Abstract

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, NFκB 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.

Highlights

  • Oral squamous cell carcinoma (OSCC) is one of the most common malignancies of the upper aerodigestive tract, with poor prognosis and high mortality rates

  • A total of 163,069 somatic mutations were found by the six callers using the default parameters in the target region

  • This study examined whether DP and minor allele frequency (MAF) were associated with false-positive variant calls

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Summary

Introduction

Oral squamous cell carcinoma (OSCC) is one of the most common malignancies of the upper aerodigestive tract, with poor prognosis and high mortality rates. In 2020 alone, 377,713 new cases of OSCC were diagnosed worldwide, among whom 177,757 have died from their disease [1]. OSCC generally develops as a result of multi-step carcinogenic processes [2]. Multiple lesions may develop concurrently and over large mucosal areas, subsequently progressing into cancers. This may be the reason for the high recurrence of OSCC after treatment [5], as well as the increased incidence and mortality of OSCC worldwide [6]. Understanding the genomic alterations which are associated with OSCC carcinogenesis is crucial for appropriate diagnosis and therapy

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