bims-fragic 2025-12-07 papers

Issue of 2025–12–07
two papers selected by
Laura Mannarino, Humanitas Research

Cell Commun Signal. 2025 Nov 29.

DECIPHER-PRAD: an advanced fragmentomics-based cell-free DNA assay for prostate cancer early detection.

Shun Zhang, Guanchen Zhu, Linfeng Xu, Qing Zhang, Xuefeng Qiu, Hua Bao, Min Wu, Xiaotian Zhao, Tao Ding, Fufeng Wang, Shuang Chang, Yang Shao, Junlong Zhuang, Hongqian Guo.

Early detection of prostate cancer is limited by the poor specificity of prostate-specific antigen (PSA)-based screening. Cell-free DNA (cfDNA) fragmentomics offers a promising non-invasive approach to improve screening accuracy and risk stratification. In this study, we enrolled 106 prostate cancer patients and 114 high-risk non-cancer individuals to develop a cfDNA fragmentomics-based screening assay using plasma whole-genome sequencing. Two fragmentomic features-copy number variation and fragment size profile-were incorporated into machine learning models for training and evaluated in an independent validation cohort of 83 cancer patients and 76 non-cancer individuals. The fragmentomics-based model achieved an area under the curve (AUC) of 0.933 in the training cohort (66.0% sensitivity at 95.6% specificity; 51.9% sensitivity at 98.2% specificity) with good calibration (slope: 0.957; intercept: 0.001), and maintained strong performance in the validation cohort (AUC: 0.887; 57.8% sensitivity at 92.1% specificity), showing rising predictive probabilities and sensitivity across advancing stages (Stage I-IV: 27.3% to 77.8%). Importantly, the model performed well in the PSA grey zone (4-10 ng/mL) with an AUC of 0.865 (69.0% sensitivity at 81.8% specificity). When integrated with total PSA levels, the combined algorithm achieved an AUC of 0.915 in the validation cohort and improved sensitivity at 98% specificity (Stage I-IV: 30.0% to 87.5%). These findings support the clinical potential of our cfDNA fragmentomic assay, particularly when combined with PSA, as a highly accurate and non-invasive tool for early prostate cancer detection.

Keywords: Cell-free DNA; Early detection; Fragmentomics; Prostate cancer

DOI: https://doi.org/10.1186/s12964-025-02522-3

Clin Chem. 2025 Dec 02. pii: hvaf163. [Epub ahead of print]

Impact of Clinical Variables on cfDNA Fragmentomic Signatures and Their Potential as Confounders in Cancer Detection.

Tae-Rim Lee, Eun Hye Cho, Jin Mo Ahn, Junnam Lee, Chang-Seok Ki, Byeong-Ho Jeong, Min-Jung Kwon, Eun-Hae Cho.

BACKGROUND: Circulating cell-free DNA (cfDNA) fragmentomic features, such as fragment size and end motifs, have emerged as promising noninvasive biomarkers for cancer detection. However, the influence of nonmalignant clinical factors on these features remains unclear, potentially confounding liquid biopsy assays.
METHODS: We analyzed cfDNA fragmentomic data from 1154 noncancerous individuals undergoing routine health checkups. Three cfDNA features were examined: cfDNA concentration, short fragment ratio (SFR), and cancer-enriched motif (CEM) frequency. Associations with 65 demographic, hematologic, and biochemical variables were assessed using univariate and multivariate analyses. High-resolution correlation mapping of fragment size (110 to 230 bp) and 4-mer end motifs was performed. Patterns were compared with profiles from 283 lung cancer patients, and confounding effects were evaluated using receiver operating characteristic (ROC) analysis.
RESULTS: Multiple nonmalignant variables significantly correlated with cfDNA features. Age was associated with all three features, while liver function markers (aspartate aminotransferase [AST], alkaline phosphatase [ALP], γ-glutamyl transferase [γ-GTP]) showed strong associations with SFR and CEM frequency. High-resolution analyses revealed that AST-related fragment size profiles closely resembled cancer-associated patterns, whereas age showed partial similarity to cancer-associated end motif alterations. ROC analyses demonstrated that elevated AST or older age reduced the discriminative performance of SFR and CEM, indicating their potential as confounders in lung cancer detection.
CONCLUSIONS: Physiological factors such as liver enzyme levels and age can significantly alter cfDNA fragmentomic profiles, generating patterns that resemble lung cancer-associated signals. These results highlight the importance of incorporating strategies to mitigate nonmalignant variability when developing cfDNA-based liquid biopsy assays, to ensure their accuracy, specificity, and clinical applicability.

DOI: https://doi.org/10.1093/clinchem/hvaf163