High homology of carcinomatous component and sarcomatous component in pulmonary carcinosarcoma and heterogeneity of gene expression among different patients.

Abstract

e20534 Background: Pulmonary carcinosarcoma (PCS) is a rare subtype of non-small-cell lung cancer (NSCLC) which is highly aggressive and currently has no optimal treatment. Previous studies have shown that some potential markers for targeted therapy and immunotherapy have been detected in PCS patients. A few studies and cases have used microdissection to separate the carcinomatous component (CaC) and sarcomatous component (SaC) component of PCS and performed DNA-based next-generation sequencing (NGS) and confirmed that the two components are highly homologous. There are no studies yet to analyze the differences between CaC and SaC in PCSs from multiple aspects including DNA, RNA, and protein expression assays. Methods: 10 tumor tissues from 5 PCS patients were divided into CaCs and SaCs by microdissection, DNA-based NGS with a 520 gene panel, RNA-based NGS with a 115 gene panel, and Immunohistochemistry (IHC) were performed on these samples. The same type of detection results for different components of the tumors were used for comparative analysis, and the overall DNA test results of the two components were used to compare with detection data of NSCLC and lung sarcoma in the TCGA database respectively. Results: No significant differences were found between CaC and SaC at both DNA, RNA, and IHC assays. The most commonly mutated genes in this cohort of patients were TP53 (10/10, 100%), KRAS (6/10, 60%), LRP1B (5/10, 50%), RBM10, PTPRT, AKT2 (both are 4/10, 40%). Notably, all the mutated genes detected were more similar to those detected in NSCLC rather than mutated genes commonly found in sarcomas. In addition, regardless of DNA or RNA sequencing, no landmark fusion variants were detected in the four available sarcoma tissues. Single sample gene set enrichment analysis (ssGSEA) was used to analyze the RNA results of the matched CaC and SaC of the three patients, no difference in RNA expression among different types of tissues in the same patient was found, but gene expression heterogeneity among the 3 patients was very high. IHC results showed that the positive rates of PD-L1, CD3 and CD8 in the 5 CaCs were 40%, 100% and 100%, while this value was 80%, 100% and 100% in the 5 SaCs. PD-L1 showed a trend of high expression rate in SaC tissues of PCS patients. Conclusions: This study showed that the CaC and SaC tissues of the same PCS patient were both highly homologous in terms of DNA, RNA and protein expression, but the RNA expression was highly heterogeneous among different patients. The landscape of genetic alterations revealed that PCSs are molecularly more likely to arise from NSCLC rather than lung sarcomas, which suggests that for these patients, it may be suitable to choose a treatment plan for the pathological type of the carcinomatous component.