Genetic polymorphisms of the X‐linked transcription factor forkhead box P3 predispose to synchronous secondary primary malignancy (SPM) of esophagus in head and neck squamous cell carcinoma patients

Abstract

AbstractPatients with head and neck squamous cell carcinoma (HNSCC) are prone to develop second primary malignancy (SPM) at the esophagus synchronously, especially those with increased forkhead box P3 (FOXP3) positive regulatory T (Treg) cell infiltration in tumor tissue. We tested whether FOXP3 genetic polymorphisms can be associated with Treg cell infiltration and synchronous SPM in HNSCC patients. HNSCC patients received screening esophagogastroduodenoscopy during 2008 to 2016 were enrolled consecutively. After excluding and matching cigarette smoking and alcohol drinking status, the final cohort went on investigation. Three tag single nucleotide polymorphisms (tag SNPs) of the FOXP3 gene (rs2232365, rs3761548, and rs3761549) were selected from the HapMap database and genotyped by RT‐PCR. FOXP3 immunohistochemistry was done to evaluate Treg cell amount in tumor tissues. A total of 270 male HNSCC patients were included, including 135 in the synchronous SPM (SynSPM group) and 135 in the HNSCC alone group. Compared with HNSCC alone group, synchronous SPM group had a HNSCC that was more commonly located at oro/hypopharynx (55.0% vs 39.6%, P = .012) and at earlier TNM stage with borderline significance (38.8% vs 29.0%, P = .124). In addition, carriage of G allele in rs3761549 of the FOXP3 gene significantly increased synchronous SPM risk (crude OR = 2.21, P = .009). After adjustment of HNSCC location and staging, rs3761549 G allele remained significantly associated with synchronous SPM risk (adjusted OR = 2.10, P = .024). Patients with G allele in rs3761549 also had higher FOXP3+ Treg cell infiltration in the tumor tissue than those with A allele (mean FOXP3+ cell number/mm2: 55.93 vs 36.39, P = .008). Male HNSCC patients with G allele in rs3761549 of the FOXP3 gene has a higher risk of synchronous SPM development and merit earlier screening endoscopy.