KIF13B C.3163G>A VARIANT IN OROPHARYNGEAL SQUAMOUS CELL CARCINOMA: ASSOCIATIONS WITH RISK AND CLINICAL OUTCOMES

Abstract

Introduction

Oropharyngeal squamous cell carcinoma (OPSCC) is a highly malignant tumor of the head and neck region, frequently diagnosed at advanced stages and associated with unfavorable clinical outcomes. Established risk factors include tobacco use, alcohol consumption, and infection with high-risk human papillomavirus (HPV) types. It is already well known that inherited genetic variations, such as single nucleotide variants (SNVs), can influence OPSCC susceptibility and tumor behavior. The KIF13B gene encodes a kinesin-3 family motor protein that mediates microtubule-dependent transport of intracellular cargoes, processes that can affect cell signaling, proliferation, and migration. Variants located in regulatory regions, such as the 3’-untranslated region (3’-UTR), may alter gene expression by affecting microRNA binding or transcript stability. A preliminary study from our group identified an association between the KIF13B c.*3163G>A SNV and tongue base cancer risk; however, its role in OPSCC and patient prognosis remains unclear.

Objective

To evaluate the association between KIF13B c.*3163G>A genotypes and OPSCC risk, clinicopathological characteristics, and patient survival, as well as investigate its functional role in the encoded protein.

Methods

A total of 250 OPSCC patients and 250 controls were included in this study. Genomic DNA was extracted from peripheral blood leukocytes, and KIF13B c.*3163G>A SNV genotypes were determined using polymerase chain reaction (PCR). The patients were treated with cisplatin chemoradiation with or without surgical resection of the tumor. Overall survival (OS) and event-free survival (EFS) were estimated using Kaplan-Meier analysis. The functional interaction between let-7e-3p and the KIF13B 3′-UTR harboring either allele was evaluated by luciferase reporter assays in FaDu and Detroit 562 pharyngeal carcinoma cell lines. Statistical significance was set at p = 0.05.

Results

The KIF13B c.*3163GG genotype was observed more frequently in OPSCC patients compared with controls (42% vs. 32%; p = 0.03), corresponding to a 1.73-fold increased risk of developing OPSCC. This genotype was also more prevalent among patients with larger tumor extension (46% vs. 28%; p = 0.01) and was associated with a 2.47-fold higher likelihood of aggressive disease (p = 0.004). At 60 months of follow-up, patients carrying the GG or GA genotypes had lower OS compared with those with the AA genotype (41.5 vs. 68.2 %, p = 0.046). No differences were observed in EFS among patients with the distinct genotypes. Functional assays demonstrated that let-7e-3p interacted more efficiently with the 3’-UTR containing the ancestral G allele than with the variant A allele in both FaDu (34.1% vs. 43.3%; p = 0.004) and Detroit 562 (37.9% vs. 61.8%; p = 0.04) pharyngeal carcinoma cell lines.

Conclusions

The KIF13B c.*3163G>A SNV is associated with increased inherited susceptibility to OPSCC, more aggressive tumor features, and reduced OS. Functional evidence suggests that allele-specific regulation by let-7e-3p may contribute to these associations by modulating post-transcriptional control of KIF13B. Together, these findings suggest that this SNV may be relevant for OPSCC risk stratification and prognosis. Further functional studies are being conducted to better understand the biological mechanisms involved.