| Title: | Expression patterns and prognostic relevance of subtype-specific transcription factors in surgically resected small cell lung cancer : an international multicenter study |
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| Authors: | ID Megyesfalvi, Zsolt (Author)
ID Barany, Nandor (Author)
ID Lantos, Andras (Author)
ID Valko, Zsuzsanna (Author)
ID Pipek, Orsolya (Author)
ID Lang, Christian (Author)
ID Schwendenwein, Anna (Author)
ID Oberndorfer, Felicitas (Author)
ID Paku, Sandor (Author)
ID Ferencz, Bence (Author)
ID Kern, Izidor, Klinika Golnik (Author)
ID Kovačević, Mile, Klinika Golnik (Author)
ID Laszlo, Viktoria (Author)
ID Dome, Balazs (Author) |
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| Files: |  PDF - Presentation file, download (4,37 MB)
MD5: 2FFA7F10276A77677F161BAF5C4D00C1
 URL - Source URL, visit https://onlinelibrary.wiley.com/doi/10.1002/path.5922
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| Language: | English |
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| Typology: | 1.01 - Original Scientific Article |
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| Organization: |  UKPBAG - University Clinic of Respiratory and Allergic Diseases Golnik
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| Abstract: | 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 have 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 reveal distinct vulnerability profiles defined by transcription regulators. |
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| Keywords: | Non-small-cell lung carcinoma, immunohistochemistry, molecular subtypes, prognostic relevance, expression pattern, neuroendocrine subtypes |
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| Publication status: | In print |
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| Publication version: | Author Accepted Manuscript |
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| Place of publishing: | ZDA |
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| Publisher: | John Wiley &Sons |
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| Year of publishing: | 2022 |
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| Number of pages: | str. [1-28] |
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| Numbering: | Vol. 257, iss. |
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| PID: | 20.500.12556/DiRROS-15120  |
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| UDC: | 616 |
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| ISSN on article: | 1096-9896 |
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| DOI: | 10.1002/path.5910 |
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| COBISS.SI-ID: | 107358467 |
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| Copyright: | © 2022 The Authors. |
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| Note: | Nasl. z nasl. zaslona;
Soavtorja iz Slovenije: Izidor Kern, Mile Kovačević;
Opis vira z dne 11. 5. 2022;
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| Publication date in DiRROS: | 27.05.2022 |
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| Views: | 1424 |
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| Downloads: | 1527 |
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