Objective(s): To characterize the somatic mutational landscape of laryngeal squamous cell carcinoma (LSCC) using AACR Project GENIE data to identify potential biomarkers for tumor progression and guide precision therapy. Methods: Clinical and genomic data from 135 LSCC samples (primary and metastatic) were analyzed from the AACR Project GENIE database. Mutations were compared by tumor site and gender using chi-squared and Mann–Whitney U tests; co-occurrence and mutual-exclusivity analyses were performed. Results: TP53 mutations were most common (89.6%), followed by KMT2D (27.4%), FAT1 (20.7%), and NOTCH1 (20.7%). CDK8 mutations were enriched in females (p = 0.011) and ATP8B1 in males (p = 0.013). DMD mutations characterized primary tumors (p = 0.049), whereas ATP8B1 and SAMD9L were linked to metastases (p < 0.001). The cohort was 85.9% male and 71.5% White; 59.2% of samples were primary and 39.2% recurrent/metastatic. Co-occurrence analysis identified distinct molecular subtypes. The identification of distinct molecular subtypes and gender-specific mutations, such as CDK8 in females and ATP8B1 in males, suggests potential avenues for tailored therapeutic interventions. Conclusions: LSCC exhibits marked genetic heterogeneity dominated by TP53 alterations. ATP8B1 and SAMD9L mutations may mark metastatic disease, and gender-specific mutations suggest avenues for personalized therapy. These insights support development of targeted strategies, including immunotherapies such as pembrolizumab in TP53-altered tumors. These insights into the genomic heterogeneity of LSCC lay the groundwork for developing targeted therapeutic strategies and patient stratification, ultimately advancing a personalized medicine approach to this disease.

Objective: We aimed to characterize the somatic mutational landscape of oropharyngeal squamous cell carcinoma (OPSCC) and identify potential genomic drivers of tumor progression and therapeutic resistance using the AACR GENIE database. Study Design: Retrospective genomic analysis was employed. Setting: We used publicly available data from the American Association for Cancer Research (AACR) Project GENIE database accessed via cBioPortal. Methods: We analyzed 412 tumor samples from 401 patients diagnosed with OPSCC. Somatic mutations, clinical variables and tumor characteristics were extracted and analyzed. Statistical comparisons of mutation frequencies across gender and tumor stage (primary vs. metastatic) were conducted. Co-occurrence and mutual exclusivity analyses were performed to identify significant genomic patterns. Results: The most frequently mutated genes included TP53 (30.1%), PIK3CA (26.0%), and KMT2D (21.6%). Gender-specific analyses suggested potential enrichment of TP53 and MET mutations in females and of ZNF750 in males. Distinct mutation patterns were observed between primary and metastatic tumors; primary tumors were enriched for mutations in TP53 and CDKN2A, while metastatic lesions harbored unique alterations in genes like CBLB and BUB1B, suggesting pathways involved in immune evasion and chromosomal instability may drive disease progression. Co-occurrence was noted between PIK3CA and FBXW7, and mutual exclusivity between TP53 and CYLD. Conclusions: This study identifies distinct genomic signatures in OPSCC subgroups, highlighting candidate biomarkers in pathways like PI3K/AKT signaling that warrant further investigation. Validating these markers in prospective trials is a critical next step to translate these findings into personalized therapeutic strategies for OPSCC patients.