bims-fragic 2025-10-05 papers

Issue of 2025–10–05
three papers selected by
Laura Mannarino, Humanitas Research

Clin Epigenetics. 2025 Oct 03. 17(1): 163

Seminal plasma cfDNA fragmentomics landscape delineates male infertility subtypes.

Xiaoyu Wu, Fan Meng, Huiping Zhang, Zeqing Li, Kai Zhao.

BACKGROUND: While cell-free DNA (cfDNA) fragmentomics has transformed liquid biopsy applications in prenatal screening and oncology, its potential in male reproductive health remains unexplored.
METHODS: Through integrated whole-genome sequencing and jagged end sequencing (Jag-Seq) coupled with non-CG(CH) methylation analysis, we established the first fragmentomic atlas of seminal plasma (SP) cfDNA from 18 healthy donors, with 20 plasma cfDNA samples. This approach was then applied to 33 patients (14 with varicocele [VC] and 19 with nonobstructive azoospermia [NOA]) to characterize disease-specific fragmentomic features. ROC analysis was employed to study the potential diagnostic ability for these two diseases.
RESULTS: Size distribution profiling showed SP cfDNA enrichment in short fragments (< 150 bp) with bimodal distribution (151 bp main peak/110 bp subpeak), contrasting with plasma's sharp 166-bp peak pattern ( P<0.001 ). Motif analysis identified SP-specific patterns: increased AAAA-end motif frequency and a strong A-base preference at positions - 2 to - 4. SP showed higher jagged end index based on Jag-Seq ( P<0.0001 ). In disease states, VC exhibited 7 altered frequency motifs and longer jagged end length, while NOA demonstrated higher methylation level at CH sites. Integrating these fragmentomic features, ROC analysis achieved 83% accuracy in distinguishing VC and 87% accuracy in distinguishing NOA.
CONCLUSIONS: The study indicates that distinct cfDNA profiles are present in certain male infertility conditions. These cfDNA metrics demonstrated disease-specific cfDNA dynamics present innovative opportunities for the development of noninvasive diagnostic tools in the field of reproductive medicine.

Keywords: Cell-free DNA; Fragmentomics; Male infertility

DOI: https://doi.org/10.1186/s13148-025-01973-2

Cancer Cell. 2025 Oct 02. pii: S1535-6108(25)00398-8. [Epub ahead of print]

Cell-free DNA fragmentomics in cancer.

W H Adrian Tsui, Peiyong Jiang, Y M Dennis Lo.

The analysis of cell-free DNA (cfDNA) fragmentation patterns, known as "fragmentomics," has opened new opportunities in noninvasive cancer diagnostics. Due to its close relationships with genomic organization and cell death, cfDNA fragmentomics lies at the intersection of many aspects of cancer biology, including epigenetic dysregulation, transcriptomic alterations, and aberrant cellular turnover patterns. Recent advances in library preparation, sequencing technologies, and integrative epigenomic-fragmentomic analyses have uncovered novel fragmentomic features that reveal specific cellular dysfunctions in cancer. Additionally, cutting-edge artificial intelligence algorithms now harness high-dimensional fragmentomic features, boosting the precision and power of cancer detection. Promising results from recent clinical trials evaluating the utility of fragmentomic analyses in real-world settings support its potential. In this review, we explore the exciting frontiers of cfDNA fragmentomics, discuss critical unanswered questions, and highlight future directions to unlock the promise of fragmentomics-based liquid biopsies in cancer care.

Keywords: artificial intelligence; cancer detection; cancer risk prediction; cancer treatment monitoring; cell-free DNA; fragmentomics; machine learning

DOI: https://doi.org/10.1016/j.ccell.2025.09.006

J Mol Diagn. 2025 Sep 26. pii: S1525-1578(25)00222-3. [Epub ahead of print]

Analysis of the Fragmentation and Integrity of Urine Cell-Free DNA as Diagnostic and Staging Biomarker for Bladder Cancer.

Raquel Herranz, Julia Oto, Emma Plana, Javier Pérez-Ardavín, Patricia Verger, Manuel Martínez-Sarmiento, César D Vera-Donoso, Pilar Medina.

Bladder cancer (BC) is a lethal urological malignancy, with current diagnostic and follow-up methods being invasive and costly. Cell-free DNA (cfDNA) in liquid biopsies has shown promise in cancer diagnostics, but its fragmentation and integrity in urine remain underexplored in BC, becoming the aim of this study. cfDNA was isolated from urine of 156 BC patients of most stages and 79 matched controls without renal or bladder conditions. The amount of a large (>250bp) and a nested small (<125pb) fragment of ACTB, AR, MYC, BCAS1 and STOX1 was quantified by quantitative real-time PCR. Fragmentation and integrity (ratio large:small) were analyzed with ordinal logistic regression. The increase in the ratio large:small ACTB fragments and the small fragments of AR and MYC may represent a valuable tool to diagnose and stage BC both when classified as non-muscle-invasive and muscle-invasive BC or considering grades and stages separately. The small fragment of MYC, leading the effect observed, displayed a valuable diagnostic capacity (AUC=0.7221; 95% CI [0.6527, 0.7915]; P<0.0001; Sensitivity=50%; Specificity=95%) particularly for muscle invasive BC (AUC=0.8098; 95% CI [0.6674, 0.9523]; P<0.0001; Sensitivity=70%; Specificity=97%). Herein, the analysis of urine cfDNA fragmentation and integrity of these surrogate markers is proposed as non-invasive biomarkers to diagnose and stage BC. Once validated, the proposed biomarkers could improve patient management by reinforcing or substituting current invasive and expensive techniques.

Keywords: ACTB; AR; MYC; biomarker; bladder cancer; cell-free DNA; fragmentation; integrity; liquid biopsy; urine

DOI: https://doi.org/10.1016/j.jmoldx.2025.08.010