bims-tumhet 2025-10-05 papers

Issue of 2025–10–05
ten papers selected by
Sergio Marchini, Humanitas Research

Brief Bioinform. 2025 Aug 31. pii: bbaf514. [Epub ahead of print]26(5):

Benchmarking copy number variation detection with low-coverage whole-genome sequencing.

Nan Wang, Zi-Yu Tao, Tao Wu, Jinyu Wang, Weiliang Wang, Huaqiu Shi, Xue-Song Liu.

Low-coverage whole-genome sequencing (lcWGS) provides a cost-effective method for genome-wide copy number variation (CNV) profiling, yet its technical limitations and analytical variability require systematic evaluation. We benchmarked five CNV detection tools using simulated and real-world datasets, focusing on sequencing depth, formalin-fixed paraffin-embedded (FFPE) artifacts, tumor purity, multi-center reproducibility, and signature-level stability. Our results demonstrate that ichorCNA outperformed other tools in precision and runtime at high purity (≥50%), making it the optimal choice for lcWGS-based workflows. Prolonged FFPE fixation induced artifactual short-segment CNVs due to formalin-driven DNA fragmentation, a bias none of the tools could computationally correct, necessitating strict fixation time control or prioritization of fresh-frozen samples. Multi-center analysis revealed high reproducibility for the same tool across sequencing facilities, but comparisons between different tools showed low concordance. Copy number features extracted by the Wang et al. method exhibited superior stability across conditions compared with the Steele et al. method and the Tao et al. method. This study establishes actionable guidelines for lcWGS: prioritize ichorCNA (ensuring ≥50% tumor purity), optimize FFPE protocol, and use Wang et al. features to ensure robust copy number profiling in precision oncology.

Keywords: CNV detection; FFPE; benchmark; copy number signature; lcWGS; tumor purity

DOI: https://doi.org/10.1093/bib/bbaf514

medRxiv. 2025 Sep 22. pii: 2025.09.17.25335919. [Epub ahead of print]

Beyond BRCA deficiency: Clinical and molecular predictors of survival in patients with BRCA -deficient tubo-ovarian high-grade serous carcinoma.

Tibor A Zwimpfer, Sian Fereday, Ahwan Pandey, Dinuka Ariyaratne, Madawa W Jayawardana, Laura Twomey, Céline M Laumont, Catherine J Kennedy, Adelyn Bolithon, Nicola S Meagher, Katy Milne, Phineas Hamilton, Jennifer Alsop, Antonis C Antoniou, George Au-Yeung, Matthias W Beckmann, Amy Berrington de Gonzalez, Christiani Bisinotto, Freya Blome, Clara Bodelon, Jessica Boros, Alison H Brand, Michael E Carney, Alicia Cazorla-Jiménez, Derek S Chiu, Elizabeth L Christie, Anita Chudecka-Głaz, Penny Coulson, Kara L Cushing-Haugen, Cezary Cybulski, Kathleen M Darcy, Cath David, Trent Davidson, Arif B Ekici, Esther Elishaev, Julius Emons, Tobias Engler, Rhonda Farrell, Anna Fischer, Montserrat García-Closas, Aleksandra Gentry-Maharaj, Prafull Ghatage, Rosalind Glasspool, Philipp Harter, Andreas D Hartkopf, Arndt Hartmann, Sebastian Heikaus, Brenda Y Hernandez, Anusha Hettiaratchi, Sabine Heublein, David G Huntsman, Mercedes Jimenez-Linan, Michael E Jones, Eunyoung Kang, Ewa Kaznowska, Tomasz Kluz, Felix K F Kommoss, Gottfried Konecny, Roy F P M Kruitwagen, Jessica Kwon, Diether Lambrechts, Cheng-Han Lee, Jenny Lester, Samuel C Y Leung, Yee Leung, Anna Linder, Jolanta Lissowska, Liselore Loverix, Jan Lubiński, Constantina Mateoiu, Iain A McNeish, Malak Moubarak, Gregg S Nelson, Nikilyn Nevins, Alexander B Olawaiye, Siel Olbrecht, Sandra Orsulic, Ana Osorio, Carmel M Quinn, Ganendra Raj Mohan, Isabelle Ray-Coquard, Cristina Rodríguez-Antona, Patricia Roxburgh, Matthias Ruebner, Stuart G Salfinger, Spinder Samra, Minouk J Schoemaker, Hans-Peter Sinn, Gabe S Sonke, Linda Steele, Colin J R Stewart, Aline Talhouk, Adeline Tan, Christopher M Tarney, Sarah E Taylor, Koen K Van de Vijver, Maaike A van der Aa, Toon Van Gorp, Els Van Nieuwenhuysen, Lilian van-Wagensveld, Andrea E Wahner-Hendrickson, Christina Walter, Chen Wang, Julia Welz, Nicolas Wentzensen, Lynne R Wilkens, Stacey J Winham, Boris Winterhoff, Michael S Anglesio, Andrew Berchuck, Francisco J Candido Dos Reis, Paul A Cohen, Thomas P Conrads, Philip Crowe, Jennifer A Doherty, Peter A Fasching, Renée T Fortner, María J García, Simon A Gayther, Marc T Goodman, Jacek Gronwald, Holly R Harris, Florian Heitz, Hugo M Horlings, Beth Y Karlan, Linda E Kelemen, G Larry Maxwell, Usha Menon, Francesmary Modugno, Susan L Neuhausen, Joellen M Schildkraut, Annette Staebler, Karin Sundfeldt, Anthony J Swerdlow, Ignace Vergote, Anna H Wu, James D Brenton, Paul D P Pharoah, Celeste Leigh Pearce, Malcolm C Pike, Ellen L Goode, Susan J Ramus, Martin Köbel, Brad H Nelson, Anna DeFazio, Michael L Friedlander, David D L Bowtell, Dale W Garsed.

BRCA -associated homologous recombination deficiency (HRD) is present in ∼50% of high-grade serous carcinomas (HGSC) and predicts sensitivity to platinum-based therapy. However, there is little understanding of why some patients with BRCA -deficient tumors experience unexpectedly poor outcomes. We profiled 154 tumors, enriched for patients with BRCA -deficient tumors that experienced short overall survival (≤3 years, n=42), using whole-genome, transcriptome, and methylation analyses. All but one BRCA -deficient tumor exceeded an accepted HRD genomic scarring threshold. However, patients with BRCA1 -deficient HGSC with a more elevated HRD score survived significantly longer. Patients with BRCA2 -deficient HGSC and loss of NF1 survived twice as long as those without NF1 loss, whereas PIK3CA or RAD21 amplification defined BRCA2 -deficient HGSC with exceptionally short survival. BRCA1 -deficient tumors in short survivors had evidence of immunosuppressive c-kit signaling and EMT. In a large HGSC cohort (n=1,389) including 282 individuals with pathogenic germline BRCA variants (g BRCA pv), the location of the mutation within functional domains stratified clinical outcomes. Notably, residual disease after primary surgery had limited prognostic effect in g BRCA pv-carriers compared to non-carriers. Our findings indicate that tumor HR proficiency in the context of therapy response and survival is not a binary property, and highlight genomic and immune modifiers of outcomes in BRCA -deficient HGSC.

DOI: https://doi.org/10.1101/2025.09.17.25335919

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

Curr Issues Mol Biol. 2025 Sep 05. pii: 726. [Epub ahead of print]47(9):

Tumor Immune Microenvironment and Checkpoint Inhibition in Clear Cell Ovarian Carcinoma: Bridging Tumor Biology and Clinical Application in Immunotherapy.

Fulvio Borella, Giulia Capella, Stefano Cosma, Niccolò Gallio, Federica Gavello, Alberto Revelli, Domenico Ferraioli, Jessica Cusato, Isabella Castellano, Paola Cassoni, Luca Bertero.

Clear cell ovarian carcinoma is a rare and aggressive histologic subtype of epithelial ovarian cancer, characterized by a chemoresistant phenotype and distinct immunogenomic features. Despite early-phase trials showing a limited response to immune checkpoint inhibitors (ICIs), emerging evidence reveals a biologically diverse tumor immune microenvironment, with implications for the efficacy of immunotherapies. Preclinical studies highlight paradoxical associations between immune infiltration and prognosis, as well as genomic drivers-including KRAS, MYC, PI3KCA, TP53, PTEN, and ARID1A-that shape immune evasion and checkpoint ligand expression. Clinically, ICI monotherapy yields modest benefit, while combination regimens-particularly dual checkpoint blockade and targeted co-inhibition-offer improved outcomes. Biomarkers such as PD-L1 CPS ≥ 1%, ARID1A mutations, elevated tumor mutational burden, and PIK3CA alterations emerge as promising predictors of therapeutic response. This review integrates current preclinical and clinical data to propose a precision immunotherapy framework tailored to the immunogenomic landscape of clear cell ovarian carcinoma.

Keywords: clear cell; immunotherapy; ovarian cancer; ovarian clear cell cancer

DOI: https://doi.org/10.3390/cimb47090726

Cell Rep. 2025 Sep 25. pii: S2211-1247(25)01114-3. [Epub ahead of print]44(10): 116343

Landscape of extrachromosomal DNA characteristics in high-grade serous ovarian cancer via long-read sequencing.

Ruoming Sun, Zongkai Li, Yi Liu, Yanbing Hou, Bowen Zhao, Chunpeng Chen, Jingwen Fang, Chuang Guo, Ying Zhou, Kun Qu, Shouzhen Li.

The non-Mendelian inheritance of extrachromosomal DNA (ecDNA) exacerbates tumor genomic heterogeneity and evolution. Due to short-read sequencing's reconstruction deficiencies, ecDNA abundance in clinical tumor tissues requires further estimation, and the mechanisms driving tumor evolution remain underexplored. Here, we perform long-read whole-genome sequencing on primary and paired metastatic tumor tissues from 12 patients with high-grade serous ovarian cancer (HGSOC) and 6 normal tubal tissues, constructing a comprehensive ecDNA profile. In HGSOC, ecDNA exhibits significantly greater genomic instability and lower methylation than chromosomal DNA. Beyond oncogene and immunomodulatory gene amplification, ecDNA amplifies extensive enhancers to promote gene expression via mechanisms including enhancer hijacking and mobile enhancers. Notably, we observe activation of transposable elements on hypomethylated ecDNA, which is strongly correlated with epithelial-mesenchymal transition gene expression and poor clinical outcomes. These findings reveal ecDNA as a multifunctional driver of genomic variations and tumor progression in HGSOC, highlighting its therapeutic potential.

Keywords: CP: Cancer; CP: Genomics; HGSOC; ecDNA; enhancer; genomic instability; long-read sequencing; transposon

DOI: https://doi.org/10.1016/j.celrep.2025.116343

Cancer Immunol Immunother. 2025 Sep 29. 74(10): 313

Dynamic remodeling of tertiary lymphoid structures in response to cancer therapy: a recent review.

Chongyu Tan, Jinliang Huang, Ning Gao, Bingquan Wu, Matsika Juliet, Jiatong Xiao, Jiao Hu, Ping Liu, Jinbo Chen.

Tertiary lymphoid structures (TLSs) in the tumor microenvironment (TME) act as local hubs for antigen presentation and lymphocyte activation, reinforcing antitumor immunity. They act as ectopic, lymph node-like niches that orchestrate local antitumor immunity through well-defined B-cell follicles, T-cell zones, follicular dendritic cells (FDCs), and high endothelial venules (HEVs). Although various cancer treatment methods can impact TLSs, thereby changing the state of the TME, the dynamic changes in TLSs caused by treatment and the mechanisms therein have not been comprehensively summarized to date. This review highlights the mechanisms of different cancer treatment effects on TLSs dynamic change, including the number and functionality of TLSs within tumors. We also summarize the value of TLSs in predicting prognosis and therapeutic effect, as well as the deficiencies in current research and future development directions.

Keywords: Chemotherapy; Combination therapies; Immunotherapy; Radiotherapy; Tertiary lymphoid structures; Viral therapy

DOI: https://doi.org/10.1007/s00262-025-04183-0

Nat Rev Genet. 2025 Sep 30.

Spatial architecture of development and disease.

Enikő Lázár, Joakim Lundeberg.

Tissue architecture is a product of a multilayered molecular landscape, where even subtle disruptions in the spatial context can initiate or reflect disease processes. Recent advances in high-throughput spatial omics technologies have enabled the investigation of this complexity in stunning detail, providing groundbreaking insights into how spatial molecular organization shapes health and disease. Spatial analysis empowers the discovery of developmental and disease-associated molecular signatures, cell states and multicellular niches, as well as the evaluation of disease heterogeneity within and across organs. This Review examines spatially resolved pathological molecular alterations in a wide range of disease processes, such as developmental disorders, tumorigenesis, fibrosis and injury responses, neurodegeneration, infection and inflammation, through the lens of these universal biological frameworks. We discuss challenges, opportunities and promising examples in advancing these technologies to clinical applications, including the increasing importance of artificial intelligence. Finally, we explore possible avenues for a more comprehensive, multidimensional assessment of tissues.

DOI: https://doi.org/10.1038/s41576-025-00892-5

Theranostics. 2025 ;15(18): 9459-9485

Dissecting Tertiary Lymphoid Structures in Cancer: Maturation, Localization and Density.

Guang-Liang Su, Meng-Jie Zhang, Hao Li, Zhi-Jun Sun.

Tertiary lymphoid structures (TLSs) refer to ectopic lymphoid aggregates that form in non-lymphoid tissues at sites of chronic inflammation including cancers. TLSs have been recognized as significant predictors of the efficacy of immune checkpoint blockade (ICB) therapies and have the potential to elicit robust anti-tumor immune response. However, recent studies have revealed substantial heterogeneity in TLSs across different individuals and cancer types, which directly impacts the effectiveness of anti-tumor immunity. Concretely, the maturation status, localization, and density of TLSs profoundly influence the dynamic interactions among immune cells within these structures, potentially leading to adverse effects. This review provides an in-depth exploration of how the heterogeneity of TLSs influences cellular composition and immune dynamics, with the objective of influencing the efficacy of ICB therapies and modulating prognostic prediction accuracy. Additionally, the potential of combining TLSs with other biomarkers for predicting anti-tumor immunity outcomes is further investigated, alongside the introduction of advanced technologies for evaluating TLS heterogeneity. Collectively, these analyses aim to advance the understanding of TLS heterogeneity and facilitate its translation into clinical and translational medicine applications.

Keywords: Density; Heterogeneity; Localization; Maturation; Tertiary lymphoid structures

DOI: https://doi.org/10.7150/thno.113940

Cancer Cell. 2025 Oct 02. pii: S1535-6108(25)00367-8. [Epub ahead of print]

Bringing immunotherapy to clinical practice in dMMR/MSI-high colon cancer.

Giovanni Randon, Isacco Montroni, Filippo Pietrantonio.

Upfront resection is the standard treatment for localized dMMR/MSI-high colon cancer. In this issue of Cancer Cell, Wang et al. showed that dual anti-CTLA-4/PD-1 IBI310/sintilimab for 6 weeks improved pathological complete response over sintilimab in patients with cT4/N+ tumors. This combination represents a referral regimen for neoadjuvant or organ-preserving strategies.

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