Causal effect of interstitial lung disease on lung cancer risk in never-smokers and prognostic insights from Mendelian randomization and transcriptome analysis.

Introduction: The relationship between interstitial lung disease (ILD) and lung cancer in nonsmokers (LCINS) has garnered increasing interest. However, the causal associations and underlying pathogenesis between ILD and LCINS remain poorly understood.

Methods: This research utilized a bidirectional two-sample Mendelian randomization (MR) method, utilizing forward MR analysis to assess the causal impact of ILD on LCINS and reverse MR analysis to evaluate the causal effect of LCINS on ILD. Additionally, transcriptome data and bioinformatics analyses were used to explore the associations between ILD and LCINS. An ILD-related gene signature (ILD risk score) was identified to examine its influence on the hallmark signaling pathways and the immune microenvironment in LCINS.

Results: The study revealed a significant causal relationship between ILD and LCINS, with ILD increasing the risk of lung cancer in nonsmoking European populations. We developed a 5-gene risk model, which includes CD1A, CDH3, KRT6B, MMP1, and MMP10, via least absolute shrinkage and selection operator (LASSO) regression. The ILD risk score independently influences the prognosis of nonsmoking patients with lung cancer, and these five genes are also significantly associated with overall survival (OS) rates. Patients in the high-ILD risk subgroup exhibited significantly poorer survival rates. A highly accurate nomogram was developed to increase the clinical applicability of the ILD risk score. Additionally, the ILD risk scores were significantly correlated with hallmark signaling pathways and immune cell infiltration.

Conclusions: This study suggested that ILD may have a positive causal effect on LCINS, with the ILD risk score serving as an effective predictor of the prognoses in LCINS patients. It is associated with tumor proliferation and the activation of metabolism-related signaling pathways. These findings also indicate that ILD may contribute to the occurrence and progression of LCINS through its influence on immune cell infiltration.