New therapeutic targets for pulmonary sarcomatoid carcinomas based on their genomic and phylogenetic profiles

Objectives: Pulmonary sarcomatoid carcinomas are rare and generally aggressive tumors composed of carcinomatous and sarcomatous components; however, the evolution of sarcomatoid cancer has not been elucidated. Here, we aimed to evaluate the mutational profiles and phylogeny of sarcomatoid carcinomas using next generation sequencing and in-silico analysis to facilitate the development of novel therapies. Methods: Four patients who underwent surgery for sarcomatoid cancer were enrolled. Cancer cells were collected from carcinomatous and sarcomatous components in each tumor by laser capture microdissection. Next-generation sequencing was performed in each component, and the mutation profiles were compared. For further inference of phylogenies, phylogenetic and PyClone analyses were performed. Mismatch repair disturbance and programmed death ligand-1 (PD-L1) expression were also evaluated. Results: Comparative genetic analysis of different histological areas revealed that the separate components shared several common mutations, which showed relatively high cellular prevalence in the PyClone statistical inference. Phylogenetic analysis showed that the sarcomatous component had ramified from the carcinomatous component in the early phase of the evolution process and accumulated a number of mutations that were different from those of the carcinomatous component. Moreover, microsatellite instability was detected in a case of sarcomatoid cancer and PD-L1 was strongly positive (≥ 50%) in all sarcomatoid cancers. Conclusions: Our data suggest that sarcomatoid carcinoma evolves from a common ancestral clone, and its phylogenetic features may reflect high-grade malignancy in pulmonary sarcomatoid carcinoma. High tumor mutation burden and strong PD-L1 staining may provide a rationale for the use of targeted immunotherapies in pulmonary sarcomatoid carcinomas.