Abstract
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.