bims-ovdlit 2025-03-16 papers

Issue of 2025–03–16
four papers selected by
Lara Paracchini, Humanitas Research

Cancer Discov. 2025 Mar 14.

Aged and BRCA mutated stromal cells drive epithelial cell transformation.

The fundamental steps in high-grade serous ovarian cancer (HGSOC) initiation are unclear presenting critical barriers in prevention and early detection of this deadly disease. Current models propose that fallopian tube epithelial (FTE) cells transform into serous tubal intraepithelial carcinoma (STIC) precursor lesions and subsequently HGSOC. Here we report that an epigenetically altered mesenchymal stem cell niche, termed high risk MSC (hrMSC), exists prior to STIC lesion formation. hrMSCs are enriched in STIC stroma and contribute to a stromal 'field effect' extending beyond the borders of STIC lesion. hrMSCs promote DNA damage in FTE cells while also fostering FTE cell survival. hrMSCs induce malignant transformation of FTE resulting in metastatic cancer in vivo, indicating hrMSCs promote cancer initiation. hrMSCs are significantly enriched in BRCA1/2 mutation carriers and increase with age. Combined, these findings indicate that hrMSCs can incite ovarian cancer initiation and have important implications for ovarian cancer detection and prevention.

DOI: https://doi.org/10.1158/2159-8290.CD-24-0805

Int J Gynecol Cancer. 2025 Jan 17. pii: S1048-891X(25)00168-9. [Epub ahead of print] 101645

Prevalence of homologous recombination deficiency among women with newly diagnosed ovarian, primary peritoneal, and/or fallopian tube cancer: the international HALO study.

Svetlana Khokhlova, Manwar Abdulelah Alnaqqash, Waleed Bahaj, Salha Bujassoum, Jooyeon Lee, Mohsen Mokhtar, Alexandra Tyulyandina, Carmen Luz Vargas Malaga, Chen-Hsuan Wu.

OBJECTIVE: The HALO study (NCT04991051) determined the prevalence of homologous recombination deficiency and its associated factors in patients with high-grade serous/endometrioid ovarian, primary peritoneal, and/or fallopian tube cancers across Asia, the Middle East, and Russia.
METHODS: This multinational, cross-sectional, real-world study enrolled adult women with newly diagnosed stage III or IV high-grade serous/endometrioid ovarian, primary peritoneal, and/or fallopian tube cancers. Formalin-fixed paraffin-embedded tumor blocks were collected within 120 days of enrollment. The prevalence of homologous recombination deficiency, high genomic instability score (GIS) without tumor BRCA mutations, and BRCA mutations were evaluated along with patient characteristics. Factors associated with homologous recombination deficiency, high GIS without BRCA mutations, and BRCA mutations were identified using a logistic-regression model.
RESULTS: Of the 734 patients (median [range] age; 59.0 [23.0-89.0] years), most (92.9%) had a primary ovarian tumor, followed by primary peritoneal (4.1%) and fallopian tube cancers (3.0%). Of the tested 662 patients; 56.0% (371) were homologous recombination deficiency-positive (Asia, 52.0%; the Middle East, 52.2%; Russia, 58.5%). Overall, 204 (30.8%) patients had a high GIS without BRCA mutations (Middle East, 23.9%; Russia, 31.9%; Asia, 41.3%), and 167 (25.2%) had BRCA mutations (Asia, 10.7%; Russia, 26.6%; Middle East, 28.3%). Patients with 1 comorbidity versus no comorbidities (96 vs 207, OR 1.54), a family history of genetically-related cancers versus no family history of cancer (82 vs 224, OR 2.64), and contraceptive use versus no history of contraceptive use (47 vs 323, OR 2.04) were more likely to have homologous recombination deficiency.
CONCLUSIONS: This real-world study reported a homologous recombination deficiency prevalence of 56.0% (ranging from 52.0% to 58.5%) across Asia, the Middle East, and Russia. Our results highlight the unmet need to implement guideline-recommended testing and real-world data collection for all patients newly diagnosed with advanced high-grade epithelial ovarian cancer to optimize treatment strategies.

Keywords: Asia; BRCA Mutation; High Genomic Instability; High-Grade Serous/Endometrioid Ovarian Cancer; Homologous Recombination Deficiency; Middle East; Russia

DOI: https://doi.org/10.1016/j.ijgc.2025.101645

Nat Rev Genet. 2025 Mar 10.

Adapting systems biology to address the complexity of human disease in the single-cell era.

David S Fischer, Martin A Villanueva, Peter S Winter, Alex K Shalek.

Systems biology aims to achieve holistic insights into the molecular workings of cellular systems through iterative loops of measurement, analysis and perturbation. This framework has had remarkable success in unicellular model organisms, and recent experimental and computational advances - from single-cell and spatial profiling to CRISPR genome editing and machine learning - have raised the exciting possibility of leveraging such strategies to prevent, diagnose and treat human diseases. However, adapting systems-inspired approaches to dissect human disease complexity is challenging, given that discrepancies between the biological features of human tissues and the experimental models typically used to probe function (which we term 'translational distance') can confound insight. Here we review how samples, measurements and analyses can be contextualized within overall multiscale human disease processes to mitigate data and representation gaps. We then examine ways to bridge the translational distance between systems-inspired human discovery loops and model system validation loops to empower precision interventions in the era of single-cell genomics.

DOI: https://doi.org/10.1038/s41576-025-00821-6