bims-tumhet 2026-10-11 papers

Issue of 2026–10–11
seven papers selected by
Sergio Marchini, Humanitas Research

Epigenomics. 2026 Oct 03. 1-13

Cell-free DNA fragmentomics: from chromatin biology to clinical stratification.

Tien-Dung Bui, Minh-Thu Phung, Teh-Ying Chou, Nguyen Quoc Khanh Le.

Plasma cell-free DNA (cfDNA) is fragmented nonrandomly, reflecting the chromatin architecture of its source cells and the nucleases that process it. The fragmentome can therefore provide an indirect readout of cellular regulatory state. This review examines how DNA methylation, chromatin accessibility, nucleosome positioning, protein occupancy, and nuclease activity shape cfDNA fragmentation and considers their implications for oncology. We organize fragmentomic measurements into four classes: coverage and protection, fragment size, fragment-end properties, and diversity and entropy metrics. We discuss the genomic contexts in which these features are informative, including repetitive and transposable elements, and compare platforms by sequencing requirements, feature portability, and the fragment populations captured by different library chemistries. We then review applications in cancer screening, tissue-of-origin inference, molecular subtyping, prognosis, minimal residual disease detection, and treatment response monitoring. A central challenge for clinical translation is attributing fragmentomic changes to their tissue of origin.

Keywords: Cell-free DNA; cancer detection; chromatin accessibility; circulating tumor DNA; end motif; fragmentomics; liquid biopsy; nucleosome positioning

DOI: https://doi.org/10.1080/17501911.2026.2740396

Cancer Gene Ther. 2026 Oct 08.

Whole-genome DNA methylation analysis reveals distinct subtype characteristics in epithelial ovarian cancer.

Qiaoling Ren, Yingqing Deng, Caizhou Zhong, Dongmei Zhou, Renci Liu, Xiujie Sheng, Deqiang Sun.

Epithelial ovarian cancer (EOC) is characterized by high mortality, insidious onset, and pronounced heterogeneity, underscoring the critical need for effective biomarkers for early detection and subtype-specific diagnosis. While DNA methylation represents a stable epigenetic marker, prior studies have largely relied on profiling techniques with limited genomic coverage and have often overlooked subtype-specific differences essential for guiding treatment decisions. To address this, we performed whole-genome bisulfite sequencing on 44 normal ovarian tissues and 89 EOC tissues encompassing all five histological subtypes, integrated with transcriptome sequencing, to comprehensively evaluate the diagnostic and prognostic utility of DNA methylation across EOC subtypes. Our analyses revealed that genome-wide methylation profiles effectively distinguished normal from tumor tissues and captured the substantial heterogeneity inherent to EOC. Differentially methylated regions (DMRs) and differentially expressed genes were enriched in immune-related processes and epithelial differentiation, aligning with the increased proportions of epithelial and immune cells identified through deconvolution analysis. Subtype-specific DMRs further implicated hormonal pathways in endometrioid (EC) and clear cell (CCOC) carcinomas, and linked mucinous ovarian cancer (MOC) to fluid regulation. Integrative analysis of DMRs and cellular composition indicated that epithelial cells in high-grade serous (HG), low-grade serous (LG), and EC tumors most closely resembled fallopian tube, ovarian, and endometrial epithelial cells, respectively, whereas MOC and CCOC epithelial cells showed similarity to gastrointestinal and renal epithelia. Moreover, weighted gene co-expression network analysis identified epithelia-associated DMRs that achieved up to 90% specificity for subtype classification in internal validation and demonstrated prognostic relevance in independent public datasets. In conclusion, the subtype-specific DNA methylation markers identified in this study accurately reflect the distinct histological features of each EOC subtype and hold promise for application in subtype classification and prognosis prediction, thereby providing a scientific foundation for future clinical interventions in EOC.

DOI: https://doi.org/10.1038/s41417-026-01079-8

Cell Rep Med. 2026 Oct 08. pii: S2666-3791(26)00519-7. [Epub ahead of print] 103102

Prognostic value of cfDNA methylation in locally advanced esophageal squamous cell cancer treated with neoadjuvant immunochemoradiotherapy.

Baoqing Chen, Zimeng Li, Yin Li, Xingyuan Cheng, Wendi Xuzhang, Ruixi Wang, Yilu Gao, Peiying Cen, Chen Yi, Lirong Tian, Guangkuo Wei, Zhengyang Li, Bingzhong Jing, Shuchun Wang, Qiaoqiao Li, Hong Yang, Huiyan Luo, Mian Xi.

We prospectively evaluated whether longitudinal cfDNA methylation predicts pathological complete response (pCR) and survival in 70 patients with esophageal squamous cell carcinoma (ESCC) receiving neoadjuvant immunochemoradiotherapy. Serial plasma samples (n = 183) were collected at four time points: pre-neoadjuvant treatment (NAT), post-NAT, pre-surgery, and post-surgery. Targeted whole-genome cfDNA methylation sequencing was performed, and cancer detection (CD) values were calculated with positivity, defined as CD ≥ 0.7. CD positivity dropped from 74% pre-NAT to 31% post-NAT (p < 0.001). Pre-surgery CD positivity was significantly higher in non-pCR versus pCR patients (33% vs. 0%; p = 0.028). A model incorporating post-NAT CD value and clinical factors achieved an area under the curve (AUC) of 0.764 for pCR. Post-NAT CD-negative patients had significantly improved disease-free survival (DFS; hazard ratio [HR] = 0.33; p = 0.035). Findings were reproduced in an expanded 30-patient cohort. Dynamic cfDNA methylation monitoring is associated with pCR and DFS, warranting further validation in larger cohorts.

Keywords: GM-seq; cancer detection status; cell-free DNA methylation; esophageal squamous cell cancer; liquid biopsy; longitudinal monitoring; neoadjuvant immunochemoradiotherapy; pathological complete response; prognosis

DOI: https://doi.org/10.1016/j.xcrm.2026.103102

OMICS. 2026 Oct 07. 15578100261495840

Genomic Amplification of CCNE1 Is Associated with an Immunosuppressive Tumor Microenvironment and Adverse Clinical Outcome in High-Grade Serous Ovarian Cancer.

Annapurna Vadaparty, Durgadevi Veeraiyan, Guruguhan Sivakumar, Soumyabrata Roy, Akhileshwar Namani, Tapas Patra.

High-grade serous ovarian cancer (HGSOC) is the most lethal gynecological malignancy, with a poor 5-year survival rate. Many patients also experience relapse of the disease due to chemotherapy resistance, highlighting an urgent need for new therapeutic modalities. Among the genomic alterations implicated in HGSOC progression, amplification of cyclin E1 (CCNE1) has emerged as a frequent and clinically significant event, occurring in ∼19% of cases. In this hypothesis-generating study, we explore the prognostic relevance of CCNE1 amplification, focusing on its role in shaping the tumor microenvironment (TME). We conducted an in silico analysis utilizing exome sequencing, clinical, and transcriptome data from HGSOC patients available in The Cancer Genome Atlas. CCNE1 amplification correlates with significantly reduced overall and disease-free survival in HGSOC patients. Differential gene expression and pathway analyses predicted that CCNE1-amplified tumors associate with replication stress, elevated mitotic activity, and increased chromosomal instability. Importantly, these tumors showed a predicted reprogrammed immune landscape, characterized by elevated stromal content, increased infiltration of M2 macrophages, myeloid-derived suppressor cells, and cancer-associated fibroblasts, alongside reduced expression of antigen-presenting machinery, particularly Human Leukocyte Antigen (HLA) class II genes. Further analysis highlighted a strong association between replication stress and upregulation of Transforming Growth Factor-beta (TGF-β) signaling pathways, which likely contribute to the observed immunosuppressive microenvironment. Together, our data suggested that CCNE1 amplification is associated with tumor progression not only through enhanced proliferation but also by adopting an immune-suppressive TME. These observations suggest the potential of targeting the TME or replication stress response pathways in CCNE1-amplified HGSOC as a therapeutic strategy to improve patient outcomes.

Keywords: M2 macrophages; cyclin E1; high-grade serous ovarian cancer; myeloid-derived suppressor cells; tumor microenvironment

DOI: https://doi.org/10.1177/15578100261495840

Nature. 2026 Oct 05.

The top cancer success stories of the past 50 years, by the numbers.

Heidi Ledford.

Keywords: Cancer; Epidemiology; Medical research

DOI: https://doi.org/10.1038/d41586-026-03157-1

Ann Oncol. 2026 Oct 08. pii: S0923-7534(26)06781-5. [Epub ahead of print]

Sofetabart mipitecan, an antibody drug conjugate targeting folate receptor alpha, in high grade ovarian cancer: Results from the first-in-human phase 1 study.

BACKGROUND: Folate receptor alpha (FRα) is overexpressed in most high-grade ovarian cancers (HGOC), but use of the FRα-targeting drug mirvetuximab soravtansine-gynx (MIRV) is limited by expression-level restrictions and toxicity profile. Sofetabart mipitecan (Sofe-M) is a novel FRα-targeting antibody-drug conjugate designed to overcome these barriers. Here we report safety, efficacy, and pharmacokinetics from the first-in-human phase 1 study.
PATIENTS AND METHODS: This multicenter, open-label, phase 1 trial evaluated Sofe-M in patients with HGOC, regardless of FRα expression level. Prior MIRV treatment was permitted.
RESULTS: One-hundred-five patients with HGOC, the majority of whom were platinum resistant, received Sofe-M at 2, 3, 4 or 6 mg/kg every 21 days. Median age was 63.0 years, median number of prior treatments was 5.0 (1-11), 19 (18.1%) patients had prior MIRV, and 54 (51.4%) had tumor FRα expression <75% at ≥2+ intensity. Overall response rate was 50.5% (95% CI 40.5, 60.4) for all patients, 58.8% (95% CI 32.9, 81.6) at 3 mg/kg, 44.4% (95% CI 30.9, 58.6) for FRα <75%, 56.5% (95% CI, 41.1, 71.1) for FRα ≥75%, and 57.9% (95% CI 33.5, 79.7) for patients with prior MIRV exposure. Median progression-free survival was 8.1 months (95% CI 6.4, 8.5) and median follow-up was 12.9 months (95% CI 10.6, 15.2). Most common treatment-emergent adverse events (TEAEs) were nausea (64.8%), fatigue (56.2%), and anemia (47.6%). No keratopathies or grade ≥3 neuropathy were observed. At 3 and 4 mg/kg, the rate of Grade ≥3 treatment-related TEAEs was 35.3% and 56.4%, respectively. Treatment discontinuation due to TEAEs occurred in 11 patients (10.5%).
CONCLUSIONS: Sofe-M demonstrated a favorable tolerability profile, notably absent of keratopathy and high-grade neuropathy, with durable clinical activity in heavily pretreated HGOC patients regardless of FRα expression level or prior MIRV. These data support 3 mg/kg as the recommended phase 3 dose and provide the basis for the FRAmework-01 trial.
CLINICAL TRIAL REGISTRATION NUMBER: Phase 1 (NCT06400472); FRAmework-01 (NCT07213804).

Keywords: antibody drug conjugate; folate receptor alpha; high grade ovarian cancer; phase 1; platinum-resistant

DOI: https://doi.org/10.1016/j.annonc.2026.10.001