Expression patterns and prognostic relevance of subtype-specific transcription factors in surgically resected small-cell lung cancer : an international multicenter study
© 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland..
The tissue distribution and prognostic relevance of subtype-specific proteins (ASCL1, NEUROD1, POU2F3, YAP1) present an evolving area of research in small-cell lung cancer (SCLC). The expression of subtype-specific transcription factors and P53 and RB1 proteins were measured by immunohistochemistry (IHC) in 386 surgically resected SCLC samples. Correlations between subtype-specific proteins and in vitro efficacy of various therapeutic agents were investigated by proteomics and cell viability assays in 26 human SCLC cell lines. Besides SCLC-A (ASCL1-dominant), SCLC-AN (combined ASCL1/NEUROD1), SCLC-N (NEUROD1-dominant), and SCLC-P (POU2F3-dominant), IHC and cluster analyses identified a quadruple-negative SCLC subtype (SCLC-QN). No unique YAP1-subtype was found. The highest overall survival rates were associated with non-neuroendocrine subtypes (SCLC-P and SCLC-QN) and the lowest with neuroendocrine subtypes (SCLC-A, SCLC-N, SCLC-AN). In univariate analyses, high ASCL1 expression was associated with poor prognosis and high POU2F3 expression with good prognosis. Notably, high ASCL1 expression influenced survival outcomes independently of other variables in a multivariate model. High POU2F3 and YAP1 protein abundances correlated with sensitivity and resistance to standard-of-care chemotherapeutics, respectively. Specific correlation patterns were also found between the efficacy of targeted agents and subtype-specific protein abundances. In conclusion, we investigated the clinicopathological relevance of SCLC molecular subtypes in a large cohort of surgically resected specimens. Differential IHC expression of ASCL1, NEUROD1, and POU2F3 defines SCLC subtypes. No YAP1-subtype can be distinguished by IHC. High POU2F3 expression is associated with improved survival in a univariate analysis, whereas elevated ASCL1 expression is an independent negative prognosticator. Proteomic and cell viability assays of human SCLC cell lines revealed distinct vulnerability profiles defined by transcription regulators. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:257 |
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| Enthalten in: |
The Journal of pathology - 257(2022), 5 vom: 29. Aug., Seite 674-686 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Megyesfalvi, Zsolt [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 01.08.2022 Date Revised 17.05.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1002/path.5922 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM340178329 |
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| 100 | 1 | |a Megyesfalvi, Zsolt |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Expression patterns and prognostic relevance of subtype-specific transcription factors in surgically resected small-cell lung cancer |b an international multicenter study |
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| 500 | |a Date Revised 17.05.2023 | ||
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. | ||
| 520 | |a The tissue distribution and prognostic relevance of subtype-specific proteins (ASCL1, NEUROD1, POU2F3, YAP1) present an evolving area of research in small-cell lung cancer (SCLC). The expression of subtype-specific transcription factors and P53 and RB1 proteins were measured by immunohistochemistry (IHC) in 386 surgically resected SCLC samples. Correlations between subtype-specific proteins and in vitro efficacy of various therapeutic agents were investigated by proteomics and cell viability assays in 26 human SCLC cell lines. Besides SCLC-A (ASCL1-dominant), SCLC-AN (combined ASCL1/NEUROD1), SCLC-N (NEUROD1-dominant), and SCLC-P (POU2F3-dominant), IHC and cluster analyses identified a quadruple-negative SCLC subtype (SCLC-QN). No unique YAP1-subtype was found. The highest overall survival rates were associated with non-neuroendocrine subtypes (SCLC-P and SCLC-QN) and the lowest with neuroendocrine subtypes (SCLC-A, SCLC-N, SCLC-AN). In univariate analyses, high ASCL1 expression was associated with poor prognosis and high POU2F3 expression with good prognosis. Notably, high ASCL1 expression influenced survival outcomes independently of other variables in a multivariate model. High POU2F3 and YAP1 protein abundances correlated with sensitivity and resistance to standard-of-care chemotherapeutics, respectively. Specific correlation patterns were also found between the efficacy of targeted agents and subtype-specific protein abundances. In conclusion, we investigated the clinicopathological relevance of SCLC molecular subtypes in a large cohort of surgically resected specimens. Differential IHC expression of ASCL1, NEUROD1, and POU2F3 defines SCLC subtypes. No YAP1-subtype can be distinguished by IHC. High POU2F3 expression is associated with improved survival in a univariate analysis, whereas elevated ASCL1 expression is an independent negative prognosticator. Proteomic and cell viability assays of human SCLC cell lines revealed distinct vulnerability profiles defined by transcription regulators. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland | ||
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| 650 | 4 | |a prognostic relevance | |
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| 650 | 7 | |a Transcription Factors |2 NLM | |
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| 700 | 1 | |a Schwendenwein, Anna |e verfasserin |4 aut | |
| 700 | 1 | |a Oberndorfer, Felicitas |e verfasserin |4 aut | |
| 700 | 1 | |a Paku, Sandor |e verfasserin |4 aut | |
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| 700 | 1 | |a Dezso, Katalin |e verfasserin |4 aut | |
| 700 | 1 | |a Fillinger, Janos |e verfasserin |4 aut | |
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| 700 | 1 | |a Moldvay, Judit |e verfasserin |4 aut | |
| 700 | 1 | |a Galffy, Gabriella |e verfasserin |4 aut | |
| 700 | 1 | |a Szeitz, Beata |e verfasserin |4 aut | |
| 700 | 1 | |a Rezeli, Melinda |e verfasserin |4 aut | |
| 700 | 1 | |a Rivard, Christopher |e verfasserin |4 aut | |
| 700 | 1 | |a Hirsch, Fred R |e verfasserin |4 aut | |
| 700 | 1 | |a Brcic, Luka |e verfasserin |4 aut | |
| 700 | 1 | |a Popper, Helmut |e verfasserin |4 aut | |
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