Week 2026-W34

This study characterized the prevalence of KRAS G12C mutations in genitourinary malignancies, an area with limited data despite the approval of targeted therapies. Comprehensive genomic profiling was performed on over 13,000 samples of renal clear cell carcinomas, urothelial bladder carcinomas, and prostate acinar adenocarcinomas. Results indicated that KRAS G12C mutations are infrequent in these tumors, with an incidence of 0% in renal carcinomas, 0.6% in urothelial bladder carcinomas, and less than 0.01% in prostate adenocarcinomas. Despite their low frequency, these mutations represent an emerging therapeutic target, warranting further investigation, particularly in basket trials for patients harboring this actionable alteration.

This study utilized genome-wide DNA methylation profiling to improve the classification of mucinous ovarian carcinoma (MOC) and differentiate it from extraovarian mucinous metastases (EOM). Analyses revealed two subtypes of mucinous borderline ovarian tumors (mBOTs) and two MOC methylation subtypes with potential prognostic relevance. A three-step machine-learning classifier was developed and validated, achieving 95.5% accuracy internally and 91.11% externally in distinguishing MOC from EOM. These findings establish an epigenetic framework for mucinous ovarian tumors and provide a robust clinical classification tool.

This phase II study investigated the efficacy and safety of durvalumab plus olaparib as maintenance therapy in 60 previously untreated extensive-stage small-cell lung cancer (ES-SCLC) patients. The combination regimen demonstrated promising efficacy, with a 12-month progression-free survival rate of 25.0%, a median progression-free survival of 6.8 months, and a median overall survival of 14.6 months. Multi-omics analysis identified a DNA hypomethylation subgroup associated with significantly improved survival outcomes. This subgroup exhibited enhanced antigen presentation, a favorable cytokine profile, and suppressed DNA damage repair pathways, suggesting a potential biomarker for patient selection.

This multi-omics and experimental study identifies Ubiquitin-conjugating enzyme E2 C (UBE2C) as a central hub gene and a key prognostic biomarker in hepatocellular carcinoma (HCC). UBE2C is significantly upregulated in HCC, predominantly in hepatocytes, and its knockdown suppresses tumor proliferation and growth. The study reveals that UBE2C-high regions are associated with an immunosuppressive microenvironment, characterized by TGFB1 enrichment and cytotoxic T-cell exclusion. A nomogram integrating UBE2C expression, T stage, and tumor stage was developed to predict patient survival and stratify immunotherapy response.

This phase 3 study, LIBRETTO-432, investigated the efficacy and safety of adjuvant selpercatinib in patients with early-stage (IB, II, or IIIA) RET fusion-positive non-small-cell lung cancer (NSCLC) after definitive therapy. Patients were randomized to receive selpercatinib or placebo for up to three years. The primary endpoint was event-free survival (EFS) in patients with stage II or IIIA disease. Results demonstrated a significant improvement in 2-year EFS with selpercatinib (92% vs 61% for stage II/IIIA, HR=0.17), with a similar trend across all stage IB-IIIA patients (94% vs 70%, HR=0.16). The safety profile was manageable, with elevated transaminases being the most common adverse events.

This study introduces an innovative dual-branch deep learning approach for predicting drug sensitivity (IC50) across various cancer types. The model integrates Graph Isomorphism Networks (GIN) to represent drug chemical structures with a Multilayer Perceptron (MLP) that incorporates 50-dimensional ssGSEA pathway activities derived from gene expression. Trained on the GDSC2 dataset, this model achieved superior performance compared to existing methods, with an R2 of 0.8553 and a Pearson Correlation Coefficient of 0.9249. The inclusion of biological pathway features was demonstrated to be crucial for enhancing prediction accuracy.

This study characterized the spectrum of TSC1 and TSC2 gene variants in a cohort of 34 Greek patients with Tuberous Sclerosis Complex (TSC). Using targeted next-generation sequencing, pathogenic or likely pathogenic variants were identified in 65% of probands. The majority of variants were found in TSC2, and seven variants were previously unreported. Exploratory genotype-phenotype analysis suggested a trend towards a more severe clinical presentation in patients with TSC2 variants. These findings underscore the utility of genetic testing for diagnosis, genetic counseling, and patient management in TSC.

This study identified a novel gene expression signature predictive of bevacizumab response in ovarian cancer patients. Utilizing machine learning approaches on RNA-seq and microarray data, researchers discovered a signature associated with significantly improved overall survival in patients receiving bevacizumab. This signature, potentially linked to stemness-like features and the CTCFL gene, was validated across multiple independent cohorts. These findings suggest transcriptional heterogeneity in ovarian cancer beyond current classifications, offering a pathway for improved patient selection.

This study investigated DNA methylation profiles in 259 sporadic colorectal cancers, aiming to identify microsatellite instability (MSI)-associated signatures beyond the CIMP phenotype and MLH1 promoter hypermethylation. Researchers discovered 656 differentially methylated CpG sites linked to MSI, including hypermethylation of LRP6, GSK3B, and CDK12, genes involved in WNT signaling and transcriptional regulation. The study also revealed heterogeneity within MSI CRCs, with co-occurrence of MLH1 and TXNRD1 promoter hypermethylation. Furthermore, anatomical location was found to be a major determinant of the CRC methylome, contributing to improved molecular stratification of the disease.

This phase 2 study investigated the addition of tislelizumab to perioperative chemotherapy for patients with locally advanced gastric or gastroesophageal junction cancer. Patients were stratified by tumor-specific MHC class II (tsMHC-II) expression. The findings revealed that the combination immunotherapy significantly increased the major pathological response (mPR) rate in tsMHC-II-positive patients (61.8% vs. 26.5% with chemotherapy alone). No benefit was observed in the tsMHC-II-negative subgroup, indicating tsMHC-II as a promising predictive biomarker.

This study developed a deep learning framework to accelerate drug discovery for triple-negative breast cancer (TNBC), an aggressive subtype with limited therapeutic options. The model predicted anticancer efficacy, toxicity, and structural similarities of compounds. By screening over 6,000 compounds, the study identified emodepside as a promising candidate. In vitro and in vivo validations confirmed its antitumor efficacy, including inhibiting tumor growth in xenograft models. Multi-omics analyses revealed that emodepside acts by inhibiting NAMPT, promoting TNBC cell apoptosis.

A new study developed and validated a non-invasive urine DNA methylation assay for prostate cancer detection, aiming to improve the specificity of PSA screening. This test, based on the methylation of two genes (ADD3 and GSX2), was developed retrospectively in 348 participants and prospectively validated in 200 participants in a multicenter study. It demonstrated robust diagnostic performance with AUCs of 0.86 and 0.91, and specificity above 90%. Integrating this tool could potentially avert approximately 55% of unnecessary biopsies without compromising cancer detection.

This study investigated the functional impact of recurrent mutations in cervical cancer. Using whole-exome sequencing, cell models, and in vivo experiments, researchers identified the PIK3CA-E545K mutation as frequently occurring. This specific mutation was shown to enhance tumor cell proliferation and invasion while suppressing apoptosis. These effects are mediated by sustained activation of the AKT/mTOR signaling pathway. The findings suggest that targeting the PI3K/AKT/mTOR axis could represent a promising therapeutic strategy for this cancer.

This study investigates strategies to overcome drug resistance in gastrointestinal stromal tumors (GIST) driven by oncogenic KIT and PDGFRA mutations. Current tyrosine kinase inhibitors (TKIs) face limitations due to off-target toxicities and resistance mutations. Researchers employed a structure-based scaffold-hopping approach to design novel selective inhibitors. Their structure-activity relationship studies and 14 co-crystal structures, including one for PDGFRA-G680R, helped define key molecular interactions underlying resistance and selectivity. The developed 6,7-quinazoline-based inhibitors demonstrate high potency against clinically relevant KIT/PDGFRA mutations and effectively suppress downstream signaling.

This study introduces a novel, complete telomere-to-telomere diploid human genome benchmark for the HG002 genome. Achieving near-perfect accuracy across 99.4% of the diploid genome, this benchmark incorporates an additional 701.4 Mb of autosomal sequence and 216.8 Mb of sex chromosomes, which were missing from prior benchmarks. The researchers annotated genes and repeats on both haplotypes, identifying nearly 20,000 protein-coding genes on the maternal haplotype and over 19,000 on the paternal. They also developed new methodologies to assess the accuracy of reads, phased variant call sets, and assemblies against this diploid reference. Genome-wide analyses reveal that de novo assembly resolves 2-7% more sequence and significantly outperforms variant calling accuracy.

This retrospective study evaluated the diagnostic and prognostic impact of DNA methylation array (MA) profiling in pediatric ependymoma. Out of 63 patients, MA profiling reclassified nearly a quarter of initial diagnoses, with a higher rate before 2019, underscoring the importance of integrated molecular diagnosis. Posterior fossa group A (PFA) ependymoma was the predominant subgroup. Gross total resection was the only factor significantly associated with improved survival, while chromosome 1q gain, exclusively found in PFA patients, was linked to a high relapse rate.