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Cancer Research and Treatment > Epub ahead of print
doi: https://doi.org/10.4143/crt.2023.764    [Epub ahead of print]
Genomic Landscape of Pulmonary Sarcomatoid Carcinoma
Hyun Jung Kwon1,2 , Sejoon Lee2, Yeon Bi Han1,2, Jeonghyo Lee1,2, Soohyeon Kwon1,2, Hyojin Kim1,2, Jin-Haeng Chung1,2,3
1Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
2Department of Pathology and Translational Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
3Artificial Intelligence Institute of Seoul National University, Seoul, Korea
Correspondence  Jin-Haeng Chung ,Tel: 82-31-787-7713, Fax: 82-31-787-4012, Email: chungjh@snu.ac.kr
Received: June 19, 2023;  Accepted: November 13, 2023.  Published online: November 14, 2023.
*Hyun Jung Kwon and Sejoon Lee contributed equally to this work.
ABSTRACT
Purpose
Pulmonary sarcomatoid carcinoma (PSC) is a rare aggressive subtype of non-small cell lung cancer (NSCLC) with limited therapeutic strategies. We attempted to elucidate the evolutionary trajectories of PSC using multiregional and longitudinal tumor samples.
Materials and Methods
A total of 31 patients were enrolled in this study and 11 longitudinal samples were available from them. Using whole-exome sequencing data, we analyzed the mutational signatures in both carcinomatous and sarcomatous areas in primary tumors of the 31 patients and longitudinal samples obtained from 11 patients. Furthermore, digital droplet polymerase chain reaction (ddPCR), and PD-L1 immunohistochemistry using the Ventana SP263 assay were performed.
Results
TP53 was identified as the most frequently altered gene in the primary (74%) and metastatic (73%) samples. MET exon 14 skipping mutations, confirmed by ddPCR, and TP53 mutations were mutually exclusive; whereas, MET exon 14 skipping mutations frequently co-occurred with MDM2 amplification. Metastatic tumors showed dissimilar genetic profiles from either primary component. During metastasis, the signatures of APOBEC decreased in metastatic lesions compared with that in primary lesions. PSC showed higher MET and KEAP1 mutations and stronger PD-L1 protein expression compared with that recorded in other NSCLCs.
Conclusion
Decreased APOBEC signatures and subclonal diversity were detected during malignant progression in PSC. Frequent MET mutations and strong PD-L1 expression distinguished PSC from other NSCLCs. The aggressiveness and therapeutic difficulties of PSC were possibly attributable to profound intratumoral and intertumoral genetic diversity. Next-generation sequencing could suggest the appropriate treatment strategy for PSC.
Key words: Pulmonary sarcomatoid carcinoma, MET, APOBEC, Programmed cell death-ligand 1, Exome sequencing
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