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TTF-1 and c-MYC-defined Phenotypes of Large Cell Neuroendocrine Carcinoma and Delta-like Protein 3 Expression for Treatment Selection

The standard treatment regimen has not yet been established for advanced pulmonary large cell neuroendocrine carcinoma (LCNEC) because of its rarity. LCNEC can be subdivided into 2 mutually exclusive molecular subgroups: STK11/KEAP1 and TP53 mutated with high neuroendocrine expression and transcript...

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Autores principales: Miyagawa-Hayashino, Aya, Okada, Satoru, Takeda-Miyata, Naoko, Takashima, Yasutoshi, Yamada, Tadaaki, Takemura, Yoshizumi, Uchino, Junji, Inoue, Masayoshi, Takayama, Koichi, Konishi, Eiichi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Lippincott Williams & Wilkins 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132912/
https://www.ncbi.nlm.nih.gov/pubmed/33031101
http://dx.doi.org/10.1097/PAI.0000000000000875
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author Miyagawa-Hayashino, Aya
Okada, Satoru
Takeda-Miyata, Naoko
Takashima, Yasutoshi
Yamada, Tadaaki
Takemura, Yoshizumi
Uchino, Junji
Inoue, Masayoshi
Takayama, Koichi
Konishi, Eiichi
author_facet Miyagawa-Hayashino, Aya
Okada, Satoru
Takeda-Miyata, Naoko
Takashima, Yasutoshi
Yamada, Tadaaki
Takemura, Yoshizumi
Uchino, Junji
Inoue, Masayoshi
Takayama, Koichi
Konishi, Eiichi
author_sort Miyagawa-Hayashino, Aya
collection PubMed
description The standard treatment regimen has not yet been established for advanced pulmonary large cell neuroendocrine carcinoma (LCNEC) because of its rarity. LCNEC can be subdivided into 2 mutually exclusive molecular subgroups: STK11/KEAP1 and TP53 mutated with high neuroendocrine expression and transcriptional profile of ASCL1(high)/DLL3(high)/NOTCH(low) (non–small cell lung carcinoma, NSCLC-like) or RB1 and TP53 mutated with reduced neuroendocrine markers and transcriptional pattern of ASCL1(low)/DLL3(low)/NOTCH(high) (small cell lung cancer, SCLC-like). Model-based clustering shows that SCLC has subdivided into 2 major proteomic subsets defined by either TTF-1(high)/c-MYC(low) or TTF-1(low)/c-MYC(high), which may correspond to 2 mutually exclusive molecular subgroups: NSCLC-like or SCLC-like, respectively. We herein investigated whether TTF-1 and c-MYC could be applied to LCNEC to identify distinct subsets immunohistochemically and assessed DLL3 expression in these subsets. The protein expression profile may be useful to select patients for potential efficacy of targeted therapies including aurora kinase inhibitors for MYC alterations or anti-DLL3 antibody-drug conjugates. TTF-1 and c-MYC expression was mutually exclusive in 25 of 27 (93%) cases; TTF-1(+)/c-MYC(-) in 10, TTF-1(−)/c-MYC(+) in 15, and TTF-1(+)/c-MYC(+) in 2. DLL3 expression was seen in 15 of 27 cases (56%). All 12 TTF-1(+) LCNEC cases were positive for DLL3. Three of 15 (20%) TTF-1(−)/c-MYC(+) cases showed DLL3 positivity. LCNEC could be separated into 2 subsets proteomically defined by TTF-1 and c-MYC expression, which may be suitable to guide treatment selection including aurora kinase inhibitors for c-MYC(+) cases. TTF-1 positivity can serve as a surrogate marker for DLL3, but caution is necessary as 20% of TTF-1(−) cases showed DLL3 positivity.
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spelling pubmed-81329122021-05-20 TTF-1 and c-MYC-defined Phenotypes of Large Cell Neuroendocrine Carcinoma and Delta-like Protein 3 Expression for Treatment Selection Miyagawa-Hayashino, Aya Okada, Satoru Takeda-Miyata, Naoko Takashima, Yasutoshi Yamada, Tadaaki Takemura, Yoshizumi Uchino, Junji Inoue, Masayoshi Takayama, Koichi Konishi, Eiichi Appl Immunohistochem Mol Morphol Research Articles The standard treatment regimen has not yet been established for advanced pulmonary large cell neuroendocrine carcinoma (LCNEC) because of its rarity. LCNEC can be subdivided into 2 mutually exclusive molecular subgroups: STK11/KEAP1 and TP53 mutated with high neuroendocrine expression and transcriptional profile of ASCL1(high)/DLL3(high)/NOTCH(low) (non–small cell lung carcinoma, NSCLC-like) or RB1 and TP53 mutated with reduced neuroendocrine markers and transcriptional pattern of ASCL1(low)/DLL3(low)/NOTCH(high) (small cell lung cancer, SCLC-like). Model-based clustering shows that SCLC has subdivided into 2 major proteomic subsets defined by either TTF-1(high)/c-MYC(low) or TTF-1(low)/c-MYC(high), which may correspond to 2 mutually exclusive molecular subgroups: NSCLC-like or SCLC-like, respectively. We herein investigated whether TTF-1 and c-MYC could be applied to LCNEC to identify distinct subsets immunohistochemically and assessed DLL3 expression in these subsets. The protein expression profile may be useful to select patients for potential efficacy of targeted therapies including aurora kinase inhibitors for MYC alterations or anti-DLL3 antibody-drug conjugates. TTF-1 and c-MYC expression was mutually exclusive in 25 of 27 (93%) cases; TTF-1(+)/c-MYC(-) in 10, TTF-1(−)/c-MYC(+) in 15, and TTF-1(+)/c-MYC(+) in 2. DLL3 expression was seen in 15 of 27 cases (56%). All 12 TTF-1(+) LCNEC cases were positive for DLL3. Three of 15 (20%) TTF-1(−)/c-MYC(+) cases showed DLL3 positivity. LCNEC could be separated into 2 subsets proteomically defined by TTF-1 and c-MYC expression, which may be suitable to guide treatment selection including aurora kinase inhibitors for c-MYC(+) cases. TTF-1 positivity can serve as a surrogate marker for DLL3, but caution is necessary as 20% of TTF-1(−) cases showed DLL3 positivity. Lippincott Williams & Wilkins 2021-04 2020-10-07 /pmc/articles/PMC8132912/ /pubmed/33031101 http://dx.doi.org/10.1097/PAI.0000000000000875 Text en Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (https://creativecommons.org/licenses/by-nc-nd/4.0/) (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/)
spellingShingle Research Articles
Miyagawa-Hayashino, Aya
Okada, Satoru
Takeda-Miyata, Naoko
Takashima, Yasutoshi
Yamada, Tadaaki
Takemura, Yoshizumi
Uchino, Junji
Inoue, Masayoshi
Takayama, Koichi
Konishi, Eiichi
TTF-1 and c-MYC-defined Phenotypes of Large Cell Neuroendocrine Carcinoma and Delta-like Protein 3 Expression for Treatment Selection
title TTF-1 and c-MYC-defined Phenotypes of Large Cell Neuroendocrine Carcinoma and Delta-like Protein 3 Expression for Treatment Selection
title_full TTF-1 and c-MYC-defined Phenotypes of Large Cell Neuroendocrine Carcinoma and Delta-like Protein 3 Expression for Treatment Selection
title_fullStr TTF-1 and c-MYC-defined Phenotypes of Large Cell Neuroendocrine Carcinoma and Delta-like Protein 3 Expression for Treatment Selection
title_full_unstemmed TTF-1 and c-MYC-defined Phenotypes of Large Cell Neuroendocrine Carcinoma and Delta-like Protein 3 Expression for Treatment Selection
title_short TTF-1 and c-MYC-defined Phenotypes of Large Cell Neuroendocrine Carcinoma and Delta-like Protein 3 Expression for Treatment Selection
title_sort ttf-1 and c-myc-defined phenotypes of large cell neuroendocrine carcinoma and delta-like protein 3 expression for treatment selection
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132912/
https://www.ncbi.nlm.nih.gov/pubmed/33031101
http://dx.doi.org/10.1097/PAI.0000000000000875
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