IMR Press / FBL / Volume 27 / Issue 3 / DOI: 10.31083/j.fbl2703108
Open Access Review
Molecular Subtypes of High-Grade Neuroendocrine Carcinoma (HGNEC): What is YAP1-Positive HGNEC?
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1 Department of Pathology, Tsukuba University Hospital, 305-8576 Ibaraki, Japan
2 Department of Pathology, Faculty of Medicine, University of Tsukuba, 305-8575 Ibaraki, Japan
3 Division of Molecular Pathology, Institute of Medical Science, University of Tokyo, 108-0071 Tokyo, Japan
*Correspondence: vzv07574@nifty.com (Daisuke Matsubara)
These authors contributed equally.
Academic Editor: Graham Pawelec
Front. Biosci. (Landmark Ed) 2022, 27(3), 108; https://doi.org/10.31083/j.fbl2703108
Submitted: 8 October 2021 | Revised: 27 January 2022 | Accepted: 24 February 2022 | Published: 19 March 2022
Copyright: © 2022 The Author(s). Published by IMR Press.
This is an open access article under the CC BY 4.0 license.
Abstract

Small cell lung cancer (SCLC) subtype classification, based on high-level expression of key transcriptional regulators; ASCL1 (SCLC-A), NEUROD1 (SCLC-N), POU2F3 (SCLC-P), and YAP1 (SCLC-Y), has recently been proposed. YAP1 (and POU2F3) has attracted attention as an important factor for non-neuroendocrine (non-NE) phenotypic subtyping of SCLC. However, subsequent studies reported that YAP1 expression alone cannot define a single group in primary SCLC, which makes it difficult to understand what SCLC-Y is by focusing only on SCLC. In this review, we concluded that YAP1 is an essential anti-neuroendocrine factor in both SCLC and non-small cell lung cancer (NSCLC) based on previous studies, including our own analysis of the cell lines and primary tumors of SCLC and NSCLC. The classification of SCLC-Y is a concept mainly established from the analysis of cell lines, and SCLC-Y cell lines correspond to “variant type” SCLC cell lines. Primary SCLC and large cell neuroendocrine carcinoma (LCNEC) are typically heterogeneous tumors composed mostly of NE-type cells, but they contain a small number of non-NE-type cells. Importantly, individual cells with NE features exhibit YAP1 loss, whereas the non-NE-type cells exhibit YAP1 expression. Although rare in primary SCLC, some cases of primary LCNEC have many YAP1-positive cells, which is correlated with chemotherapy resistance. YAP1 staining may be useful in the exclusion diagnosis of SCLC or in the selection of treatment for LCNEC.

Keywords
review
YAP1
SCLC
LCNEC
HGNEC
SCLC-Y
SCLC-I
chemo-sensitivity
Funding
21K15381/JSPS KAKENHI
20K16165/JSPS KAKENHI
21K07091/JSPS KAKENHI
19K07441/JSPS KAKENHI
Figures
Fig. 1.
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