Associations of HMGA2 single-nucleotide polymorphisms with clinicopathological features of tongue squamous cell carcinoma in Taiwanese men with distinct lifestyle-related risk factors

Abstract

Background Oral squamous cell carcinoma (OSCC) is a predominant malignancy of the oral cavity, with tongue squamous cell carcinoma (TSCC) accounting for a substantial proportion of cases worldwide. High-mobility group A protein 2 (HMGA2) is a nonhistone chromatin-binding factor implicated in aggressive malignant phenotypes of various human cancers. However, the effects of HMGA2 variants on OSCC susceptibility and tumor clinicopathological aggressiveness remain unclear. Methods We examined the associations of functional HMGA2 single-nucleotide polymorphisms (SNPs) with TSCC susceptibility and aggressive tumor characteristics in Taiwanese men. Four tagging SNPs (rs6581658 A>G, rs10573247 T>del, rs968697 T>C, and rs8756 A>C) were genotyped using a TaqMan allelic discrimination assay. In addition, HMGA2 expression patterns, as well as their associations with disease aggressiveness and patient survival outcomes, were analyzed using multiple independent datasets, including TCGA, CPTAC, and GEO. Results Our results indicated no significant association between the four SNPs and TSCC susceptibility. However, carriers of the rs6581658 G allele had significantly increased risks of large tumors (>T2) and advanced clinical stage (stage III or IV) in the dominant model. Moreover, the rs10573247 variant was significantly associated with an increased risk of lymph node metastasis in patients exposed to environmental carcinogens, including betel quid and cigarette smoke. By contrast, the rs968697 variant exerted a protective effect against advanced disease and lymph node metastasis in patients without such environmental exposure. Analyses of clinical datasets pertaining to an American cohort with head and neck squamous cell carcinoma and a Taiwanese cohort with OSCC revealed that HMGA2 expression was upregulated in tumor tissues and was associated with poor prognosis. Conclusion These findings suggest potential exposure-stratified association in TSCC and highlight HMGA2 polymorphisms as promising biomarkers for risk assessment and disease monitoring in male patients with TSCC.