Molecular profiling of Head and Neck Squamous Cell Carcinomas identifies possible tumour cell vulnerabilities.

Head and Neck Squamous Cell Cancer (HNSCC) originates from the oral cavity, oropharynx, hypopharynx, and larynx, and it ranks sixth among global cancers. Despite modest 5-year survival gains, the integration of molecular personalization lags behind and there is an urgent need to develop novel therapies and biomarkers. This study outlines the mutational profile of 15 HNSCC-enriched genes in a case series from north-eastern Italy, the region with the highest national HNSCC incidence. We conduct a comparative analysis with prior case studies and assess the prognostic implications of the mutations that we found in these genes. Consistent with previous studies, oral cavity tumours show a lower gene mutation frequency, being mutations in CASP8 the most frequent. We highlight a significant enrichment of AJUBA mutations in the hypopharyngeal region, linked to a poorer prognosis. Moreover, KMT2C mutations co-occurring with CDKN2A or NOTCH1 mutations are associated with a worse prognosis. At the same time, only 7% of the cases exhibit mutations that are predictive biomarker in HNSCC according to compelling clinical evidence but that need further investigation in the clinical trial setting.Our findings underline novel differences in gene mutations among the four anatomic sites. However, at present, the identified mutations cannot yet be considered predictive biomarkers either for the lack of supporting clinical findings or for the lack of approved targeted therapies in HNSCC. This underscores the imperative for continued investigation into the biology of HNSCC to unveil novel vulnerabilities that can be leveraged to enhance patient treatment strategies.