bims-tumhet 2026-01-11 papers

Issue of 2026–01–11
seven papers selected by
Sergio Marchini, Humanitas Research

Int J Gynecol Cancer. 2026 Jan;pii: S1048-891X(25)01982-6. [Epub ahead of print]36(1): 102858

Circulating tumor DNA in ovarian cancer diagnosis: from signal to standard.

Keywords: Circulating Tumor DNA; DNA Methylation; Early Detection; Liquid Biopsy; Ovarian Cancer

DOI: https://doi.org/10.1016/j.ijgc.2025.102858

Int J Gynecol Cancer. 2025 Dec 11. pii: S1048-891X(25)01983-8. [Epub ahead of print]36(2): 102859

Homologous recombination deficiency in endometrial cancer: shedding light on recent clinical findings.

Griffin Willman, Vivek Podder, Shannon Neville Westin, Bradley R Corr, Robert L Coleman, Bhavana Pothuri, Kathleen N Moore, Brian M Slomovitz.

Endometrial cancer is the most common gynecologic malignancy in the United States, with rising incidence and high recurrence rates. Immune checkpoint inhibitors (ICIs) benefit patients with mismatch repair-deficient (dMMR) tumors, but options remain limited for those with mismatch repair-proficient (pMMR) disease. Homologous recombination deficiency (HRD), a genomic instability phenotype, has emerged as a therapeutic target. Poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPis) are being investigated in endometrial cancer, with studies exploring whether HRD predicts response, particularly in combination with ICIs or chemotherapy. This review examines HRD in endometrial cancer, focusing on its molecular basis, clinical implications, and emerging therapeutic strategies. HRD occurs in a sub-set of endometrial cancers, particularly non-endometrioid sub-types, and is linked to genomic instability and platinum sensitivity. The Cancer Genome Atlas (TCGA) molecular classification has improved understanding of HRD prevalence across sub-types. HRD testing remains challenging due to a lack of standardization, with current methods including genomic-scar assays, next-generation sequencing, and functional assays. Clinical trials, such as DUO-E and RUBY-2, suggest that PARPi combined with ICIs or chemotherapy may improve outcomes in pMMR tumors, whereas PARPi monotherapy offers limited benefits. Resistance to PARPi is common, driven by the restoration of homologous recombination repair, replication fork stabilization, and drug efflux. HRD is a promising biomarker and therapeutic target in endometrial cancer. Evidence supports the integration of PARPi for select populations, although further research is needed to refine testing, optimize patient selection, and overcome resistance. Future trials should prioritize predictive biomarkers and novel combinations to maximize the benefits of PARPi in HRD endometrial cancer.

Keywords: Biomarkers; DNA Repair; Endometrial Cancer; Homologous Recombination Deficiency; Immunotherapy; Poly(ADP-Ribose) Polymerase Inhibitors; Synthetic Lethality; Targeted Therapy

DOI: https://doi.org/10.1016/j.ijgc.2025.102859

Cancers (Basel). 2025 Dec 24. pii: 51. [Epub ahead of print]18(1):

Molecular Classification of Endometrial Carcinomas: Review and Recent Updates.

Anita Kumari, Himani Kumar, Samuel E Harvey, Deyin Xing, Zaibo Li.

Endometrial carcinoma (EC) continues to represent a major cause of gynecologic cancer-related mortality among women worldwide. Its multifactorial etiopathogenesis and underlying molecular heterogeneity have been the focus of extensive investigation. While traditional histological classification provides essential diagnostic insight, it is limited in predicting prognosis and therapeutic response due to significant interobserver variability. Recent advances in molecular biology and cancer genomics have profoundly enhanced understanding of EC pathogenesis. The Cancer Genome Atlas (TCGA) project delineated four distinct molecular subtypes of EC, POLE ultra-mutated, microsatellite instability hypermutated (MSI-H), copy number low (CNL) and copy number high (CNH), each defined by unique genomic alterations, histopathologic features, and clinical behaviors. These molecular groups demonstrate significant prognostic and therapeutic implications, correlating with differential outcomes and treatment responses. This review summarizes current evidence on the genomic landscape of endometrial carcinoma and underscores the pivotal role of molecular classification in improving diagnostic accuracy, prognostic stratification, and personalized therapy. Ongoing research into molecular biomarkers holds promise for refining patient management and optimizing clinical outcomes.

Keywords: POLE-ultramutated; endometrial carcinoma; microsatellite instability; p53

DOI: https://doi.org/10.3390/cancers18010051

Nucleic Acids Res. 2026 Jan 05. pii: gkaf1484. [Epub ahead of print]54(1):

CellMap: precision mapping of cellular landscape in spatial transcriptomics.

Hongjia Liu, Huamei Li, Amit Sharma, Guoyan Tang, Zongyu Xie, Yunyao Shen, Qiong Li, Chen Gong, Xiao Sun, Kun Luo, Hongde Liu.

Integrating single-cell RNA sequencing and spatial transcriptomics is the current imperative to manually explore the landscape of cellular mixtures. Herein, we developed CellMap (https://github.com/liuhong-jia/CellMap), a computational tool that allows spatial transcriptomic spots to be resolved at single-cell resolution. CellMap combines strategies that incorporate the co-linearity of seed genes, the random forest model, and the linear assignment algorithm to achieve optimal assignment of single cells to spatial spots. Using comprehensive benchmarking across various platforms and tissue types, we demonstrated that CellMap outperforms existing methods.

DOI: https://doi.org/10.1093/nar/gkaf1484

Nat Biotechnol. 2026 Jan 05.

Mapping isoforms and regulatory mechanisms from spatial transcriptomics data with SPLISOSM.

Jiayu Su, Yiming Qu, Megan Schertzer, Haochen Yang, Jiahao Jiang, Tenzin Lhakhang, Theodore M Nelson, Stella Park, Qiliang Lai, Xi Fu, Seung-Won Choi, David A Knowles, Raul Rabadan.

Transcript diversity including splicing and alternative 3' end usage is crucial for cellular identity and adaptation, yet its spatial coordination remains poorly understood. Here we present SPLISOSM (spatial isoform statistical modeling), a method for detecting isoform-resolution patterns from spatial transcriptomics data. SPLISOSM uses multivariate testing with nonparametric kernels to account for spot-level and isoform-level dependencies, achieving high statistical power on sparse data. In the mouse brain, we identify over 1,000 spatially variable transcript diversity events, primarily in synaptic signaling pathways linked to neuropsychiatric disorders, and uncover both known and previously unknown regulatory relationships with region-specific RNA binding proteins. We further show that these patterns are evolutionarily conserved between mouse and human prefrontal cortex. Analysis of human glioblastoma highlights pervasive transcript diversity in antigen presentation and adhesion genes associated with specific microenvironmental conditions. Together, we present a comprehensive spatial splicing analysis in the brain under normal and neoplastic conditions.

DOI: https://doi.org/10.1038/s41587-025-02965-6

Nat Med. 2026 Jan 06.

Real-world clinical utility of comprehensive genomic profiling in advanced solid tumors.

Yuki Saito, Sara Horie, Yasunori Kogure, Kota Mizuno, Yuta Ito, Yosuke Mizukami, Haryoon Kim, Zen Tamura, Junji Koya, Takeru Funakoshi, Kenro Hirata, Keisuke Kataoka.

Comprehensive genomic profiling (CGP) is crucial in precision oncology, yet its real-world utility remains unclear. Here we analyzed data from the Japanese nationwide Center for Cancer Genomics and Advanced Therapeutics database, including clinical and genetic data from 54,185 patients with advanced solid tumors (consisting of 81 common and rare tumor types) who received CGP with a targeted sequencing panel covering 324 genes as part of their clinical care. We assessed the prognostic value of CGP-guided clinical evidence-level classification, showing that alterations predicting response to Pharmaceuticals and Medical Devices Agency-approved or Food and Drug Administration-approved therapies and to therapies supported by well-powered studies with expert consensus are detected in 16.6% and 8.1% of patients, respectively, and are associated with better prognosis than those with lower clinical evidence levels. Only 8% of patients receive CGP-guided approved-experimental genomic biomarker-linked therapies, although the proportion has improved over time. Substantial differences were observed across tumor types, with the proportions exceeding 20% in thyroid and lung cancers but remaining below 2% in pancreatic and liver cancers. Tumor-agnostic biomarker analyses reveal that tumor mutational burden (TMB) ≥20 mutations per megabase predicts better outcome across tumor types, regardless of microsatellite instability status, in TMB-high patients receiving pembrolizumab. Conversely, extramammary Paget's disease is exceptionally resistant to pembrolizumab. The large-scale nationwide database allows evaluating inter-tumor type differences and investigating evidence-scarce situations, delineating where CGP offers greater benefit. These real-world findings complement those from clinical trials and prospective sequencing projects regarding CGP, providing valuable information for individualized treatment.

DOI: https://doi.org/10.1038/s41591-025-04086-8