IntroductionThe translation of gene expression profile of SCLC to clinical testing remains relatively unexplored. In this study, gene expression variations in SCLC were evaluated to identify potential biomarkers. MethodsRNA expression profiling was performed on 44 tumor samples from 35 patients diagnosed with having SCLC with the clinically validated RNA Salah Targeted Expression Panel (RNA STEP). RNA sequencing (RNA-Seq) and immunohistochemistry were performed on two different SCLC cohorts, and correlation analyses were performed for the ASCL1, NEUROD1, POU2F3, and YAP1 genes/proteins. RNA STEP and RNA-Seq results were evaluated for gene expression profiles and heterogeneity between SCLC primary and metastatic sites. RNA STEP gene expression of independent SCLC samples (n = 35) was compared with lung adenocarcinoma (n = 160) and squamous cell carcinoma results (n = 25). ResultsThe RNA STEP results were significantly correlated with RNA-Seq and immunohistochemistry results. The dominant transcription regulator by RNA STEP was ASCL1 in 74.2% of the samples, NEUROD1 in 20%, and POU2F3 in 2.9%. The ASCL1, NEUROD1, and POU2F3 gene expression was heterogeneous between primary and metastatic sites. SCLCs displayed significantly high expression for targetable genes DLL3, EZH2, TERT, and RET. SCLCs were found to have relatively colder immune profiles than lung adenocarcinomas and squamous cell carcinomas, characterized by lower expression of HLA genes, immune cell, and immune checkpoint genes, except LAG3. ConclusionsClinical-grade SCLC RNA expression profiling has value for SCLC subtyping, design of clinical trials, and identification of patients for trials and potential targeted therapy.