Investigation of CBX4 Polymorphisms and Their Association with Clinicopathological Features in Asian Patients with Oral Squamous Cell Carcinoma

Head and neck squamous cell carcinomas (HNSCCs) are derived from the mucosal epithelium in the oral cavity, pharynx and larynx, and are predominantly linked to behavioral risk factors such as tobacco use and excessive alcohol consumption. In Taiwan, oral squamous cell carcinoma (OSCC) is one of the most prevalent subtypes of HNSCC and ranks as the fifth leading cause of cancer-related mortality in the country. The Chromobox (CBX) gene family encodes core subunits of the canonical Polycomb Repressive Complex 1 (cPRC1), a key epigenetic regulator mediating chromatin compaction and transcriptional silencing through histone modification. Dysregulation of CBX gene expression, whether at the transcriptional or post-transcriptional level, has been increasingly linked to tumorigenesis, metastasis, and cancer recurrence in a variety of malignancies. In particular, CBX4 has been implicated in the progression of gastric cancer, with growing evidence suggesting its broader role in cancer development. From the TCGA database, we found that levels of CBX4 are lower in Asian OSCC patients compared with other races. This prompted us to further investigate the genetic landscape of CBX4 in oral cancer. We conducted a case-control study involving 1184 male OSCC patients and 1188 healthy controls to evaluate whether genetic variants in CBX4, in conjunction with environmental exposures, contribute to OSCC susceptibility and progression in an Asian population. Four single-nucleotide polymorphisms (SNPs) of CBX4 (rs1285251, rs2289728, rs3764374 and rs77447679) were selected for genotyping using real-time PCR. After adjusting for confounding factors such as age, smoking, alcohol intake, and betel-nut chewing, our analysis revealed that individuals harboring the CC or CT genotype at rs3764374 had a significantly increased risk of developing OSCC compared to those with the wild-type genotype. Notably, among male patients who had no history of betel-quid chewing, those carrying the CC/CT genotype at rs3764374 or the CA/AA genotype at rs77447679 exhibited a greater likelihood of presenting with stage II or III OSCC, indicating more advanced disease. These findings support the notion that specific CBX4 polymorphisms may contribute to the pathogenesis and clinical progression of OSCC, particularly in populations exposed to distinct environmental risk factors. This study provides new insights into the gene-environment interplay in OSCC and suggests potential biomarkers for risk stratification and disease monitoring in Asian male populations.