Molecular characterization of EBV-associated primary pulmonary lymphoepithelial carcinoma by multiomics analysis.

Background: Primary pulmonary lymphoepithelial carcinoma (pLEC) is a subtype of non-small cell lung cancer (NSCLC) characterized by Epstein-Barr virus (EBV) infection. However, the molecular pathogenesis of pLEC remains poorly understood.

Methods: In this study, we explored pLEC using whole-exome sequencing (WES) and RNA-whole-transcriptome sequencing (RNA-seq) technologies. Datasets of normal lung tissue, other types of NSCLC, and EBV-positive nasopharyngeal carcinoma (EBV+-NPC) were obtained from public databases. Furthermore, we described the gene signatures, viral integration, cell quantification, cell death and immune infiltration of pLEC.

Results: Compared with other types of NSCLC and EBV+-NPC, pLEC patients exhibited a lower somatic mutation burden and extensive copy number deletions, including 1p36.23, 3p21.1, 7q11.23, and 11q23.3. Integration of EBV associated dysregulation of gene expression, with CNV-altered regions coinciding with EBV integration sites. Specifically, ZBTB16 and ERRFI1 were downregulated by CNV loss, and the FOXD family genes were overexpressed with CNV gain. Decreased expression of the FOXD family might be associated with a favorable prognosis in pLEC patients, and these patients exhibited enhanced cytotoxicity.

Conclusion: Compared with other types of NSCLC and NPC, pLEC has distinct molecular characteristics. EBV integration, the aberrant expression of genes, as well as the loss of CNVs, may play a crucial role in the pathogenesis of pLEC. However, further research is needed to assess the potential role of the FOXD gene family as a biomarker.