Abstract
Information regarding the molecular features of pulmonary pleomorphic carcinoma (PPC) is insufficient. Here, we performed next-generation sequencing to determine the genomic and transcriptomic profiles of PPC. We sequenced the DNAs and RNAs of 78 specimens from 52 patients with PPC. We analyzed 15 PPC cases to identify intratumoral differences in gene alterations, tumor mutation burden (TMB), RNA expression, and PD-L1 expression between epithelial and sarcomatoid components. The genomic alterations of six cases of primary tumors and corresponding metastatic tumors were analyzed. KRAS mutations (27%) were the most common driver mutations, followed by EGFR (8%), and MET (8%) mutations. Epithelial and sarcomatoid components shared activating driver mutations, and there were no significant differences in CD274 expression or TMB between the two components. However, PD-L1 was highly expressed in the sarcomatoid component of several cases compared with the epithelial component. Primary and metastatic tumors shared oncogenic mutations among genes such as KRAS and TP53, and additional alterations including NOTCH4 mutations were specifically identified in the metastatic regions. Our data suggest that therapies targeting activating driver mutations may be effective for patients with PPC and that immune checkpoint inhibitors of PPC may be recommended after careful assessment of PD-L1 expression in each epithelial and sarcomatoid component.
Highlights
Pulmonary pleomorphic carcinoma (PPC) is a rare subtype of nonsmall cell lung cancer (NSCLC) that accounts for 0.4–1.6% of malignant lung tumors[1,2]
Sixty-six samples were from the primary tumors, and the other eight samples were obtained from the metastatic regions
When we searched for biomarkers that distinguished between epithelial and sarcomatoid components using the Wald test, we found that ACE2, AQP3, BCAS1, BNIPL, FHDC1, MUC21, PARM1, PGC, SCGB3A2, and SFTA) were significantly expressed only in the epithelial group (q < 0.05, Fig. 4c)
Summary
Pulmonary pleomorphic carcinoma (PPC) is a rare subtype of nonsmall cell lung cancer (NSCLC) that accounts for 0.4–1.6% of malignant lung tumors[1,2]. According to the 4th edition of the World Health Organization Classification of Lung Tumors[3], PPC is defined as a poorly differentiated NSCLC comprising ≥10% spindle or giant cells. These tumors, which predominantly arise in men who heavily smoke, are characterized by a poor response to cytotoxic chemotherapy and a worse outcome than other types of NSCLC4,5. Many PPCs comprise an admixture of sarcomatoid (spindle or giant cell elements or both) and epithelial components (adenocarcinoma, squamous cell carcinoma, or undifferentiated NSCLC)
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