bims-fragic 2026-01-25 papers

Issue of 2026–01–25
four papers selected by
Laura Mannarino, Humanitas Research

Adv Sci (Weinh). 2026 Jan 22. e14819

Cancer-Like Fragmentomic Characteristics of Somatic Variants in Cell-Free DNA.

Zhenyu Zhang, Yunyun An, Mengqi Yang, Yuqi Pan, Xiaoyi Liu, Fanglei Gong, Huizhen Lin, Bianbian Tang, Yunxia Bai, Xin Zhao, Yu Zhao, Changzheng Du, Kun Sun.

Cell-free DNA (cfDNA) in plasma consists of short DNA fragments resulting from a non-random fragmentation process, with distinct fragmentomic characteristics that are related with their cellular origins. Here, we report that somatic variant signatures in cfDNA markedly differ between non-cancerous controls and cancer patients, indicating that tumor-associated signals are retained in these variants. Surprisingly, even in controls, cfDNA molecules harboring somatic variants exhibit cancer-like fragmentomic characteristics, such as reduced size, decreased DNA methylation, and altered end motif usages and distributions in the nucleosome structure. Further investigations suggest that such cancer-like traits are associated with somatic variants derived from clonal hematopoiesis. Importantly, these somatic variants-associated fragmentomic aberrations are more pronounced in cancer patients, enabling cancer diagnosis. In a large pan-cancer cohort, we utilize AI to integrate genomic, fragmentomic, and epigenomic features to develop diagnostic models named FreeSV and FreeSV+. Leveraging somatic variant-associated features alone, the FreeSV model achieved area under the ROC curves (AUCs) between 0.81-0.92 across cancer types; however, when genomewide features are also included, the AUCs of FreeSV+ model substantially increased to 0.93-0.99 across cancer types, highlighting the significance of integrative genomic and fragmentomic analyses in cfDNA for cancer liquid biopsy.

Keywords: artificial intelligence; cancer diagnosis; end motif; epigenomics; liquid biopsy

DOI: https://doi.org/10.1002/advs.202514819

J Liq Biopsy. 2026 Mar;11 100455

End-repair causes methylation underestimation in cell-free DNA sequencing libraries.

Tobin E Groth, Andrew A Mishin, Varsha Rao, Ruby Tibet, Christopher J Troll.

Cell-free DNA methylation sequencing provides insight into tissue of origin and chromatin structure. In some workflows, generating libraries includes end-repair. Using matched single-stranded and double-stranded libraries prepared from the same cfDNA extracts, we show that end-repair in double-stranded DNA libraries reduces globally inferred CpG methylation leading to decreased tissue of origin accuracy. Trimming read termini partially mitigates this bias but decreases coverage and removes fragmentomic information compared to single-stranded DNA libraries, which forego end-repair.

Keywords: Cell-free DNA (cfDNA); Double-stranded DNA (dsDNA) library preparation; End-repair; Fragmentomics; Methylation sequencing; Nucleosome positioning; Single-stranded DNA (ssDNA) library preparation; Tissue of origin (TOO)

DOI: https://doi.org/10.1016/j.jlb.2026.100455

Endocrine. 2026 Jan 19. 91(1): 38

Utility of Cell-Free DNA integrity index in differentiating malignant from benign lesions in indeterminate thyroid nodules.

Soham Tarafdar, Susmita Dutta, Nitai P Bhattacharyya, Pradip Mukhopadhyay, Sujoy Ghosh.

Keywords: Cell-free DNA; CfDNA integrity index; Differentiated thyroid cancer; Indeterminate cytology; Thyroid nodules

DOI: https://doi.org/10.1007/s12020-025-04546-8

Adv Sci (Weinh). 2026 Jan 20. e20383

Cell-Free DNA-Based Theranostics for Inflammatory Disorders.

Jiatong Li, Yumei Wang, Xiaoxi Fan, Miao Xu, Jiawen Li, Wenfei Tan, Jianxiang Zhang, Heran Li.

Inflammatory disorders are characterized by immune-mediated inflammatory cascades that can affect multiple organs. Cell-free DNA (cfDNA) is not only a biomarker for various inflammatory diseases, but also a driver in innate immune responses, offering emerging diagnostic and therapeutic possibilities for inflammatory diseases. This review begins by examining immune signatures in inflammation, with particular focus on the vicious cycle between cfDNA and inflammatory responses. We then discuss cfDNA detection strategies and their clinical applications as disease biomarkers. Crucially, we highlight design principles and formulation strategies for cfDNA-based interventions for inflammation regulation, considering physical, biochemical, and immunological properties of cfDNA. These approaches encompass advanced nanotechnologies such as drug loading, targeted delivery, inflammation-responsive release, and microenvironment reprogramming. Subsequently, we examine cfDNA intervention strategies for precision treatment of inflammatory diseases, including inflammatory bowel diseases, rheumatoid arthritis, sepsis, periodontitis, and psoriasis. Finally, we present key insights and future perspectives, as well as discuss translational challenges and clinical considerations, thereby paving the way for innovative approaches to inflammation modulation and disease management.

Keywords: cGAS‐STING pathway; cell‐free DNA; inflammation; inflammatory disorders; toll‐like receptors

DOI: https://doi.org/10.1002/advs.202520383