Assessment of the Mutation Profile of Tonsillar Squamous Cell Carcinomas Using Targeted Next-Generation Sequencing

Abstract

Data regarding driver mutation profiles in tonsillar squamous cell carcinomas (TSCCs) remain scarce, limiting the understanding of its pathogenesis and unexpected behavior in the updated staging system. We investigated the incidence of clinically relevant mutations and their contribution in the prognosis of the condition, and their association with human papillomavirus (HPV) infection and adjuvant therapy. We subjected 43 surgically resected TSCC samples to targeted next-generation sequencing, determined their HPV status using polymerase chain reaction, and performed The Cancer Genomic Atlas and Gene Set Enrichment analyses. Thirty-five TSCC samples (81.4%) showed at least one oncogenic/likely oncogenic mutation among twenty-nine cancer-related genes. The top five mutated genes were TP53 (46.5%), PIK3CA (25.6%), PTEN (18.6%), EGFR (16.3%), and SMAD4 (14.0%). The EGFR pathway was the most frequently affected (51.2%), followed by the p53 (48.8%), PI3K (39.5%), and RTK (34.9%) pathways. The gene set enrichment analysis confirmed that the genes involved in signal transduction, such as growth factor receptors and second messengers, EGFR tyrosine kinase inhibitors, and PI3K signaling pathways, were mostly related with TSCCs. TP53 mutation was an independent prognostic factor predicting worse overall survival in the adjuvant therapy group. RTK mutations were related to survival in all patients and in the HPV-positive group, but multivariate analyses showed no significance. In conclusion, oncogenic/likely oncogenic mutations were relatively high in TSCCs, and TP53 and RTK mutations may be candidate predictors for poor prognosis in the adjuvant therapy and HPV-positive groups, respectively, under the updated staging system.

Dysregulated microRNA Expression Relevant to TERT Promoter Mutations in Tonsil Cancer—A Pilot Study

“…These molecular distinctions highlight the unique attributes of HPV-positive SCCs, further reinforcing the stark contrast with HPV-negative SCCs [10][11][12]. We have recently conducted clinicopathological investigations focused on identifying clinically significant mutations and their association with prognosis and HPV infection in patients with TSCC [10,13]. We determined the prevalence of oncogenic/likely oncogenic mutations among 30 cancer-related genes, including TP53, PIK3CA, PTEN, EGFR, SMAD4, and TERT promoter (TERTp) genes, where mutations in TP53, receptor tyrosine kinase (RTK) pathway genes, and TERTp demonstrated prognostic relevance [10,13].…”

“…A retrospective analysis of 80 consecutive patients with TSCC who underwent primary resection at Hallym University Sacred Heart Hospital between 1997 and 2018 was conducted using the electronic search of the Pathology Department database, considering patients without prior treatment and with comprehensive medical records available. These patients also participated in previous studies [10,13]. A total of 58 patients were excluded due to insufficient mutational results; unsuitability of formalin-fixed, paraffin-embedded (FFPE) tissue blocks; and the absence of contralateral normal tonsil tissues, which are required for molecular investigation of miRNA expression profiling.…”

“…Delineating between HPV-associated and HPV-negative head and neck squamous cell carcinomas (SCCs) reveals significant molecular disparities, ranging from genetic variations to epigenetic changes and distinct protein expression patterns [10,11]. These molecular distinctions highlight the unique attributes of HPV-positive SCCs, further reinforcing the stark contrast with HPV-negative SCCs [10][11][12].…”

“…Delineating between HPV-associated and HPV-negative head and neck squamous cell carcinomas (SCCs) reveals significant molecular disparities, ranging from genetic variations to epigenetic changes and distinct protein expression patterns [10,11]. These molecular distinctions highlight the unique attributes of HPV-positive SCCs, further reinforcing the stark contrast with HPV-negative SCCs [10][11][12]. We have recently conducted clinicopathological investigations focused on identifying clinically significant mutations and their association with prognosis and HPV infection in patients with TSCC [10,13].…”

“…We have recently conducted clinicopathological investigations focused on identifying clinically significant mutations and their association with prognosis and HPV infection in patients with TSCC [10,13]. We determined the prevalence of oncogenic/likely oncogenic mutations among 30 cancer-related genes, including TP53, PIK3CA, PTEN, EGFR, SMAD4, and TERT promoter (TERTp) genes, where mutations in TP53, receptor tyrosine kinase (RTK) pathway genes, and TERTp demonstrated prognostic relevance [10,13]. Moreover, emerging evidence suggests that the primary driving forces behind head and neck SCC may be epigenetic rather than genetic factors, highlighting the crucial involvement of miRNAs in modulating these epigenetic changes [11].…”