YAP1 Expression in Small Cell Lung Cancer Defines a Distinct Subtype with T-cell Inflamed Phenotype.

Abstract Background The clinical and biological significance of the newly described small cell lung cancer (SCLC) subtypes, SCLC-A, SCLC-N, SCLC-Y and SCLC-P, defined respectively by the dominant expression of transcription factors ASCL1, NeuroD1, YAP1 or POU2F3, remain to be established. Methods We generated new RNA-Seq expression data from a discovery set of 59 archival tumor samples of neuroendocrine tumors and new protein expression data by immunohistochemistry in 99 SCLC cases. We validated the findings from this discovery set in two independent validation sets consisting of RNA-Seq data generated from 51 SCLC cell lines and 81 primary human SCLC samples. Results We successfully classified 71.8% of SCLC and 18.5% of carcinoid cases in our discovery set into one of the four SCLC subtypes. Gene Set Enrichment Analysis (GSEA) for differentially expressed genes between SCLC survival outliers (top and bottom decile) matched for clinically relevant prognostic factors, showed significant upregulation of IFN-γ response genes in long-term survivors. SCLC-Y subtype was associated with high expression of IFN-γ response genes, highest weighted score on a validated 18-gene T-cell inflamed gene expression profile score as well as high expression of HLA and T-cell receptor genes. YAP1 protein expression was more prevalent and more intensely expressed in limited stage versus extensive stage SCLC (30.6% vs. 8.5%; p=0.0058) indicating good prognosis for the SCLC-Y subtype. We replicated the inflamed phenotype of SCLC-Y in the two independent validation datasets from SCLC cell lines and tumor samples. Conclusion SCLC subtyping using transcriptional signaling hold clinical relevance with the inflamed phenotype associated with SCLC-Y subset.