Background: Chordoma is a rare primary tumor originating from embryonic notochord remnants, with limited systemic therapeutic options due to a poor understanding of its genomic landscape. This study aims to characterize the genetic alterations in chordoma using a large national patient-level genomic repository, the AACR Project GENIE, to identify potential therapeutic targets and improve disease modeling. Methods: A retrospective analysis of chordoma samples was conducted using the AACR Project GENIE database. Targeted sequencing data were analyzed for recurrent somatic mutations, tumor mutational burden, and chromosomal copy number variations, with significance set at p < 0.05. Results: Frequent mutations were observed in genes associated with SWI/SNF complex affecting chromatin remodeling (SETD2, PBRM1, ARID1A). Mutations were also common among the TERT promoter regions, and cell cycle regulation (CDKN2A). Significant co-occurrences were identified among PBRM1, BRCA2, and KMT2D mutations. CDKN2A/B deletions were enriched in metastatic tumors, and pediatric cases demonstrated distinct mutation profiles compared to adults. Conclusions: This study provides a genomic profile of chordoma, identifying key mutations and potential therapeutic targets. These findings highlight the roles of chromatin remodeling and cell cycle pathways in chordoma biology, offering insights for future precision medicine approaches and therapeutic interventions.

Background: Mycosis fungoides (MF) is a rare cutaneous T-cell lymphoma (CTCL) that presents clinically on the skin as patches, plaques, or tumors. MF often mimics benign inflammatory conditions which leads to difficult and delayed diagnosis, worsening prognosis despite available treatment options. This study seeks to improve diagnosis and identify potential therapeutic targets by better characterizing MF’s genetic landscape using the AACR Project GENIE dataset. Methods: Retrospective analysis of MF cases was conducted using the AACR Project GENIE database accessed from cBioPortal (v17.0-public) on 5 June 2025. Data analysis included identifying recurrent somatic mutations, assessing patterns of mutation co-occurrence and mutual exclusivity using non-parametric tests with Benjamini–Hochberg False Discovery Rate (FDR) correction, and examining enrichment of specific mutations based on sex and race, with significance of p < 0.05. Results: Recurrent alterations included FAT1 (28.2%), KMT2D (19.2%), TP53 (13.5%), JAK3 (11.5%), and SETBP1 (11.5%), highlighting the role of Wnt signaling, epigenetic dysregulation, the p53 pathway, and JAK/STAT signaling in MF pathogenesis. Mutations with significant co-occurrence and enrichment in White, Black, and Asian populations were identified. Conclusions: The findings of this study provide a comprehensive understanding of MF’s molecular profile. The discovery of commonly mutated pathways (Wnt, p53, JAK/STAT, and epigenetic regulators) suggests potential targets for the development of future therapies. Furthermore, the enrichment of certain mutations based on race and patterns of alteration co-occurrence offer possibilities for patient-tailored treatment approaches.

Background: Despite the high mortality associated with angiosarcoma, its low prevalence has limited sample sizes in prior studies. To address these gaps, we analyzed the AACR Project GENIE registry, a large, multi-institutional database. Methods: 359 tumor samples from 346 patients with angiosarcoma were identified from the AACR Project GENIE v18.0-public database using cBioPortal. Somatic mutations and copy number alterations were assessed. Statistical significance was assessed by t-test for continuous variables and a chi-squared test for categorical data, with significance set at p < 0.05. Results: Recurrent mutations included TP53 (20.6%), KDR (13.6%), and PIK3CA (10.6%). Copy number alterations occurred in MYC (27.3%), CRKL (10.4%), FLT4 (5.5%), and KDR (4.8%). Homozygous deletions occurred in CDKN2A (6.6%), CDKN2B (6.56%), and MTAP (3.81%). Significant co-occurrence included FAT1-NOTCH2, TP53-ATRX, and NOTCH1-ARID1A. Mutual exclusivity was seen with KDR-FLT4 and KDR-ATRX. Females exhibited enrichment in MYC and HRAS, while males exhibited enrichment in POT1, NTRK2, and FAT1. Compared with primary tumors, metastatic tumors more often displayed ZFHX4, FGFR1, MSI2, HIST1H1C, and TOP1 mutations, while MAPK7 mutations occurred only in primary tumors. Conclusions: In one of the largest genomic analyses of angiosarcoma to date, we identified recurrent alterations, suggesting potential future therapeutic targets.

Bladder and urothelial carcinoma are marked by profound genomic diversity. Using a large, multi-institutional dataset, we performed comprehensive genomic profiling of 4631 tumor samples from 4050 individuals. A retrospective analysis of bladder and urothelial cancer was performed using the AACR Project GENIE database. Demographic associations, mutation frequencies, copy number changes, and survival correlations were analyzed with a p-value < 0.05. Frequent mutations were identified in TP53, TERT, KDM6A, KMT2D, ARID1A, and FGFR3. Mutation frequencies varied by sex and race, with specific alterations enriched in female and Asian patients. Distinct patterns of co-occurrence, including TP53 with RB1, and mutual exclusivity, including TP53 with FGFR3 or KDM6A, revealed distinct molecular subtypes. This study highlights the extensive heterogeneity of bladder cancer, and our findings emphasize the clinical importance of molecular stratification and support the need for further mechanistic and prospective studies to inform the development of targeted therapies.

Background: Cutaneous squamous cell carcinoma (cSCC) represents one of the most common keratinocyte-derived malignancies encountered in clinical practice; however, its genomic landscape remains far less comprehensively characterized than that of other cutaneous cancers. This study aims to identify key molecular drivers and potential therapeutic targets by comprehensively characterizing the genomic landscape of cSCC using data from the American Association for Cancer Research (AACR) Project Genomics, Evidence, Neoplasia, Information, Exchange (GENIE) consortium. Methods: A retrospective cohort analysis of cSCC samples was performed utilizing AACR Project GENIE data accessed via the cBioPortal platform (v18.0-public) on 22 November 2025. Analyses included identification of recurrent somatic and copy-number alterations, pairwise gene–gene co-occurrence testing using Fisher’s exact tests with Benjamini–Hochberg False Discovery Rate (FDR) correction, and exploratory subgroup comparisons by sex and race, with statistical significance defined as p < 0.05. Results: Recurrent mutations were identified in TP53 (83.5%), NOTCH1 (56.3%), KMT2D (47.0%), CDKN2A (44.4%), TERT (41.4%), ROS1 (34.3%), FAT1 (33.3%), NOTCH2 (31.2%), ERBB4 (28.4%), and KMT2A (24.3%), reflecting disruption of the p53 pathway, cell-cycle control, Notch signaling, epigenetic regulation, telomere maintenance, RTK/MAPK pathways, and Wnt signaling. Statistically significant co-occurrence patterns were observed, and exploratory subgroup analyses evaluated mutation frequency differences by sex and race. Conclusions: This large, multi-institutional genomic analysis defines recurrent mutational and structural alterations in cSCC and highlights an integrated pattern of pathway disruption involving genomic integrity, differentiation, epigenetic control, and proliferative signaling. These findings enhance current understandings of the molecular architecture underlying this common yet genomically understudied malignancy and provide a foundation for future mechanistic studies and development of targeted diagnostic and therapeutic strategies.

Background: Nasopharyngeal carcinoma (NPC) is a rare head and neck cancer arising from the mucosal lining of the nasopharynx, for which systemic therapeutic options remain scarce, reflecting the limited characterization of its genomic profile. This study utilized a large patient-level genomic repository to characterize genetic alterations, identify potential therapeutic targets, and improve disease modeling in NPC. Methods: A retrospective analysis of NPC samples was conducted using the AACR Project GENIE database. Targeted sequencing data were analyzed for recurrent somatic mutations, tumor mutational burden, and chromosomal copy number variations, with significance set at p < 0.05. Results: Frequent mutations were identified in KMT2D (20%), TP53 (16%), CYLD (9.6%), NFKBIA (6.4%), and PIK3CA (5.6%), implicating the p53, NF-κB, and PI3K pathways in NPC development. Notably, significantly distinct mutational profiles were observed based on both sex and race, with female patients exhibiting higher frequencies of PIK3C2G, ETV6, and CDKN1B mutations and non-Asian patients showing enrichment in KDM5A, CCND2, and TP53 mutations. Conclusions: This study presents a detailed genomic profile of NPC, identifying key mutations within established cancer-associated pathways. The identification of frequently mutated pathways (p53, NF-κB, and PI3K) suggests potential targets for novel therapies. Furthermore, distinct mutational landscapes in female and Asian NPC patients offer possibilities for precision therapeutic interventions.