Precise Identification of Recurrent Somatic Mutations in Oral Cancer Through Whole-Exome Sequencing Using Multiple Mutation Calling Pipelines

Understanding the genomic alterations in oral carcinogenesis remains crucial for the appropriate diagnosis and treatment of oral squamous cell carcinoma (OSCC). To unveil the mutational spectrum, in this study, we conducted whole-exome sequencing (WES), using six mutation calling pipelines and multiple filtering criteria applied to 50 paired OSCC samples. The tumor mutation burden extracted from the data set of somatic variations was significantly associated with age, tumor staging, and survival. Several genes (MUC16, MUC19, KMT2D, TTN, HERC2) with a high frequency of false positive mutations were identified. Moreover, known (TP53, FAT1, EPHA2, NOTCH1, CASP8, and PIK3CA) and novel (HYDIN, ALPK3, ASXL1, USP9X, SKOR2, CPLANE1, STARD9, and NSD2) genes have been found to be significantly and frequently mutated in OSCC. Further analysis of gene alteration status with clinical parameters revealed that canonical pathways, including clathrin-mediated endocytotic signaling, NF kappa B signaling, PEDF signaling, and calcium signaling were associated with OSCC prognosis. Defining a catalog of targetable genomic alterations showed that 58% of the tumors carried at least one aberrant event that may potentially be targeted by approved therapeutic agents. We found molecular OSCC subgroups which were correlated with etiology and prognosis while defining the landscape of major altered events in the coding regions of OSCC genomes. These findings provide information that will be helpful in the design of clinical trials on targeted therapies and in the stratification of patients with OSCC according to therapeutic efficacy.

Automated summary

Understanding genomic alterations in oral carcinogenesis is crucial for the diagnosis and treatment of OSCC. The study used WES to uncover mutational spectrum in OSCC samples, revealing associations between tumor mutation burden and clinical parameters. Several high frequency false positive mutation genes were identified, along with known and novel genes frequently mutated in OSCC. Pathway analysis showed associations with OSCC prognosis, and a catalog of targetable genomic alterations was defined, showing potential for targeted therapies in OSCC patients. Analysis also revealed molecular subgroups in OSCC correlated with etiology and prognosis, providing valuable information for clinical trial design and patient stratification.