Background: Medullary thyroid cancer (MTC), a neuroendocrine tumor originating from thyroid parafollicular C-cells, presents therapeutic challenges, particularly in advanced stages. While RET proto-oncogene mutations are known drivers, a comprehensive understanding of the broader somatic mutation landscape is needed to identify novel therapeutic targets and improve prognostication. This study leveraged the extensive AACR Project GENIE dataset to characterize MTC genomics. Methods: A retrospective analysis of MTC samples from GENIE examined recurrent somatic mutations, demographic/survival correlations, and copy number variations using targeted sequencing data (significance: p < 0.05). Results: Among 341 samples, RET mutations predominated (75.7%, mostly M918T), followed by HRAS (10.0%) and KRAS (5.6%), with mutual exclusivity between RET and RAS alterations. Recurrent mutations included KMT2D (5.3%), CDH11 (5.3%), ATM (5.0%), and TP53 (4.1%). NOTCH1 mutations were enriched in metastatic cases (p = 0.023). Preliminary associations included sex-linked mutations (BRAF/BRCA1/KIT in females, p = 0.028), and survival (ATM associated with longer survival, p = 0.016; BARD1/BLM/UBR5/MYH11 with shorter survival, p < 0.05), though limited subgroup sizes warrant caution. Conclusions: This large-scale genomic analysis confirms the centrality of RET and RAS pathway alterations in MTC and their mutual exclusivity. The association of NOTCH1 mutations with metastasis suggests a potential role in disease progression. While findings regarding demographic and survival correlations are preliminary, they generate hypotheses for future validation. This study enhances the genomic foundation for understanding MTC and underscores the need for integrated clinico-genomic datasets to refine therapeutic approaches.

Background/Objectives: Astrocytoma, IDH-mutant, CNS WHO grade 3, is a diffuse glioma with poor prognosis, molecularly defined by IDH mutations and frequently co-occurring TP53 and ATRX alterations. This study aimed to delineate the genomic landscape and identify clinically relevant molecular features of astrocytoma, IDH-mutant, CNS WHO grade 3 using this resource. Methods: Patients in the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange (AACR Project GENIE) database were selected based on histological diagnosis of “anaplastic astrocytoma”, confirmed IDH1/2 mutation, and exclusion of CDKN2A/B homozygous deletions. We analyzed frequencies of somatic mutations, copy number alterations (CNAs), structural variants (SVs), assessed co-occurrence/exclusivity patterns, and explored associations with available demographic and limited survival data. Results: The most common somatic mutations were in IDH1 (98.0%), TP53 (94.8%), and ATRX (55.2%). The observed ATRX mutation frequency was lower than some historical reports (e.g., ~86%). Other recurrent alterations included phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) (6.9%), Notch receptor 1 (NOTCH1) (6.9%), and platelet-derived growth factor receptor alpha (PDGFRA) (mutations 4.3%; CNAs also observed). Conclusions: This study provides a comprehensive genomic characterization of astrocytoma, IDH-mutant, CNS WHO grade 3 using the AACR GENIE database, confirming core mutational signatures while also highlighting potential variations in alteration frequencies, such as for ATRX. The findings establish a valuable real-world genomic benchmark for this tumor type, while promoting the need for continued data integration with robust clinical outcomes to identify actionable prognostic and therapeutic targets.