Our previous large-scale genotyping study identified more than 6,000 single nucleotide polymorphisms (SNPs) associated with base of tongue (BT) squamous cell carcinoma (SCC) risk in 49 patients and 49 controls. The SNP c.*293A>G of the ERP29, a tumor-suppressor chaperone, was selected for further analyses. An in silico analysis showed that microRNA (miR)-4421 shared binding site with 3’-untranslated region of variant allele of referred SNP while wild-type allele disrupt this target site. However, the role of this SNP in the risk and prognosis of oropharynx SCC (OPSCC) patients is still unknown. We aimed to verify whether the distinct genotypes or ERP29 c.*293A>G SNP influence the OPSCC risk and prognosis, and the ERP29 and miR-4421 expressions.
DNA from 250 OPSCC patients and 250 controls was analyzed by RT-PCR. The patients were treated with surgery, radiotherapy and/or platinum based agents. The ERP29 and miR-4421 levels were evaluated by qPCR using RNA of 58 controls. The differences between groups were calculated by chi-square, logistic regression model and Mann-Whitney tests. Progression-free survival (PFS) and overall survival (OS) times were calculated by Kaplan-Meier and Cox regression methods.
ERP29 variant GG genotype was more common in OPSCC patients than in controls (6.4% vs. 3.6%, P = 0.002). Individuals with GG genotype were under 8.86-fold increased risk of OPSCC than others (95% CI: 2.20-35.69). Considering only the BTSCC patients, at 36 months of follow-up, shorter PFS were seen in patients with variant GG genotype (0.0% vs. 39.1%, P = 0.01, Cox: HR: 2.68, 95% CI: 1.21-5.95, P = 0.01). Individuals with ERP29 wild-type genotype showed higher levels of ERP29 mRNA when compared to others (1.44 vs. 1.10 arbitrary units AUs, P = 0.005). In addition, lower miR-4421 expression was observed in individuals with ERP29 AA genotype when compared to those with AG or GG genotypes (0.42 vs. 0.73 AUs, P = 0.05).
Our data present, for the first time, that ERP29 c.*293A>G SNP is associated with increased risk of OPSCC and with worst survival of BTSCC patients, possibly due to variation of ERP29 mRNA levels modulated by miR-4421.
Clinical trial identification
Legal entity responsible for the study
University of Campinas
São Paulo Research Foundation (FAPESP) and Coordination for the Improvement of Higher Education Personnel (CAPES)
All authors have declared no conflicts of interest.