Genetic variations and clinical significance in young-onset nasopharyngeal cancer: Analysis of EBV interaction with cellular receptor variants and viral glycoproteins

Abstract

Nasopharyngeal cancer (NPC), although rare in young individuals worldwide, is significantly influenced by the Epstein-Barr virus (EBV). Considering EBV's widespread prevalence, understanding its role in NPC's future occurrence, disease progression, clinical symptoms, metastatic tendencies, and prognosis is crucial. In this study, we extensively analyzed two young patients with NPC, who displayed distinct clinical features. We utilized Whole Exome Sequencing (WES), concentrating on EBV-interacting receptors, and applied advanced in silico methods for a deeper investigation. These methods included structural analysis via SWISS-MODEL, stability assessments using PremPS, and molecular docking studies with ClusPro. Our focus was to analyze genetic variants identified by WES and confirm EBV presence using RT-qPCR. Our comparative study between the two subjects showed that the first had milder symptoms and a lower metastasis than the second. In the first subject, we identified unique genetic variants: NRP1 c.536T > C (p.Val179Ala) and MYH9 c.4876A > G (p.Ile1626Val). Notably, the NRP1 p.Val179Ala variant caused structural changes leading to protein instability. Molecular docking suggested that this variant enhances interaction more than the wild-type. RT-qPCR validation of EBV showed lower levels in subject one (mutant-NRP1) compared to subject two (wild-type-NRP1). This finding implies that the p.Val179Ala variant in subject one could obstruct EBV entry, possibly leading to less severe clinical symptoms Our research provides new insights into the genetic factors influencing the clinical presentation of NPC, identifying promising targets for further research and therapeutic interventions. However, additional validation in a larger cohort is required to elucidate the broader impact of these genetic variants.

Keywords: EBV; Genetic variant; In-silico; NRP1; Nasopharyngeal cancer.

Fig. 1

Three-dimensional CT scans. (a) subject 1; (b) subject 2.

Fig. 2

Qualitative Evaluation of Blind Docking Results on both Wild-Type and Mutant Models with the EBV Envelope. a) NRP1-gB 1; b) NRP1-gB 2; c) NRP1-gH/gL 1.

Fig. 3

Proposed Mechanism of Interaction between NRP1 (NM_003873.7:c.536T > C, p.Val179Ala) and EBV. The variant NRP1 NM_003873.7:c.536T > C results in the alteration of the A allele to the G allele, leading to a substitution of valine with alanine at position 179 (p.Val179Ala). During protein synthesis, this variant induces alterations in the structure, leading to the instability of the NRP1 protein. This modified structure enhances the energy binding between NRP1 and EBV, which could potentially inhibit the entry of EBV. As a consequence, the presence of this variant might be associated with milder clinical.