Comprehensive genomic profiling of adenoid cystic carcinoma using the AACR Genie Database.

6072 Background: Adenoid cystic carcinoma (ACC) is a rare neoplasm of the secretory glands, comprising <1% of head and neck tumors. While most commonly arising in salivary glands, ACC has also been reported in the skin, breasts, prostate, and female genital tract. Despite multimodal treatment, no standardized therapeutic approach exists, and prognosis remains poor, with a 5-year survival rate of 50-60%. This study utilizes the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database to characterize the genomic landscape of ACC and identify prognostic biomarkers and therapeutic targets. Methods: The AACR GENIE database was accessed via cBioPortal (v18.0-public) on December 12, 2025, to identify ACC cases. Frequently mutated genes, demographic associations, and patterns of mutual exclusivity were evaluated using two-sided t-tests and non-parametric analyses with Benjamini-Hochberg false discovery rate correction. Results: A total of 540 samples from 500 patients were analyzed, of whom 229 (45.8%) were male, and 266 (53.2%) were female. The cohort included 334 (66.8%) non-Hispanic patients and 39 (7.8%) Hispanic patients. By race, 334 (66.8%) were White, 46 (9.2%) Asian, and 42 (8.4%) Black. Most tumor samples were metastatic (293, 54.3%), followed by primary tumors (217, 40.2%). The most frequently mutated genes were NOTCH1 (n=152; 28.1%), KDM6A (n=59; 10.9%), ARID1A (n=54; 10.0%), BCOR (n=52; 9.6%), KMT2C (n=44; 8.1%), and KMT2D (n=42; 7.7%). Sex-stratified analysis demonstrated FH mutations occurring exclusively in females (n=4, p<0.001), and a higher prevalence of KMT2C in female patients (n=25 vs n=8, p<0.001). TET2 alterations were more frequent in males (n=8 vs n=1). Race-based analysis identified GATA3 mutations exclusively in Asian patients (n=2; p=0.002) and a higher frequency of FGFR3 alterations in Asians compared with non-Asian patients (n=2 vs n=1; p=0.0447). Co-occurrence was observed between NOTCH1 and ARID1A (n=21/106; p<0.001), CREBBP (n=17/98; p<0.001), and KDM6A (n=22/117; p=0.003). Additional co-occurrence was noted between KDM6A and ARID1A (n=14/80; p<0.001), and CREBBP with PIK3CA (n=8/50; p=0.001). Mutations in APC (n=6; p<0.001), CDK12 (n=4; p=0.05), ELF3 (n=4; p<0.05), MDM2 (n=4; p<0.05), and JAK2 (n=4; p<0.05) were observed exclusively in primary tumors. Conclusions: To our knowledge, this is the first comprehensive analysis of ACC using the GENIE database. Our findings corroborate prior reports implicating CREBBP , NOTCH1 , and KDM6A in ACC while identifying a novel demographic association with GATA3 mutations exclusive to Asian patients. These findings highlight CREBBP , NOTCH1 , KDM6A, and GATA3 as potential targets for future therapeutic development.