<p>Next-Generation Sequencing Analysis Identified Genomic Alterations in Pathological Morphologies of 3 Cases of Pulmonary Carcinosarcoma</p>

Abstract

Background: Pulmonary carcinosarcomas (PCSs) are a heterogeneous group of non-smallcell lung carcinomas (NSCLCs) with aggressiveness and a poor prognosis. Although genetic mutations of some common lung cancer subtypes have been extensively studied, the molecular characteristics of PCSs and the existence of abnormal target genes are unknown. Methods: In this study, the clinical and molecular characterization in 3 pulmonary sarcomatoid carcinomas (PSCs) were presented using microscope analysis and next-generation sequencing (NGS) analysis. Results: The results revealed a carcinosarcomas subtype presenting squamous cell carcinoma and sarcoma components in all 3 cases. NGS analysis showed that 182, 316 and 230 shared mutations were detected between sarcoma and lung carcinoma from 3 patients. Two identical alterations in two genes (CSMD3 and RYR3) that were all shared by the two components in 3 patients. Tumor suppressor gene TP53 (5/6, 83%) showed the highest mutation frequency for driver genes here. Additionally, we focused on an LYST mutation which was mainly present in the sarcoma components. Moreover, the clonal evolution and signature analysis confirm that lung squamous cell carcinoma and sarcoma in each PCS patient may have come from a common ancestor, and mutagenesis was possibly related to indirect effects of tobacco, age or other unknown factors. Conclusion: Our results indicate that genetic analysis and molecular targeted therapy are necessary for the identification and treatment of these rare lung tumors. CSMD3 and LYST, as common mutation genes, may be a potential therapeutic target in PCS.

Molecular and expressional characterization of tumor heterogeneity in pulmonary carcinosarcoma

“…9 In terms of PCSs comprising squamous cell carcinoma, CSMD3 and LYST were reported to be common mutation genes of both components. 20 However, two cases in our study, including one adenosquamous carcinoma, did not show any alterations. 7 Instead, Case #2 in our study harbored a PIK3CA mutation in the trunk.…”

“…Although TP53 mutations are frequently observed, there seems to be no specific mutation in the development of PCS containing squamous cell carcinoma. However, considering that both epithelial and mesenchymal components of PCSs had TP53 mutations in any of the presented cases, and previously reported to be a frequent mutation, 7,9,14,17,20 TP53 may be an important mutation in the development of the mesenchymal component from carcinoma.…”

“…To date, only 10 PCS cases have been comprehensively analyzed for genetic alterations using next-generation sequencing in both components. 7,9,20 Previous reports showed that two PCSs comprising adenocarcinoma and chondrosarcoma harbored an exon 19 deletion of the epidermal growth factor (EGFR) gene in both components, 8,9 and two other PCSs comprising adenocarcinoma and sarcoma harboring EML4-ALK fusion. 7 In our study, one PCS comprising adenocarcinoma and sarcoma harbored KRAS G12C mutation in both components, and these driver mutations were detected in the trunk of all cases, although EGFR mutation or ALK fusion was not detected in any of the cases.…”

“…To date, only 10 PCS cases have been comprehensively analyzed for genetic alterations using next‐generation sequencing in both components 7,9,20 . Previous reports showed that two PCSs comprising adenocarcinoma and chondrosarcoma harbored an exon 19 deletion of the epidermal growth factor (EGFR) gene in both components, 8,9 and two other PCSs comprising adenocarcinoma and sarcoma harboring EML4 ‐ ALK fusion 7 .…”

“…Moreover, because both components shared driver gene alterations specific to non‐small cell lung cancer and a low frequency of TP53 mutation in sarcoma other than osteosarcoma, 21 it was suggested that the carcinoma component arose before the sarcoma component arose as described before 9 . In terms of PCSs comprising squamous cell carcinoma, CSMD3 and LYST were reported to be common mutation genes of both components 20 . However, two cases in our study, including one adenosquamous carcinoma, did not show any alterations 7 .…”