1. YAP1 Expression in SCLC Defines a Distinct Subtype With T-cell-Inflamed Phenotype
- Author
-
Gabriel Sica, Chao Zhang, Jennifer W Carlisle, Shi-Yong Sun, Edmund K. Waller, Guojing Zhang, Vinicius Ernani, Taofeek K. Owonikoko, Zhengjia Chen, Walter J. Curran, Bhakti Dwivedi, Benjamin G. Barwick, Melissa Gilbert-Ross, Fadlo R. Khuri, Andrey A. Ivanov, Haian Fu, Suresh S. Ramalingam, and Sagar Lonial
- Subjects
0301 basic medicine ,Pulmonary and Respiratory Medicine ,Lung Neoplasms ,T-Lymphocytes ,Human leukocyte antigen ,Neuroendocrine tumors ,Article ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,Gene expression ,medicine ,Humans ,Gene ,neoplasms ,YAP1 ,business.industry ,medicine.disease ,Phenotype ,Small Cell Lung Carcinoma ,humanities ,respiratory tract diseases ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Immunohistochemistry ,Biomarker (medicine) ,business - Abstract
Introduction The clinical and biological significance of the newly described SCLC subtypes, SCLC-A, SCLC-N, SCLC-Y, and SCLC-P, defined by the dominant expression of transcription factors ASCL1, NeuroD1, YAP1, and POU2F3, respectively, remain to be established. Methods We generated new RNA sequencing 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 sequencing 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 for differentially expressed genes between the SCLC survival outliers (top and bottom deciles) matched for clinically relevant prognostic factors revealed substantial up-regulation of interferon-γ response genes in long-term survivors. The SCLC-Y subtype was associated with high expression of interferon-γ response genes, highest weighted score on a validated 18-gene T-cell–inflamed gene expression profile score, and 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% versus 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 data sets from the SCLC cell lines and tumor samples. Conclusions SCLC subtyping using transcriptional signaling holds clinical relevance with the inflamed phenotype associated with the SCLC-Y subset.
- Published
- 2020