A multicenter analysis of genomic profiles and PD-L1 expression of primary lymphoepithelioma-like carcinoma of the lung

Abstract

To understand the molecular mechanism of tumorigenesis of pulmonary lymphoepithelioma-like carcinoma and explore potential therapeutic strategies, we investigated the genomic profiles and PD-L1 expression of 29 Chinese pulmonary lymphoepithelioma-like carcinoma patients at various stages. We performed capture-based targeted sequencing on tissue samples collected from 27 patients with sufficient samples using a panel consisting of 520 cancer-related genes, spanning 1.64 Mb of the human genome. We identified 184 somatic mutations in 109 genes from 26 patients. One patient had no mutations detected by this panel. Copy number variations were detected in 52% (14/27) of the patients, with a majority having advancedstage disease (10/14). Except for the detection of ERBB2 amplification and KRAS mutation in two patients, no other classic lung cancer driver mutations were detected. Interestingly, 78% (21/27) of the patients had mutations in epigenetic regulators. Of the 184 mutations identified, 51 occurred in 29 epigenetics-related genes. Furthermore, we performed PD-L1 immunohistochemistry staining using the Dako 22C3 assay and demonstrated that 69% (20/29) of the cohort had positive PD-L1 expression, of which three patients received and benefited from a PD-1 inhibitor. In conclusion, we elucidated a distinct genomic landscape associated with pulmonary lymphoepithelioma-like carcinoma with no classic lung cancer driver mutation but an enrichment of mutations in epigenetic regulators. The detection of high PD-L1 expression and lack of any canonical druggable driver mutations raises the potential of checkpoint immunotherapy for pulmonary lymphoepithelioma-like carcinoma.

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

“…In this study, 79% of pulmonary LELC were positive with PD-L1 at TPS ≥ 1% by the assessment of PD-L1 IHC 22C3. The result was consistent with previous findings of 66-76% of pulmonary LELC patients positive for PD-L1, with the threshold of 5% positively stained tumor cells [6,9,34]. Among case reports of primary pulmonary LELC patients treated with PD-1 inhibitors, two partial responses were noted, and five patients had stable disease [9,[35][36][37].…”

“…The findings of a distinct genomic background provided insight into how the genetics of pulmonary LELC varied from other NSCLC subtypes. In concordance with previous studies, pulmonary LELC showed a low degree of somatic mutation rate [9,10]. Its median mutation rate was 0.9 and 1.7 mutations per Mb by whole genome sequencing (78×) and targeted sequencing (907×), respectively.…”

“…Notably, both the present study and the previous report observed the enrichment of genetic aberrations in the multiple negative regulators of NF-κB, which have been reported as a genetic feature of the dysregulated NF-κB pathway in a recent genomic study of NPC [15]. In fact, Hong et al identified TRAF3 as one of the frequently mutated genes and Xie et al reported that NFKBIA mutations were frequently detected in pulmonary LELC [9,10]. Intriguing, we revealed multiple loss-of-function mutations in TRAF3, CYLD, NFKBIA and TNFAIP3.…”

The clinicopathological features and prognosis of primary pulmonary lymphoepithelioma-like carcinoma: A systematic review and meta-analysis

“…Besides, the relationship between PD-L1 expression and gene mutations of lung was also arouse concern in recent studies [25,44,45]. Unlike other NSCLC subtypes, PPLELC patients showed lower mutation rates of some common gene, such as ALK, KRAS and EGFR [25,44,45]. The explanation for this may be that there had a unique gene profile in LELC of lung [45].…”

Application of large-scale targeted sequencing to distinguish multiple lung primary tumors from intrapulmonary metastases

“…The copy number cut-off of 1.5 corresponds to copy number deletion and 2.64 for copy number amplifications 21 . Variants were filtered using the VarScan fpfilter pipeline, and loci with depth less than 100 were filtered out 38 . DNA translocation analysis was performed using Tophat2 and Factera1.4.3.…”