Genomic Profiling of Laryngeal Squamous Cell Carcinoma Reveals Novel Biomarkers for Precision Medicine

<b>Objective(s):</b> 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. <b>Methods</b>: 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. <b>Results:</b><i>TP53</i> mutations were most common (89.6%), followed by <i>KMT2D</i> (27.4%), <i>FAT1</i> (20.7%), and <i>NOTCH1</i> (20.7%). <i>CDK8</i> mutations were enriched in females (<i>p</i> = 0.011) and <i>ATP8B1</i> in males (<i>p</i> = 0.013). <i>DMD</i> mutations characterized primary tumors (<i>p</i> = 0.049), whereas <i>ATP8B1</i> and <i>SAMD9L</i> were linked to metastases (<i>p</i> < 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 <i>CDK8</i> in females and <i>ATP8B1</i> in males, suggests potential avenues for tailored therapeutic interventions. <b>Conclusions:</b> LSCC exhibits marked genetic heterogeneity dominated by <i>TP53</i> alterations. <i>ATP8B1</i> and <i>SAMD9L</i> 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 <i>TP53</i>-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.