Bioinformatics profiling of NECTIN4 in lung cancer and comparative evaluation of NECTIN4-targeted ⁶⁸Ga-N188 and ¹⁸F-FDG PET/CT

BACKGROUND: The nectin cell adhesion molecule 4 (NECTIN4) has been implicated in tumor progression and immune evasion, yet its role and translational targeted imaging potential in lung cancer remain unclear. Therefore, this study aims to elucidate the significance of NECTIN4 by integrating multi-omics analyses, and to evaluate the diagnostic efficacy of the NECTIN4-targeted PET/CT imaging in lung cancer. METHODS: Transcriptomic and proteomic datasets from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Gene Expression Omnibus (GEO) and other bioinformatic tools were used to characterize NECTIN4 expression, genomic alterations, epigenetic regulation, and prognostic relevance in lung cancer. Subsequently, in a prospective clinical cohort study involving 20 patients with suspected primary lung cancer, paired PET/CT imaging using 68Ga-N188 and 18F-FDG was conducted. Diagnostic performances were assessed by quantitatively comparing the tumor-to-blood pool ratio between malignant and inflammatory lesions. RESULTS: Bioinformatics analyses indicated that NECTIN4 was significantly upregulated across multiple cancer types and correlated with genomic instability and poor prognosis in non-small cell lung cancer (NSCLC). NECTIN4 expression was positively associated with DNA methyltransferases and RNA modifications, suggesting that it may be regulated by epigenetic and post-transcriptional. As for NECTIN4-targeted imaging, ⁶⁸Ga-N188 PET/CT exhibited superior specificity (100% vs. 50%) and comparable sensitivity (87.5% vs. 93.8%) to ¹⁸F-FDG PET/CT in differentiating malignant from inflammatory lung lesions, but with lower sensitivity (42.2% vs. 100.0%) for detecting lymph node metastases and fewer identified distant metastatic lesions (21 vs. 51). CONCLUSION: Integrated bioinformatics analyses prove that overexpression of NECTIN4 is associated with occurrence and progression of lung cancer. Further preliminary clinical translation study suggests the potential of NECTIN4-targeted radiotracer ⁶⁸Ga-N188 to aid in the differential diagnosis of lung cancer, highlighting a promising clinical application warrants further validation.