Distinct Molecular Landscape of Epstein-Barr Virus Associated Pulmonary Lymphoepithelioma-Like Carcinoma Revealed by Genomic Sequencing

Pulmonary lymphoepithelioma-like carcinoma (LELC) is a subtype of non-small cell lung cancer (NSCLC) characterized by marked lymphocytic infiltration and association with Epstein-Barr virus (EBV). The molecular basis underlying the disease remains unclear. We sought to study the molecular landscape by multiple approaches including whole genomic sequencing, capture-based targeted sequencing, fluorescent in situ hybridization and immunohistochemistry. Tumor cells from 57 EBV-positive pulmonary LELCs were isolated by careful microdissection prior to genomic sequencing. Integrated analysis revealed a distinct genomic landscape of lowTP53mutation rate (11%), low incidence of known drivers in the RTK/RAS/RAF (11%) and PI3K/AKT/mTOR pathways (7%), but enriched for loss-of-function mutations in multiple negative regulators of the NF-kappa B pathway. High level programmed cell death ligand-1 (PD-L1) expression was shown with 47% and 79% of the cases showing positive PD-L1 immunoreactivity at >= 50% and >= 1% tumor proportion score, respectively. Subsets of the patients with actionable fibroblast growth factor receptor 3 (FGFR3)aberrations (4%) and mismatch repair deficiency (4%) were potentially eligible for precision medicine. Pulmonary LELC showed a distinct genomic landscape, different from major NSCLC subtypes but resembled that of EBV-associated nasopharyngeal carcinoma. Our work facilitated the understanding of molecular basis underlying pulmonary LELC to explore potential therapeutic options.