Abstract
Amplification of 11q13.3 is a frequent event in human cancers, including head and neck squamous cell carcinoma. This chromosome region contains several genes that are potentially cancer drivers, including FADD (Fas associated via death domain), an apoptotic effector that was previously identified as a novel oncogene in laryngeal/pharyngeal cancer. This study was designed to explore the role of FADD in oral squamous cell carcinomas (OSCCs) samples from Taiwanese patients, by assessing copy number variations (CNVs) and protein expression and the clinical implications of these factors in 339 male OSCCs. The intensity of FADD protein expression, as determined by immunohistochemistry, was strongly correlated with gene copy number amplification, as analyzed using a TaqMan CNV assay. Both FADD gene copy number amplification and high protein expression were significantly associated with lymph node metastasis (P < 0.001). Patients with both FADD copy number amplification and high protein expression had the shortest disease-free survival (DFS; P = 0.074 and P = 0.002) and overall survival (OS; P = 0.011 and P = 0.027). After adjusting for primary tumor status, tumor differentiation, lymph node metastasis and age at diagnosis, DFS was still significantly lower in patients with either copy number amplification or high protein expression (hazard ratio [H.R.] = 1.483; 95% confidence interval [C.I.], 1.044–2.106). In conclusion, our data reveal that FADD gene copy number and protein expression can be considered potential prognostic markers and are closely associated with lymph node metastasis in patients with OSCC in Taiwan.
Highlights
Gene amplification refers to the somatically acquired increase in copy number of a restricted region of the genome, and this process is one of the underlying genomic mechanisms that results in overexpression of a dominantly acting oncogene [1]
In the current study of male head and neck squamous cell carcinoma (HNSCC) patients, we showed that FADD amplification was present in 69 of 339 cases (20.4%), and gene amplification was associated with a higher incidence of lymph node metastasis (LNM) and extracapsular spread (ECS)
FADD protein overexpression is closely associated with FADD copy number
Summary
Gene amplification refers to the somatically acquired increase in copy number of a restricted region of the genome, and this process is one of the underlying genomic mechanisms that results in overexpression of a dominantly acting oncogene [1]. Amplification of oncogenes such as the epidermal growth factor receptor (EGFR) gene is accompanied by protein overexpression and can be associated with poor prognosis in human cancers [2]. Several studies have demonstrated that there are at least three candidate oncogenes, CCND1, FADD (Fas associated via death domain) and CTTN, within 11q13.3 [3]. Its amplification has been reported in breast cancer, HNSCC, esophageal squamous cell carcinoma, hepatocellular cancer, melanoma and neuroblastoma. FADD amplification has been demonstrated to play a role in laryngeal/pharyngeal cancer [17], and high protein expression (43%) was shown to be associated with worse survival in patients with tongue cancer [18]
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