Role of molecular driver mutations in recurrence of early-stage laryngeal cancer following narrow field definitive radiotherapy

Recurrence in early-stage laryngeal carcinoma after radiation therapy often necessitates a total salvage laryngectomy (TSL). Understanding the genetic landscape that influences cancer progression after radiation therapy may help future treatments. We investigated early-stage laryngeal carcinoma patients treated with radiotherapy to identify mutation patterns that predispose to disease recurrence. The patient cohort had 35 early-stage laryngeal head and neck squamous cell carcinoma (HNSCC) patients (T1 = 15, T2 = 20) treated with radiotherapy (RT). We stratified patients: Responders (no recurrence, N = 14), non-responders (recurrence within 12 months, N = 21), and non-responders undergoing TSL (N = 18). We employed whole exome sequencing to characterize gene mutations using the Genome Analysis Toolkit (GATK) for variant detection and impact on critical biological pathways and post-radiotherapy patient outcomes. Pathway analysis Ingenuity and Reactome Pathway Analysis tools were used to explore the mutated gene pathways. – Differential mutation analysis was performed in the respective groups to find driver genes. In the pre-treatment samples, KCNT2 and AGAP6 mutations were exclusively found in non-responders (OR = 0, P = 0.005 and OR = 0, P = 0.027, respectively), while ADAMTS7 mutations were solely present in responders (OR = inf, P = 0.019). PLEC mutations were more prevalent in responders (OR = 11.6, P = 0.006). Pathway analysis revealed that significant genes were involved in the RND2 GTPase cycle, protein O-glycosylation-related diseases, and apoptotic pathways. Post-treatment analysis in patients undergoing TSL had enrichment of mutations in apoptosis regulation pathways. – The study reveals that mutations in apoptosis controlling genes were predominantly represented in the larynx non-responder patients both in the pre-radiotherapy and post-TSL populations. • Treatment failure is a significant unresolved issue in laryngeal cancer. • Early-stage laryngeal SCC patients were stratified based on radiotherapy response. • Responders and non-responders pre- and post-treatment were sequenced for genetic driver mutations Mutated genes KCNT2 and AGAP6 were found to be specific to non-responders. • Apoptotic cycling genes were found to be mutated in non-responder patients.