Prognostic and Clinicopathological Significance of FADD Upregulation in Head and Neck Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis

Abstract

Fas-associated death domain (FADD) upregulation, i.e., gene amplification, protein phosphorylation and/or overexpression, has shown promising prognostic implications in head and neck squamous cell carcinoma (HNSCC). This systematic review and meta-analysis aims to evaluate the clinicopathological and prognostic significance of FADD upregulation in HNSCC. We searched studies published before February 2020 through PubMed, Embase, Web of Science, Scopus and Google Scholar. We evaluated the quality of the studies included using the QUIPS tool. The impact of FADD upregulation on survival and clinicopathological variables was meta-analysed. We explored heterogeneity and their sources, conducted sensitivity analyses and investigated small-study effects. Thirteen studies (1,923 patients) met inclusion criteria. FADD immunohistochemical overexpression was statistically associated with worse overall survival (hazard ratio [HR] = 1.52, 95% confidence intervals [CI] = 1.28–1.81, p < 0.001), disease-specific survival (HR = 2.52, 95% CI = 1.61–3.96, p < 0.001), disease-free survival (HR = 1.67, 95% CI=1.29–2.15, p < 0.001), higher clinical stage (odds ratio [OR] = 1.72, 95% CI = 1.17–2.51, p = 0.005) and a large magnitude of effect with N+ status (OR = 2.36, 95% CI = 1.85–3.00, p < 0.001). FADD phosphorylation in ser-194 demonstrated no prognostic value, while no conclusive results can be drawn for FADD gene amplification. In conclusion, our findings indicate that immunohistochemical assessment of FADD overexpression could be incorporated into the prognostic evaluation of HNSCC.

FAS receptor regulates NOTCH activity through ERK-JAG1 axis activation and controls oral cancer stemness ability and pulmonary metastasis

“…Free N-terminal FLIP fragment can interact with TRAF1/2 induce NF-κB activation [ 44 ]. Recently, FADD upregulation or S194 phosphorylation are important prognostic biomarkers in multiple cancer progression, especially in OSCC [ 45 – 47 ]. Moreover, constitutively phosphoryl-mimicking mutation of FADD also enhances Notch-1 signaling in muscle regeneration through promoting ERK phosphorylation is consistent with our finding in oral cancer cells [ 48 ].…”

Development and Validation of an Autophagy-Related Signature for Head and Neck Squamous Cell Carcinoma

“…Also, a study found that high FADD expression always results in worse OS, DSS, and DFS in patients with HNSCC and thus has potential values for prognostic prediction and treatment planning development [ 26 , 27 ]. A meta-analysis has found that immunohistochemical assessment of FADD could be incorporated into the prognostic evaluation of HNSCC [ 28 ]. In addition, NKX2-3 is a member of the NKX family, which is a series of the homeodomain transcription factors.…”

Prognostic Gene Signature for Squamous Cell Carcinoma with a Higher Risk for Treatment Failure and Accelerated MEK-ERK Pathway Activity

“…Finally, BZW1 and CAMK2A were not reported in SCC tumors yet; however, they were identified as prognostic markers in non-SCC tumors [46][47][48][49]. In the past, several prognostic biomarkers or gene sets have been published of which some have been confirmed by systematic reviews and meta-analyses for HNSCC more recently [50][51][52]. It is worth noting that none of them are included in our list of survival-related candidate genes and consequently are not part of the prognostic 18 gene signature for risk prediction.…”