Molecular characteristics of primary pulmonary lymphoepithelioma-like carcinoma based on integrated genomic analyses

Abstract

Primary pulmonary lymphoepithelioma-like carcinoma (pLELC) is a rare non-small cell lung cancer (NSCLC) subtype. Clinical features have been described in our previous report, but molecular characteristics remain unclear. Herein, pLELC genomic features were explored. Among 41,574 lung cancers, 128 pLELCs and 162 non-pLELC NSCLCs were enrolled. Programmed cell death ligand 1 (PD-L1) and protein 53 (p53) expression was detected in 47 surgically resected pLELC samples by immunohistochemical assays. Multiomics genomic analyses, including whole-genome sequencing (WGS), RNA whole-transcriptome sequencing (RNA-seq), and Epstein-Barr virus (EBV) integration analyses, were performed on eight frozen pLELC tissues and compared with 50 lung adenocarcinomas (LUADs) and 50 lung squamous cell carcinomas (LUSCs) from The Cancer Genome Atlas (TCGA) and another 26 EBV-positive nasopharynx cancers (EBV+-NPCs). Progression-free survival (PFS) and overall survival (OS) of pLELC patients were better than those of non-pLELC patients. High PD-L1 or p53 expression was associated with extended disease-free survival (DFS). pLELC had 14 frequently mutated genes (FMGs). Somatically mutated genes and enrichment of genetic lesions were found, which differed from observations in LUAD, LUSC, and EBV+-nasopharyngeal carcinoma (NPC). Three tumor-associated genes, zinc finger and BTB domain-containing 16 (ZBTB16), peroxisome proliferator activated receptor gamma (PPARG), and transforming growth factor beta receptor 2 (TGFBR2), were downregulated with copy number variation (CNV) loss. EBV was prone to integrating into intergenic and intronic regions with two upregulated miR-BamH1-A rightward transcripts (BARTs), BART5-3P and BART20-3P. Our findings reveal that pLELC has a distinct genomic signature. Three tumor-associated genes with CNV loss and two miR-BARTs might be involved in pLELC tumorigenesis.

Pathogenic Role of Epstein–Barr Virus in Lung Cancers

“…The latest literature search was performed in March 2021. Having carefully evaluated the extracted studies, we selected 42 relevant studies and the EBV status in LCs was summarized in Table 2 [ 12 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 ].…”

“…Indeed, elevated levels of multiple immune checkpoint molecules, such as indoleamine 2,4-dioxygenase (IDO), programmed cell death 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), lymphocyte-activation gene 3 (LAG3), B and T lymphocyte attenuator (BTLA), and v-domain Ig suppressor of T cell activation (VISTA) were also detected in EBV(+) LCs [ 12 ]. Further, several studies have reported that high levels of programmed death-ligand 1 (PD-L1) were observed in EBV(+) LCs [ 64 , 66 ]. These immune inhibitors may contribute to EBV-associated tumor immune tolerance.…”

“…In another study, Chen and colleagues did whole genome sequencing analyses of eight EBV(+) LC samples with LELC subtype [ 66 ]. The somatic mutation profiles were compared to the ones of 50 EBV(−) LUAD, 50 EBV(−) LUSC, and 26 EBV(+) NPC samples.…”

Prognostic Significance of Regional/Systemic Metabolic Parameters on 18F-FDG PET in Pulmonary Lymphoepithelioma-Like Carcinoma

“…Pulmonary LELC has been recognized as a unique lung carcinoma which is closely related to EBV infection with genomic landscape and clinicopathological features strikingly distinctive to NSCLC ( 16 ). Pulmonary LELC had better prognosis, and previous studies also have discovered that classic lung cancer oncogenic drivers including KRAS, EGFR, BRAF, ALK, and ROS1 were limitedly involved in tumorigenesis and progression of pulmonary LELC ( 8 , 17 ).…”

Microfluidics applications for high-throughput single cell sequencing

“…Single cell sequencing is a new technology for high-throughput sequencing analysis of genetic material at individual cell level, which promotes rapid advances in revealing heterogeneity in cell subtype classification and physiology identification. Genome, transcriptome, and epigenome sequencing are fundamental constitutions that reflect single-cell developmental trajectory [ 54 ]. Single cell genome sequencing, that is scDNA-seq, reveals mutations and structural changes of the cell genomes, and highlights the somatic clonal structure and track the evolution and spread of the diseases [ 55 ].…”