bims-ovdlit 2025-12-28 papers

Issue of 2025–12–28
five papers selected by
Lara Paracchini, Humanitas Research

Clin Transl Sci. 2026 Jan;19(1): e70463

Lexicon for Clonal Hematopoiesis in Liquid Biopsy.

Historically, clonal hematopoiesis (CH) has been recognized as a confounder of cell-free DNA (cfDNA) testing. Recent evidence now demonstrates the role of CH as a risk factor in health, generating distinct sources of cfDNA that can be leveraged for liquid biopsy diagnostics. Nonetheless, gaps in standardization challenge the advancement of such diagnostics from development to regulatory approval, through clinical trials, and ultimately, to routine implementation. In 2024, the Blood Profiling Atlas in Cancer (BLOODPAC) Consortium, a collaborative infrastructure for developing standards and best practices for liquid biopsy assays, established the CH/clonal hematopoiesis of indeterminate potential (CHIP) Working Group to address the need for accurate identification and removal of CH from liquid biopsy results. As a first step to support the interpretability of CH/CHIP results, the Working Group developed this lexicon to standardize terms and provide a unified vocabulary related to CH and liquid biopsy, DNA sequencing tests, biomarkers, and clinical use cases, facilitating communication within the field. BLOODPAC's CH/CHIP Working Group believes that terminology agreement across these various stakeholders can improve communication in the field and unify future data collection efforts across studies.

Keywords: CH; CHIP; liquid biopsy

DOI: https://doi.org/10.1111/cts.70463

Clin Chim Acta. 2025 Dec 19. pii: S0009-8981(25)00676-X. [Epub ahead of print]582 120797

Recent advances in the early detection of ovarian Cancer.

Anahita Soleimani, Akbar Amirfiroozy, Mohammad M Pourseif, Mahmoud Shekari Khaniani.

Ovarian cancer (OC), predominantly epithelial OC, remains the most lethal gynecological malignancy. Owing to its often asymptomatic or non-specific clinical presentation, approximately 70 % of patients are diagnosed at advanced stages (FIGO III-IV), typically characterized by extensive peritoneal dissemination. Although early detection is critical for improving survival outcomes, current standard diagnostic modalities, including serum CA125 and transvaginal ultrasound, lack sufficient sensitivity and specificity for population-level screening of early-stage disease. This review comprehensively evaluates emerging biomarkers and advanced diagnostic technologies, with a particular focus on liquid biopsy analytes, including circulating tumor DNA, microRNAs, and uterine liquid biopsies. We further discuss the clinical utility of multi-biomarker panels and artificial intelligence (AI)-driven models that integrate genomic, proteomic, and radiomic data, while highlighting their current performance limitations and stage-dependent diagnostic accuracy. Despite the considerable potential of liquid biopsies and AI-based approaches, challenges related to assay standardization and the need for large-scale prospective validation remain major barriers to widespread clinical implementation. Overall, this review underscores the need for robust, multimodal diagnostic strategies that may enable earlier detection and ultimately reduce OC-associated mortality.

Keywords: Artificial intelligence; CA125; Circulating tumor DNA; Early detection; HE4; Liquid biopsy; Multi-omics; Ovarian Cancer

DOI: https://doi.org/10.1016/j.cca.2025.120797

bioRxiv. 2025 Dec 12. pii: 2025.12.09.693327. [Epub ahead of print]

The Impact of Variant Calling on Substitution Mutational Signature Inference.

Zichen Jiang, Jessica N Au, Mariya Kazachkova, Marcos Díaz-Gay, Raviteja Vangara, Ludmil B Alexandrov.

Identifying mutational signatures is a key component of cancer genomics studies, yet the influence of variant calling strategies on signature extraction has not been systematically evaluated. Here, we analyzed over 8,900 whole exomes from The Cancer Genome Atlas (TCGA) and over 1,800 whole genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) consortium to assess how mutation callers shape de novo single-base substitution (SBS) signatures. We found that consensus calling yielded stable de novo signatures across reference genomes and pipeline versions, whereas individual callers introduced false-positive SBSs that manifested as artifactual signatures that were reproducibly detected by three independent signatures extraction tools. A minimal consensus approach requiring agreement between only two variant calling algorithms effectively removed these artifacts while preserving true biological signal. Together, these results establish consensus variant calling as essential for robust inference of de novo SBS mutational signatures and provide practical guidelines for distinguishing genuine mutational processes from technical artifacts.

DOI: https://doi.org/10.64898/2025.12.09.693327

Clin Cancer Res. 2025 Dec 22.

CtDNA detection with low-pass whole genome bisulfite sequencing in RAS wild-type metastatic colorectal cancer: an exploratory objective of the VALENTINO trial.

PURPOSE: Longitudinal measuring of circulating tumor DNA (ctDNA) during systemic treatment of metastatic colorectal cancer (mCRC) is promising for disease monitoring, but it is hampered by high costs and lacks formal demonstration of clinical usefulness.
PATIENTS AND METHODS: We leveraged METER, a novel, highly reproducible, computational workflow that infers ctDNA presence and fraction from low-pass whole genome bisulfite sequencing to investigate baseline and 8-week ctDNA dynamics in patients with RAS wild-type mCRC undergoing first-line treatment with panitumumab/FOLFOX in the VALENTINO randomized phase 2 trial. IchorCNA was used to provide a benchmark for METER.
RESULTS: A total of 154 patients were evaluable. Baseline ctDNA was detected in 72.7% of patients and was associated with significantly higher risk of progression (1.65, 95%CI: 1.13-2.42; p=0.010) and death (HR: 2.24, 95%CI: 1.37-3.66; p<0.001). CtDNA clearance at 8 weeks was observed in 80.2% of patients with baseline detectable ctDNA; persistence of ctDNA was associated with significantly higher risk of progression (2.70, 95%CI: 1.63-4.49; p<0.001) and death (HR: 3.37, 95%CI: 2.00-5.69; p<0.001). CtDNA clearance was associated with a more profound depth of response (DoR) (median -48.4% vs -41.2%; p=0.023) but not with a higher frequency of early tumor shrinkage (72.0% vs 73.7%, p=1.00). METER expanded the number of ctDNA-positive patients relative to a copy number alteration- and a variant allele frequency-based methods.
CONCLUSION: CtDNA detection and quantification with METER is a promising tool for cost-effective treatment monitoring in mCRC and can complement radiological assessment of response dynamics.

DOI: https://doi.org/10.1158/1078-0432.CCR-25-2773

Eur J Hum Genet. 2025 Dec 22.

Hereditary diffuse gastric cancer in progress: Comparative lessons from Lynch syndrome.

Joana Pereira, Luísa Carvalho, Soraia Melo, Patrícia Carneiro, Maria Sofia Fernandes, Raquel Seruca, Joana Figueiredo.

Hereditary diffuse gastric cancer (HDGC) and Lynch syndromes are dominant hereditary diseases caused by pathogenic germline variants in specified genes, and characterised by a broad spectrum of malignancies. Whereas HDGC is associated with CDH1 and CTNNA1 variants and defined by an increased risk of diffuse gastric cancer and lobular breast cancer, Lynch syndrome results from alterations in mismatch repair genes, whose main manifestations include colorectal, endometrial, ovarian, breast, prostate, stomach, and urological tumours. Remarkably, a huge difference remains in the knowledge surrounding the molecular mechanisms that drive these disorders, and in current approaches for patient management. In fact, the HDGC narrative is still in its early stages when compared with Lynch syndrome, which accumulates more than a century of research. Herein, we propose an analogy between HDGC and Lynch syndromes, highlighting intricacies across genetic origin, variant effects, cellular landscapes, and associated clinical outcomes. Further, we postulate that the history of Lynch syndrome may be useful to advance HDGC aetiology, namely strategies for identification of new candidate genes, rules for variant interpretation, sources of phenotypic heterogeneity, and improved surveillance protocols. This collected data will impact clinical perspectives, as well as future research programs addressing HDGC unmet challenges.

DOI: https://doi.org/10.1038/s41431-025-01992-w