poor overall survival.   Conclusion: ctDNA sequencing can successfully identify molecular genetic alterations in patients with advanced BTC, providing insights into potential biomarkers and therapeutic targets.    

Blood Circulating Tumor DNA‐based Genomic Profiling and Serial Analysis in Patients With Advanced Biliary Tract Cancer

Anticancer Research

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30 2025

Pairwise analysis of plasma cell-free DNA before and after palliative second-line paclitaxel plus ramucirumab treatment in patients with metastatic gastric cancer

Abstract   Background This study compared plasma cell-free DNA (cfDNA) and tumor tissue DNA (ttDNA) to explore the clinical applicability of cfDNA in patients with metastatic gastric cancer (mGC) receiving palliative second-line paclitaxel + ramucirumab treatment. Methods Targeted sequencing of 106 genes was conducted using germline DNA and cfDNA at baseline (baseline-cfDNA) and progressive disease (PD-cfDNA). The results were compared with those of ttDNA-based cancer panel data. Results Of 76 consecutive patients, 46 (27 males; median age 57.5 [range, 32–73] years) who had all three samples were included. Combined analysis of ttDNA and baseline-cfDNA revealed that TP53 (58.7%) was the most frequently mutated gene, followed by CDH1 (26.1%), KRAS (21.7%), and APC (13.0%). For these genes, the sensitivity and positive predictive value of baseline-cfDNA over ttDNA were 71.8% and 51.9%, respectively. When baseline-cfDNA and PD-cfDNA results were combined, 34 patients (73.9%) were found to have additional mutations compared with ttDNA results alone. PD-cfDNA analysis revealed 14 novel pathogenic mutations in ten patients (21.7%). At baseline, patients with a high circulating tumor DNA fraction concentration showed a significantly shorter progression-free survival (PFS) (P = 0.016) in univariable and multivariable analyses. High maximal variant allele frequency (VAF) (P = 0.022), high sum of VAF (P = 0.028), and high TP53 VAF (P = 0.022) were associated with worse PFS in univariable analysis. Conclusions Although cfDNA alone cannot replace ttDNA entirely, cfDNA analysis revealed additional mutations. Notably, PD-cfDNA analysis revealed novel pathogenic mutations that emerged during treatment. Moreover, the baseline circulating tumor DNA fraction concentration and VAF values were associated with longer PFS.

Pairwise analysis of plasma cell-free DNA before and after palliative second-line paclitaxel plus ramucirumab treatment in patients with metastatic gastric cancer

Gastric Cancer

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29 2025

Analytical validation of a hybrid-approach combining tumor-informed and tumor-agnostic bespoke ctDNA panel assay for the sensitive detection of minimal residual disease

Abstract This study reports the analytical validation of CancerDetect™, a hybrid ctDNA assay that combines tumor-informed bespoke targets and tumor-agnostic clinically actionable  mutations to sensitively detect minimal residual disease (MRD). CancerDetect™ achieved an ultra-sensitive limit of detection of 0.001% with high specificity (99.9%),  demonstrating robust performance for MRD detection.   Purpose The purpose of this study was to analytically validate a hybrid ctDNA assay (CancerDetect™) designed to detect minimal residual disease (MRD) with higher sensitivity  than existing liquid biopsy approaches. The assay integrates both personalized tumor-informed mutation targets and tumor-agnostic hotspot regions to expand the detection space  and improve sensitivity beyond conventional fixed-panel methods.   Materials and Methods -The CancerDetect™ assay combines large-scale mutation profiling with hybridization capture sequencing, integrating both patient-specific (bespoke) mutations and    clinically actionable hotspot mutations across 15 genes. -Reference materials with serially diluted variant allele fractions (VAFs) were prepared to assess the limit of detection (LoD) and limit of blank (LoB). -The assay’s specificity, precision, repeatability, and reproducibility were evaluated using control samples, varying operators, reagents, and interference materials to    simulate real-world testing conditions. -Analytical performance metrics were measured using deep targeted sequencing and proprietary error-suppression technology Results -CancerDetect™ achieved a limit of detection (LoD) down to 0.001% ctDNA, indicating ultra-sensitive MRD detection capabilities.-Analytical specificity was 99.9% for bespoke regions, with very low false-positive rates.-The test showed robust precision, repeatability, and reproducibility across operators and reagent lots, confirming consistent performance.-Matrix interference tests (e.g., bilirubin, wash buffer) demonstrated that the assay’s performance was not significantly affected by common plasma components.-The assay’s design ensures both high sensitivity and specificity, enabling reliable differentiation between true tumor signals and background noise.   Conclusions This study demonstrates that the CancerDetect™ hybrid ctDNA panel assay provides ultra-sensitive and highly specific detection of minimal residual disease,  outperforming conventional approaches. Its combination of tumor-informed and tumor-agnostic targets, along with robust analytical performance, supports its potential utility in  clinical MRD monitoring to inform treatment decisions and improve patient outcomes. 

Analytical validation of a hybrid-approach combining tumor-informed and tumor-agnostic bespoke ctDNA panel assay for the sensitive detection of minimal residual disease

PLOS One

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28 2025

Whole genome DNA methylation patterns in tissue and cfDNA associated with fibrosis reflect the complex signature of MASLD

Abstract Whole-genome DNA methylation sequencing (WGMS) of liver tissue and circulating cell-free DNA (cfDNA) in patients with MASLD identified fibrosis-associated methylation patterns in both sample types,  along with clear sex-specific and immune-related signals. These results demonstrate the potential of cfDNA-based WGMS as a non-invasive approach for comprehensively monitoring MASLD-related fibrosis.     Purpose The study aimed to investigate the relationship between whole-genome DNA methylation (DNAm) patterns and fibrosis in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)  by analyzing both liver tissue and circulating cell-free DNA (cfDNA). Prior research on MASLD methylation was limited to specific CpG sites or tissue only, with little consideration of sex differences.  This research sought to address these gaps and explore whether cfDNA methylation profiles could reflect fibrosis-associated changes non-invasively.   Materials and Methods  Liver tissue and cfDNA samples were collected fr|om patients with MASLD. Whole-genome methylation sequencing (WGMS) was performed on both sample types.  After quality filtering, the data were grouped by sex and sample type. CpG bins showing significant correlation with fibrosis stage using statistical filtering were selected.  Pathway analyses were conducted based on genomic locations of significant CpG bins. Additionally, cell type deconvolution was performed to infer cellular contributions to the methylation signal,  and comparative analyses between tissue and cfDNA profiles were carried out. Results  The WGMS analysis identified overlapping and distinct methylation patterns associated with fibrosis across tissue and cfDNA, and between males and females.  Pathway analysis revealed multiple fibrosis-related signaling pathways, including Wnt and Notch signaling, with sex-specific differences.  Tissue samples showed immune cell signatures associated with fibrosis. cfDNA analysis reflected increased liver-derived DNA fragments and methylation changes similar to tissue patterns,  indicating that cfDNA captures fibrosis-associated alterations. Predictive modeling using cfDNA methylation also showed potential for distinguishing fibrosis severity.   Conclusions Whole-genome methylation sequencing reveals complex DNA methylation changes associated with MASLD and fibrosis in both tissue and cfDNA.  The findings demonstrate that cfDNA WGMS can capture fibrosis-related epigenetic alterations and holds promise as a non-invasive diagnostic approach for fibrosis in MASLD,  potentially enabling blood-based detection and monitoring of disease progression.

Whole genome DNA methylation patterns in tissue and cfDNA associated with fibrosis reflect the complex signature of MASLD

PLOS One

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27 2025

Enhanced Detection of Druggable Mutations in Non–Small Cell Lung Cancer Using Targeted Collection of Bronchial Washing Fluid Compared With Plasma and Tumor Tissue

Abstract   PurposeNext-generation sequencing (NGS) has become the gold standard for the molecular testing of patients with non–small cell lung cancer (NSCLC). This prospective study evaluated the performance of NGS using cell-free tumor DNA (ctDNA) extracted fr|om bronchial washing fluid (BWF) collected via a targeted washing technique to detect druggable mutations. Materials and Methods All study participants simultaneously underwent NGS using three sample types: (1) BWF, (2) plasma, and (3) tumor tissue collected during bronchoscopy. The full patient set (FPS) included all enrolled patients, whereas the analysis intent group (AIG) included patients who underwent successful NGS across all specimen types (BWF, plasma, and tissue). Results Sixty and 50 patients were included in the FPS and AIG groups, respectively. In FPS, the detection rate of druggable mutations in BWF using NGS was 65%, which was significantly higher than that of plasma (47%) and tissue samples (48%; P 5 .003 and P 5 .002, respectively). In the AIG, the concordance rate for detecting druggable mutations between BWF and tissue samples was 94%. In addition, the detection rate of co-occurring genetic alterations in BWF using NGS was significantly higher than that in plasma samples (92% v 64%, P 5 .001), whereas it was comparable with that in tissue samples (92% v 94%, P 5 1.000). No significant adverse events occurred during the BWF collection. ConclusionsNGS using ctDNA fr|om BWF obtained through a targeted washing technique is a feasible and reliable method for genomic profiling of NSCLC, providing a promising approach for identifying druggable mutations.

Enhanced Detection of Druggable Mutations in Non–Small Cell Lung Cancer Using Targeted Collection of Bronchial Washing Fluid Compared With Plasma and Tumor Tissue

JCO Precision Oncology

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