bims-tumhet 2026-05-03 papers

bims-tumhet

Biomed News

on Tumor heterogeneity

Issue of 2026–05–03
seven papers selected by
Sergio Marchini, Humanitas Research

Spatial-aware detection of copy number alterations from spatial transcriptomics using SpaCNA.
The development of ovarian carcinosarcoma from serous tubal intraepithelial carcinoma: an immunohistochemical case report with literature review.
Contemporary risk assessment and risk-reducing strategies for tubo-ovarian cancer in women with BRCA pathogenic variants.
From Genomic Instability to Epigenetic Signatures: The Evolving Landscape of Circulating Cell-free DNA in Metabolic Dysfunction-Associated Steatotic Liver Disease.
Resolving sensitivity, specificity and signal contamination in Xenium spatial transcriptomics.
A potential mutation-defined POLE/MMR/TP53 group classifications to stratify BRCA wild type epithelial ovarian cancer.
Tumor DNA methylation subtypes predict immunotherapy outcomes in pleural mesothelioma patients in the NIBIT-EPI-MESO study.

Nat Commun. 2026 Apr 29.

Spatial-aware detection of copy number alterations from spatial transcriptomics using SpaCNA.

Zihui Zhang, Xiaochen Wang, Hong Xuan, Yan Xu, Zijie Jin, Ruibin Xi.

Spatial transcriptomics (ST) profiles genome-wide gene expression while preserving spatial context, yet accurate detection of copy number alterations (CNAs) in tumor ST data remains challenging. Here, we present SpaCNA, a computational framework that integrates multi-modal information of ST for robust CNA detection. SpaCNA aggregates expression from neighboring spots with similar morphological features and leverages a hidden Markov random field model incorporating spatial continuity for reliable CNA detection in ST datasets. Further, SpaCNA can reconstruct 3D CNA profiles with spatial continuity across consecutive slices when applied to 3D ST datasets. Extensive benchmarking on simulated data and real cancer datasets demonstrates SpaCNA's superior accuracy, achieving up to 0.95 F1-score in CNA detection and tumor region identification. In applications to breast cancer and colorectal cancer, SpaCNA reveals tumor boundaries and spatially distinct subclones with context-dependent interactions within the microenvironment. Notably, SpaCNA performs CNA detection in a 3D ST dataset of head and neck squamous cell carcinoma, revealing the tumor evolution trajectory of three subclones in 3D space. By providing accurate CNA inference, SpaCNA facilitates the analysis of intratumoral heterogeneity and spatial cancer biology.

DOI: https://doi.org/10.1038/s41467-026-72284-0
Front Oncol. 2026 ;16 1727634

The development of ovarian carcinosarcoma from serous tubal intraepithelial carcinoma: an immunohistochemical case report with literature review.

Paula Szlendak, Dorota Lewkowicz, Andrea Romano, Marek Semczuk, Maciej Jóźwik, Andrzej Semczuk.

  Ovarian carcinosarcoma (OCS) is an uncommon and highly aggressive subtype of ovarian carcinoma characterized by the simultaneous occurrence of two malignant components: carcinomatous and sarcomatous. Located at the fimbrial region of the fallopian tube, serous tubal intraepithelial carcinoma (STIC) represents a form of precursor lesion for high-grade serous carcinoma (HGSC). In the current report, we present an intriguing case study of left OCS concomitant with ipsilateral STIC. Immunohistochemical (IHC) assessment showed a similar staining pattern of the carcinomatous OCS component and STIC. In conclusion, the development of OCS from STIC should be considered. Such a situation represents both a rare phenomenon and a challenge for preoperative diagnostic protocol. A careful application of selected IHC markers, p53 and Ki-67 in particular, may substantially help not only in the differential diagnosis but also in clinicopathological algorithms based on OCS molecular profiling into HGSC-like and non-HGSC-like variants.

Keywords:  Ki-67; immunohistochemistry; ovarian carcinosarcoma; p53; serous tubal intraepithelial carcinoma

DOI:  https://doi.org/10.3389/fonc.2026.1727634
Int J Gynecol Cancer. 2026 Apr 03. pii: S1048-891X(26)00207-0. [Epub ahead of print]36(6): 104676

Contemporary risk assessment and risk-reducing strategies for tubo-ovarian cancer in women with BRCA pathogenic variants.

David Viveros-Carreño, Isabel Beshar, Nuria Agustí, Ananya Murthy, Nathalia Mora-Soto, Maria D Iniesta, Karla Barajas, Alexander Melamed, J Alejandro Rauh-Hain, Roni Nitecki Wilke.

  Tubo-ovarian cancer represents the most lethal gynecologic malignancy, and its burden is compounded by the absence of effective screening and the substantial lifetime risk carried by women with germline BRCA1 or BRCA2 pathogenic variants. While risk-reducing salpingo-oophorectomy remains the standard for prevention, conferring reduction in tubo-ovarian cancer risk and improved overall survival, it also induces premature menopause with significant effects on quality of life and bone, cardiovascular, and sexual health. These consequences have driven the exploration of alternative preventive strategies, and a paradigm shift toward individualized risk assessment. Emerging data highlight that tubo-ovarian cancer risk among BRCA pathogenic variant carriers is not uniform but influenced by gene type, variant position, family history, and modifiable factors such as parity, breastfeeding, and oral contraceptive use. Modern risk models integrate genetic, familial, and lifestyle data to refine personalized estimates and guide the timing of intervention. Concurrently, the understanding that many high-grade serous carcinomas originate in the fallopian tube has prompted evaluation of risk-reducing salpingectomy with delayed oophorectomy as a staged surgical strategy that may balance oncologic safety with preservation of hormonal function. Ultimately, management of BRCA pathogenic variant carriers must combine genomic precision, reproductive planning, and patient-centered counseling to align cancer prevention with quality of life, supporting truly individualized care in hereditary tubo-ovarian cancer risk reduction. Despite several reviews on hereditary tubo-ovarian cancer prevention, a clinically relevant gap remains in translating contemporary evidence into a practical counseling framework for women with BRCA1/2 pathogenic variants. This narrative review aims to synthesize current evidence on tubo-ovarian cancer risk assessment and risk-reducing strategies in this population, with a focus on individualized counseling and shared decision-making.

Keywords:  BRCA1 Protein/Genetics; BRCA2 Protein/Genetics; Ovarian Neoplasms; Risk Assessment; Salpingo-Oophorectomy

DOI:  https://doi.org/10.1016/j.ijgc.2026.104676
Hepatol Res. 2026 May 02.

From Genomic Instability to Epigenetic Signatures: The Evolving Landscape of Circulating Cell-free DNA in Metabolic Dysfunction-Associated Steatotic Liver Disease.

Wei-Yue Lim, Rosmawati Mohamed, Yuh-Fen Pung, Shamsul Mohd Zain.

  Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a leading global health burden, yet its diagnosis and staging rely heavily on invasive liver biopsies. Liquid biopsy, utilizing circulating cell-free DNA (cfDNA), offers a promising noninvasive alternative to capture hepatic genomic instability. This review consolidates current knowledge on cfDNA biomarkers in MASLD, moving from established quantitative metrics to emerging epigenetic insights. The role of mitochondrial DNA copy number (mtDNAcn) is examined as a dynamic marker of oxidative stress, highlighting its biphasic response: compensatory upregulation in early disease versus depletion in advanced fibrosis. Furthermore, key nuclear copy number variations (CNVs) specifically the XPO4 duplication (13q12.11), CES1 deletion (16q12.2), and ACOT1 deletion (14q24.3) are discussed regarding their mechanistic drivers of fibrogenesis and lipid metabolism dysregulation. Addressing the complexity of MASLD pathogenesis, the discussion extends to emerging multi-modal metrics, including DNA methylation and fragmentomics. These modalities offer superior specificity by tracing the "tissue of origin" and distinguishing apoptotic from necrotic fragmentation patterns, effectively addressing the diagnostic challenges posed by the "burnout" phenomenon in advanced cirrhosis. Finally, critical future directions are outlined, emphasizing the necessity for standardized pre-analytical protocols and the integration of multi-omics data with machine learning. This comprehensive approach will shed light on the transition cfDNA from a research tool to a precise clinical instrument for early risk stratification and therapeutic monitoring.

Keywords:  MASLD; biomarkers; copy number variation; liquid biopsy; metabolic dysfunction‐associated steatotic liver disease; mitochondrial DNA

DOI:  https://doi.org/10.1111/hepr.70198
Nat Methods. 2026 Apr 30.

Resolving sensitivity, specificity and signal contamination in Xenium spatial transcriptomics.

Mariia Bilous, Daria Buszta, Jonathan Bac, Senbai Kang, Yixing Dong, Stephanie Tissot, Sylvie Andre, Marina Alexandre Gaveta, Christel Voize, Solange Peters, Krisztian Homicsko, Raphael Gottardo.

Spatial transcriptomics enables high-resolution gene expression mapping in intact tissues. Xenium is widely adopted for its reliability, accessibility and data quality, yet the properties and limitations of Xenium-derived data remain poorly characterized. Here we present one of the most comprehensive Xenium datasets so far, encompassing over 40 breast and lung tumor sections profiled using diverse gene panels. Leveraging this resource, we systematically dissect technical noise-including transcript spillover-along with assay specificity, panel performance and segmentation strategies. We demonstrate that single-nucleus RNA sequencing enables precise quantification of transcript contamination. Building on these insights, we introduce SPLIT (Spatial Purification of Layered Intracellular Transcripts), a method that improves signal purity by resolving mixed transcriptomic signals. SPLIT enhances background correction and cell-type resolution and enables the revelation of T-cell exhaustion signatures associated with malignant cell colocalization-signals that would otherwise remain obscured. Together, our findings provide a critical benchmark for Xenium performance and introduce a scalable strategy for signal refinement.

DOI: https://doi.org/10.1038/s41592-026-03089-8
J Ovarian Res. 2026 May 01.

A potential mutation-defined POLE/MMR/TP53 group classifications to stratify BRCA wild type epithelial ovarian cancer.

Yi-Ting Chen, Po-Han Lin, Yi-Jou Tai, Heng-Cheng Hsu, Kuan-Ting Kuo, Ying-Cheng Chiang.

   BACKGROUND: TCGA molecular classification has prognostic value in endometrial cancer, but its application in epithelial ovarian cancer is not clear.
METHODS: We investigated the somatic mutations of POLE, MMR (MLH1, MLH3, MSH2, MSH3, MSH6, PMS1, PMS2) and TP53, in 181 BRCA wild type EOC patients.
RESULTS: The patterns were different in histology [ serous vs. endometrioid vs. clear cell (POLEmut: 0% vs. 2.8% vs. 0%, MMRmut: 6.4% vs. 22.2% vs. 11.9%, TP53mut: 75.7% vs. 16.7% vs. 4.5%, NSMP: 17.9% vs. 58.3% vs. 83.6%, p < 0.001)]; FIGO stage [early vs. advanced (POLEmut: 1.4% vs. 0%, MMRmut: 11.3% vs. 11.8%, TP53mut: 9.8% vs. 55.5%, NSMP: 77.5% vs. 32.7%, p < 0.001)]; tumor grade [low vs. high (POLEmut: 3.8% vs. 0%, MMRmut: 19.2% vs. 10.3%, TP53mut: 11.5% vs. 41.9%, NSMP: 65.5% vs. 47.8%, p = 0.002)]; tumor recurrence [no vs. yes (POLEmut: 1.4% vs. 0%, MMRmut: 11.3% vs. 11.9%, TP53mut: 21.1% vs. 47.7%, NSMP: 66.2% vs. 40.4%, p = 0.002)] and tumor-related death [no vs. yes (POLEmut: 1.0% vs. 0%, MMRmut: 9.2% vs. 14.5%, TP53mut: 25.5% vs. 51.8%, NSMP: 64.3% vs. 33.7%, p < 0.001)]. There was difference in median disease-free survival [months (POLEmut: not reached, MMRmut: 12.5, TP53mut: 8.5, NSMP: 36.5; p = 0.002)] and overall survival [months (POLEmut: not reached, MMRmut: 41, TP53mut: 47, NSMP: not reached; p = 0.008)]. In multivariate regression analysis, R0 resection (HR: 0.54 [0.32-0.90], p < 0.001) was important prognostic factor of tumor recurrence. Platinum partial sensitive response (HR: 9.27 [3.73-23.01], p < 0.001) and platinum resistant response (HR: 26.29 [11.75-58.82], p < 0.001) were important prognostic factors of tumor-related death.
CONCLUSIONS: The pattern of mutation-defined POLE/MMR/TP53 group classifications varied in histological subtypes, FIGO stage and clinical outcomes in BRCA wild type EOC. BRCA wild type EOC patients with POLEmut or NSMP had favorable survival than those with MMRmut or TP53mut. The panel could be a potential marker for EOC patients.

Keywords:   MMR ; P53 ; POLE ; Epithelial ovarian cancer; Gene mutation group classifications

DOI:  https://doi.org/10.1186/s13048-026-02123-9
Nat Genet. 2026 Apr 27.

Tumor DNA methylation subtypes predict immunotherapy outcomes in pleural mesothelioma patients in the NIBIT-EPI-MESO study.

Luana Calabrò, Francesca P Caruso, Alessia Covre, Teresa M R Noviello, Maria F Lofiego, Rossella Tufano, Luigi Ferraro, Piera Grisolia, Antonio De Falco, Vincenzo Lagano, Francesco Sgambelluri, Giovanna Sabella, Giulia Rossi, Giulia Gibilisco, Francesco Marzani, Emma Bello, Elena Simonetti, Vincenzo D'Alonzo, Michele Caraglia, Sandra Coral, Antonina De Angelis, Luigi Cerbone, Sara Delfanti, Diana Giannarelli, Federica Grosso, Anna Maria Di Giacomo, Massimo Milione, Roberta Mortarini, Andrea Anichini, Michele Ceccarelli, Michele Maio.

Pleural mesothelioma (PM) has a poor prognosis and standard therapy with immune checkpoint inhibitors (ICIs) CTLA-4 and PD-1 is still clinically unsatisfying. No predictive biomarkers of ICI efficacy in PM are available yet. In the retrospective multicenter NIBIT-EPI-MESO study, multi-omics analysis of pre-ICI therapy tumor lesions from 91 patients with PM treated in earlier clinical trials or in daily practice identified four PM subsets with progressively increasing global DNA methylation profiles-demethylated, LOW, intermediate and CpG island methylator phenotype (CIMP). These methylation subsets predicted response and survival to ICI therapy. The LOW subset was enriched in responder patients, who had the longest median overall survival and the highest 3-year overall survival rate, and showed a T cell- and B cell-rich immune microenvironment. Conversely, the CIMP subtype was enriched in nonresponder patients with the shortest median overall survival and overall survival, along with a depleted immune microenvironment. A methylation-based probabilistic decision-making classification tool to predict the outcome of ICI treatment in patients with PM was developed.

DOI: https://doi.org/10.1038/s41588-026-02580-4