Greater susceptibility of patients with idiopathic pulmonary fibrosis to basal cell carcinoma: a combined genomics and Mendelian randomization analysis

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal lung disease associated with significant morbidity and frequent complications. Basal cell carcinoma (BCC) is a common skin malignancy often diagnosed at the intermediate to advanced stages. Emerging evidence suggests that a epidemiological link exists between these conditions. This study aimed to investigate the shared genomic landscape and causal relationship between IPF and BCC and to clarify the related underlying molecular mechanisms and therapeutic implications. Methods: Gene expression datasets (GSE10667, GSE24206, and GSE53845) were obtained from the Gene Expression Omnibus database. After normalization and integration, differential expression analysis identified 1,333 differentially expressed genes (DEGs) between patients with IPF and controls. Subsequently, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway functional enrichment analyses were performed. Mendelian randomization (MR) analysis was conducted with summary statistics from genome-wide association studies to infer the effect of IPF on BCC risk. Furthermore, a gene-drug interaction network and a competing endogenous RNA (ceRNA) network (consisting of long noncoding RNAs, microRNAs, and messenger RNAs) were constructed via Cytoscape to identify potential therapeutic targets. Results: Enrichment analysis indicated a significant overrepresentation of the BCC signaling pathway among the DEGs, with 12 core genes shared between IPF and BCC pathogenesis being identified. These genes involved in critical molecular pathways and are correlated with certain immune cell interactions, suggesting a mechanistic link between IPF and BCC. The MR analysis provided evidence of a genetic basis for the causal relationship: compared to the general population, individuals with a genetic predisposition to IPF have a significantly higher risk of developing BCC. The networks highlighted key regulatory nodes and potential drug targets within the shared pathophysiology of the two diseases. Conclusions: This study integrating genomic and causal inference study demonstrated that patients with IPF are at an increased risk of developing BCC. Further MR analysis indicated that this association is underpinned by shared genetic pathways, immune-related interactions, and a causal relationship. The core genes and regulatory networks identified in this study help clarify the molecular nature of the link between these diseases and offers novel avenues for devising therapeutic strategies targeting IPF and comorbid BCC.