| Sumario: | Simple Summary: Lung squamous cell carcinoma (LUSC) frequently develops in patients with chronic lung diseases, including idiopathic pulmonary fibrosis (IPF), pulmonary emphysema, and smoking-related interstitial fibrosis (SRIF); however, the underlying carcinogenetic mechanisms remain unclear. We investigated selected molecular alterations in tumor and non-tumorous lung tissues from patients with LUSC arising in these underlying diseases. Methylation-specific PCR revealed frequent p16 exon 2 methylation in tumor tissues across all cases. Notably, p16 exon 2 methylation was also detected in distant non-tumor lung tissue from patients with IPF, a pattern not observed for the promoter of p16, CDH13, or RASSF1A. Furthermore, p16 protein expression was lower in IPF- or PE-associated LUSC than in SRIF-associated LUSC. These results suggest that the carcinogenetic processes underlying LUSC may vary according to the type of pre-existing lung disease. Elucidating these disease-specific molecular pathways may contribute to improved detection and therapeutic strategies for LUSC in patients with chronic lung disorders. Lung squamous cell carcinoma (LUSC) tends to arise in the setting of interstitial or emphysematous lung diseases, including idiopathic pulmonary fibrosis (IPF), pulmonary emphysema (PE), and smoking-related interstitial fibrosis (SRIF), where field cancerization may extend. DNA methylation of promoter regions of p16, CDH13, and RASSF1A and p16 exon 2 was assessed by methylation-specific PCR. Tumor, adjacent (<3 cm), and distant (≥3 cm) lung tissues were obtained from 25 patients with LUSC (IPF, n = 7; PE, n = 8; SRIF, n = 10). p16 exon 2 methylation was significantly higher in tumors than in non-tumorous tissues in PE and SRIF cases. In contrast, IPF cases showed p16 exon 2 hypermethylation also in distant tissues. Across tumor samples, p16 promoter hypermethylation was frequently observed in stage II or higher. p16 expression in tumors was generally reduced in IPF and PE cases, compared with SRIF cases. No consistent methylation or expression patterns were observed for CDH13 or RASSF1A. p16-associated molecular alterations exhibited disease- and stage-related differences, suggesting heterogeneity in LUSC carcinogenesis. These findings indicate a broader epigenetic field effect, as reflected by p16 exon 2, in IPF-associated LUSC and suggest that complex, elusive mechanisms underlying p16 aberrations may contribute to this phenomenon.
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