Thymic Carcinoma

This Japanese real-world study investigated comprehensive genomic profiling and tumor mutational burden (TMB) in parathyroid carcinoma, a rare endocrine malignancy. Among 25 patients, 28% exhibited elevated TMB (≥ 10 mut/Mb), with frequent alterations observed in CDC73, TP53, and MEN1 genes. POLE alterations and microsatellite instability (MSI-high) were also identified in some cases. These findings highlight the molecular heterogeneity of the disease and the value of genomic profiling for uncovering potential therapeutic opportunities.

This study investigates predictive biomarkers for immune checkpoint inhibitor (ICI) response in metastatic urothelial carcinoma. Researchers found that ICI responders exhibited higher tumor mutational burden (TMB) and enriched mutations in genes such as PIK3CA. Functional in vitro and in vivo studies demonstrated that PIK3CA mutations enhance tumor immunogenicity by activating the IRF1-NLRC5-MHC-I axis, thereby improving antigen presentation and CD8+ T-cell cytotoxic response. These findings suggest that PIK3CA mutation could serve as a biomarker to predict ICI sensitivity and represents a novel immune-modulating mechanism.

This retrospective study investigated the frequency and molecular profiles of PAX8-positive conventional urothelial carcinomas (UCs) of the urinary bladder. Out of 101 cases, 10% were found to be PAX8-positive by immunohistochemistry. Next-generation sequencing (NGS) was performed on 20 cases, including all PAX8-positive UCs. The findings revealed that PAX8-positive UCs frequently harbored TERT promoter mutations, TSC1 alterations, NOTCH1 loss, and WT1 loss, while notably lacking RB1 loss, distinguishing them from PAX8-negative UCs. These results indicate a distinct molecular signature for PAX8-positive UCs, emphasizing the need for careful diagnostic interpretation of PAX8.

This large genomic analysis of 2901 endometrial carcinomas refines molecular classification by addressing several clinical questions. The study confirms that all four mismatch repair genes (MLH1, MSH2, MSH6, PMS2) confer an equivalently favorable prognosis, validating dMMR status as a class-level prognostic designation. It demonstrates that the exceptional survival benefit associated with POLE-ultramutated tumors is confined to canonical exonuclease-domain hotspot mutations, excluding variants of uncertain significance. Finally, patients with TP53 mutations and high copy-number instability (CNH) are identified as having the most urgent unmet therapeutic need.

This study performed whole genome and transcriptome sequencing on 50 tumor samples from 37 patients with locally advanced or metastatic breast cancer. It uncovered extensive genomic complexity, with triple-negative breast cancer (TNBC) showing the highest tumor mutational burden. Homologous recombination deficiency (HRD) was found in 27% of patients, frequently in BRCA1/2 wild-type cases due to deleterious structural variants in other repair genes. Therapeutically actionable alterations were identified in 84% of patients, including a novel ESR1::EP300 fusion potentially linked to endocrine resistance. These findings underscore the utility of whole-genome sequencing for characterizing metastatic disease and guiding therapies.