TERT

This international study aimed to identify genetic prognostic biomarkers in a specific subgroup of intermediate-risk neuroblastoma patients, over 18 months old, without MYCN amplification, with localized unresectable or stage 3 tumors, and unfavorable histology, who experience poorer outcomes. Researchers analyzed chromosomal copy number alterations, next-generation DNA sequencing, telomere maintenance mechanisms, and gene expression. The findings revealed that oncogene amplifications, p53 pathway alterations, and typical segmental chromosomal aberrations (tSCAs) are independent prognostic markers associated with significantly reduced event-free and overall survival. These discoveries suggest that these patients might benefit from intensified or alternative treatments.

This study assesses the performance of in silico prediction tools for genetic variant curation within a panel of cancer predisposition genes. Researchers applied ClinGen SVI Working Group recommended thresholds and AlphaMissense predictions to variants in genes such as BRCA1, BRCA2, TP53, TERT, and ATM, which have established pathogenicity or benignity. The findings indicated insufficient sensitivity for pathogenic TERT variants and benign TP53 variants. The study emphasizes that the performance of these tools can be gene-specific and is influenced by their training datasets. Consequently, it is crucial to validate these tools for individual genes, especially for missense variants.

This single-center retrospective study investigated the prognostic impact of MGMT promoter methylation and TERT promoter mutations in 54 patients with WHO grade 4 glioblastoma. The findings indicate that MGMT methylation is independently associated with improved overall survival, whereas TERT mutations predict worse survival. Adjuvant chemoradiotherapy was also confirmed to improve outcomes. A combined stratification using both biomarkers allows for the identification of four distinct prognostic subgroups, with MGMT-methylated/TERT-wild-type patients exhibiting the longest survival.

This study compared clinical characteristics and survival between molecularly defined IDH-wild-type glioblastoma (MolGBM) and histologically defined IDH-wild-type glioblastoma (HistGBM). It also characterized lower-grade IDH-wild-type astrocytic tumors lacking glioblastoma-defining genomic alterations. MolGBM exhibited a more favorable adjusted overall survival (HR 0.40) compared to HistGBM, particularly in patients aged 60 years or older. These findings highlight the clinical and biological heterogeneity among molecularly defined IDH-wild-type diffuse gliomas and the critical role of comprehensive molecular characterization. Lower-grade IDH-wild-type astrocytic tumors without glioblastoma-defining alterations warrant further in-depth molecular investigation.

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 study investigates the impact of next-generation sequencing (NGS) on the diagnosis of BAP1 inactivated melanocytic tumors (BIMTs), which often exhibit significant morphological atypia, complicating their classification. A survey among dermatopathologists revealed that incorporating NGS results significantly improved diagnostic accuracy and interobserver agreement. Specific genomic aberrations, including pathogenic variants in TERT-p, CDKN2A, PTEN, and MYC amplification, were found exclusively in malignant cases. These findings suggest that NGS could refine melanoma diagnosis, which is critical for guiding access to effective therapies.

Somatic mutations in GC-rich promoter regions are significant drivers of cancer, yet their detection is challenging due to poor sequencing coverage in these areas. This study introduces a hybrid capture assay optimized for over 3000 cancer gene promoters, enabling deep sequencing of these complex regions. This method facilitates the discovery of reliable point mutations, short insertions/deletions, copy number variants, and mutational signatures. The assay nominated candidate noncoding driver mutations in CDK4, SMAD3, and GATA3 in breast cancer, paving the way for future functional follow-up.