The - 216G/T polymorphism in the EGFR gene: A review focusing on Non-Small lung cancer.

The epidermal growth factor receptor (EGFR) is a key regulator of cell proliferation and a well-established therapeutic target in non-small-cell lung cancer (NSCLC). Somatic mutations in the EGFR gene have been widely studied in the context of tyrosine kinase inhibitors (TKIs), but germline polymorphisms as potentially predictive biomarkers have emerged as a variants of interest over the years. Among these, the - 216G/T (rs712829) single nucleotide polymorphism (SNP), located in the EGFR promoter region, is gaining attention for its potential clinical relevance. This narrative review aims to provide a comprehensive chronological overview of the discovery, functional implications, clinical relevance, and broader oncological and non-oncological associations of the EGFR - 216G/T SNP. Relevant studies were identified from 2005 to 2025 through literature searches across publicly available databases and bibliographies of key publications. This SNP was associated to increased EGFR promotor activity, pleural metastasis, susceptibility to EGFR mutations, NSCLC risk, and different inter-individual and inter-ethnic allele frequencies. Conflicting findings regarding survival outcomes and toxicity underscore the need for further validation. Beyond NSCLC, this SNP has demonstrated relevance in colorectal cancer, glioma, breast cancer, cardiovascular disease, and even COVID-19 susceptibility. The - 216G/T polymorphism represents a promising germline biomarker for NSCLC susceptibility. However, population-specific studies and investigations integrating multi-omics data, along with machine learning models are essential to clarify its utility in precision oncology.