YAP1 Expression in SCLC Defines a Distinct Subtype With T-cell-Inflamed Phenotype

• Type of Material: Article
• Authors: Taofeek Owonikoko, Emory University; Bhakti Dwivedi, Emory University; Zhengjia Chen, Emory University; Chao Zhang, Emory University; Benjamin Barwick, Emory University; Vinicius Ernani, University of Nebraska; Guojing Zhang, Emory University; Melissa Gilbert-Ross, Emory University; Jennifer Carlisle, Emory University; Fadlo Khuri, Emory University; Walter Curran Jr, Emory University; Andrey Ivanov, Emory University; Haian Fu, Emory University; Sagar Lonial, Emory University; Suresh Ramalingam, Emory University; Shi-Yong Sun, Emory University; Edmund Waller, Emory University; Gabriel Sica, Emory University
• Language: English
• Date: 2021-02-26
• Publisher: ELSEVIER SCIENCE INC
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.jtho.2020.11.006
• Title of Journal or Parent Work: JOURNAL OF THORACIC ONCOLOGY
• Volume: 16
• Issue: 3
• Start Page: 464
• End Page: 476
• Grant/Funding Information: Funding for this study was provided by Novartis Oncology under a grant award to TKO (CLDK378AUS39T). Additional support was provided by the DoD grant award to TKO (LC150291); the NIH SPORE grant award to SSR (P50CA217691) and the NIH NCI CTD2 network to HF (U01CA217875). Research reported in this publication was supported in part by the Biostatistics and Bioinformatics Shared Resource and the Tissue Procurement and Pathology Shared Resource of Winship Cancer Institute of Emory University, Atlanta, GA 303022 and NIH/NCI under award number P30CA138292. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
• Keywords: Life Sciences & Biomedicine; Biomarker; Respiratory System; Subtype; GENOMIC PROFILES; Inflamed phenotype; SCLC; Science & Technology; TUMORS; GENE; LUNG-CANCER; IMMUNE CONTEXTURE; Oncology

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.