Biomarkers for predicting second primary malignancy risk in head and neck squamous cell carcinoma: An integrated molecular perspective

Second primary malignancies (SPMs) threaten long-term survival in head and neck squamous cell carcinoma (HNSCC). Advancing our understanding of the molecular events driving these secondary tumors is essential. This review has explicated molecular drivers of SPM development, including epigenetic alterations such as DNA hypermethylation, genetic polymorphisms affecting detoxification pathways, and shifts in gene and protein expression profiles. Disruptions in the p53 signaling pathway, immune-related pathways, and impairments in glutathione S-transferase–mediated detoxification, emerge as central contributors to SPM risk. Additionally, direct comparisons of tumor specimens with adjacent or distant normal mucosa highlight field cancerization biomarkers, underscoring widespread carcinogen-induced damage. Loss of heterozygosity at chromosome arm 13q, p53 overexpression in tumor-distant epithelia, and proteomic abnormalities in ostensibly healthy mucosa collectively promote a tumor-prone field that encourages the formation of independent secondary tumors. This interplay underscores a multifactorial landscape of SPM pathogenesis, involving genetic susceptibility, environmental exposures, and intricate epigenetic and transcriptomic networks. By recognizing and validating reliable biomarkers, clinicians may pinpoint high-risk patients with greater precision, intervene earlier, and customize follow-up protocols and treatment regimens. Ultimately, translating these insights into routine practice promises a more proactive, individualized approach to preventing SPMs in HNSCC.