Abstract
As the incidence and the mortality rate of head and neck squamous cell carcinoma (HNSCC) is increasing worldwide, gaining knowledge about the genomic changes which happen in the carcinogenesis of HNSCC is essential for the diagnosis and therapy of the disease. SMAD4 (DPC4) is a tumor suppressor gene. It is located at chromosome 18q21.1 and a member of the SMAD family. Which mediates the TGF-β signaling pathway, thereby controlling the growth of epithelial cells. In the study presented here, we analyzed tumor samples by multiplex PCR-based next-generation sequencing (NGS) and found deleterious mutations of SMAD4 in 4.1% of the tumors. Knock-down experiments of endogenous and exogenous SMAD4 expression demonstrated that SMAD4 is involved in the migration and invasion of HNSCC cells. Functional analysis of a missense mutation in the MH1 domain of SMAD4 may be responsible for the loss of function in suppressing tumor progression. Missense SMAD4 mutations, therefore, could be useful prognostic determinants for patients affected by HNSCCs. This report is the first study where NGS analysis based on multiplex-PCR is used to demonstrate the imminent occurrence of missense SMAD4 mutations in HNSCC cells. The gene analysis that we performed may support the identification of SMAD4 mutations as a diagnostic marker or even as a potential therapeutic target in head and neck cancer. Moreover, the analytic strategy proposed for the detection of mutations in the SMAD4 gene may be validated as a platform to assist mutation screening.
Highlights
Head and neck squamous cell carcinomas (HNSCC), which include oral squamous cell carcinomas, are the sixth most prevalent malignancy worldwide [1, 2]
For the evaluation of the performance of SMAD4 in clinical assessments, 122 HNSCC samples were analyzed by multiplex PCR-based next-generation sequencing (NGS) and loss of heterozygosity status (LOH) analysis
Varying rates of SMAD4 mutations have been detected in a wide range of cancers by large-scale exome sequencing
Summary
Head and neck squamous cell carcinomas (HNSCC), which include oral squamous cell carcinomas, are the sixth most prevalent malignancy worldwide [1, 2]. The pathogenesis of HNSCC is affected by many molecular factors, among them e.g., mutations in TP53, and genes related to PIK3CA and Notch family signaling [3,4,5,6,7,8,9]. The role which these factors are playing in the progression of the tumors remains unclear to a wide extent [3, 4, 6, 10, 11]. The analysis of WES data which was obtained from The Cancer Genome Atlas (TCGA) [6, 14] pointed to novel genes with significant mutations and underlined the complex molecular pathogenesis of HNSCC, which includes a high degree of heterogeneity between tumors [15]
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