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

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.

• Authors: Taofeek K Owonikoko, Bhakti Dwivedi, Zhengjia Chen, Chao Zhang, Benjamin Barwick, Vinicius Ernani, Guojing Zhang, Melissa Gilbert-Ross, Jennifer Carlisle, Fadlo R Khuri, Walter J Curran, Andrey A Ivanov, Haian Fu, Sagar Lonial, Suresh S Ramalingam, Shi-Yong Sun, Edmund K Waller, Gabriel L Sica
• Journal: Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer (J Thorac Oncol) Vol. 16 Issue 3 Pg. 464-476 (03 2021) ISSN: 1556-1380 [Electronic] United States
• PMID: 33248321 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Topics

• Cell Line, Tumor
• Gene Expression Regulation, Neoplastic
• Humans
• Lung Neoplasms (genetics)
• Phenotype
• Small Cell Lung Carcinoma (genetics)
• T-Lymphocytes