Cancer Res Treat.  2024 Apr;56(2):442-454. 10.4143/crt.2023.764.

Genomic Landscape of Pulmonary Sarcomatoid Carcinoma

• Kwon HJ
• Lee S
• Han YB
• Lee J
• Kwon S
• Kim H
• Chung JH

• KMID: 2554335
• DOI: http://doi.org/10.4143/crt.2023.764

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 programmed death-ligand 1 (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.

Keyword

Pulmonary sarcomatoid carcinoma; MET; APOBEC; Programmed cell death-ligand 1; Exome sequencing

Figure

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  Fig. 1. Study design. LN, lymph node; PSC, pulmonary sarcomatoid carcinoma; QC, quality control; TCD, carcinomatous component of the primary tumor; TD, primary tumor; TID, primary tumor with inseparable components; TSD, sarcomatous component of the primary tumor.

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  Fig. 2. Mutational landscape of pulmonary sarcomatoid carcinoma. Whole exome sequencing results of primary tumors (A) and metastatic tumors (B). Lollipop plot of the most commonly mutated gene, TP53, in both primary and metastatic PSC (C). MET exon 14 skipping mutations, validated by digital droplet polymerase chain reaction, were present in five cases (D). Distant metastasis, metastasis to sites other than regional lymph nodes, detected clinically; MD, metastatic tumor; PD-L1, programmed death-ligand 1; PSC, pulmonary sarcomatoid carcinoma; TD, primary tumor including all histologic components; TMB, tumor mutation burden; TPS, tumor proportion score.

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  Fig. 3. Copy number variation analysis of micro-dissected carcinomatous and sarcomatous components in pulmonary sarcomatoid carcinoma. Copy number variation of primary carcinomatous (A) and primary sarcomatous (B) components. TCD, carcinomatous component of primary tumor; TSD, sarcomatous component of primary tumor.

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  Fig. 4. Mutational profiling and phylogenic analysis of the selected seven pulmonary sarcomatoid carcinoma cases. Comparison of frequently mutated genes in the micro-dissected three tissue samples of each case (A). Phylogenic trees of representative cases, including case SC13 with no driver mutations, case SC14 with EGFR and TP53 mutation, and case SC33 with KRAS and TP53 mutation (B). Overlapping mutations in the three types of tumor samples are indicated by black trunks, and mutations common only to primary samples are indicated by red trunks. Mutations specific to TCD, TSD, and MD samples are indicated by orange, blue, and black lines, respectively. Length is proportional to the number of variants. ADC, adenocarcinoma; ASC, adenosquamous carcinoma; EGFR, epidermal growth factor receptor; MD, metastatic tumor; n, number of mutations; PD-L1, programmed death-ligand 1; SqCC, squamous cell carcinoma; TCD, carcinomatous component of primary tumor; TPS, tumor proportion score; TSD, sarcomatous component of primary tumor.

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  Fig. 5. Mutational signature of the selected seven pulmonary sarcomatoid carcinoma cases. The APOBEC mutational signature (Signature 2) was characteristically absent or reduced in metastatic tumor samples. MD, metastatic tumor; TCD, carcinomatous component of primary tumor; TSD, sarcomatous component of primary tumor.

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  Fig. 6. Comparative analysis of frequent mutations in untreated primary lung cancer using whole exome sequencing. The Cancer Genome Atlas (TCGA) data from cbioportal.org and East Asian data from two large cohorts [18,19] were compared to pulmonary sarcomatoid carcinoma whole exome sequencing results obtained in this study. SNV/INDEL were considered. INDEL, insertion and deletion; LUAD, lung adenocarcinoma; LUSC, squamous cell carcinoma; PSC, pulmonary sarcomatoid carcinoma; SNV, single nucleotide variation; VAF, variable allelic frequency.

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