Tracing Tumor Heterogeneity of Pleomorphic Carcinoma of the Lung.

ABSTRACT

INTRODUCTION: Pulmonary pleomorphic carcinoma (PPC) is an aggressive and highly heterogeneous NSCLC whose underlying biology is still poorly understood. METHODS: A total of 42 tumor areas from 20 patients with PPC were microdissected, including 39 primary tumors and three metastases, and the histologically distinct components were subjected to whole exome sequencing separately. We further performed in silico analysis of microdissected bulk RNA sequencing and methylation data of 28 samples from 14 patients with PPC. We validated our findings using immunohistochemistry. RESULTS: The epithelial and the sarcomatoid components of PPCs shared a large number of genomic alterations. Most mutations in cancer driver genes were clonal and truncal between the two components of PPCs suggesting a common ancestor. The high number of alterations in the RTK-RAS pathway suggests that it plays an important role in the evolution of PPC. The metastases morphologically and genetically resembled the epithelial or the sarcomatoid components of the tumor. The transcriptomic and epigenetic profiles of the sarcomatoid components of PPCs with matched squamous-like or adenocarcinoma-like components differed from each other, and they shared more similarities to their matched epithelial components. NCAM1/CD56 was preferentially expressed in the sarcomatoid component of squamous-like PPCs, whereas CDH1/E-Cadherin expression was down-regulated in the sarcomatoid component of most PPCs. CONCLUSION: Lung adenocarcinoma-like PPCs are mainly driven by RTK-RAS signaling, whereas epithelial-mesenchymal transition programs as highlighted by increased NCAM1 and decreased CDH1 expression govern the epithelial-sarcomatoid transition between the clonally related tumor components. Several alterations in PPCs pinpoint therapeutic opportunities.