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Expression patterns and prognostic relevance of subtype-specific transcription factors in surgically resected small-cell lung cancer : an international multicenter study

Megyesfalvi, Zsolt ; Barany, Nandor ; Lantos, Andras ; Valko, Zsuzsanna ; Pipek, Orsolya ; Lang, Christian ; Schwendenwein, Anna ; Oberndorfer, Felicitas ; Paku, Sandor and Ferencz, Bence , et al. (2022) In Journal of Pathology 257(5). p.674-686
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
ASCL1, expression pattern, immunohistochemistry, molecular subtypes, NEUROD1, neuroendocrine subtypes, POU2F3, prognostic relevance, small cell lung cancer, YAP1
in
Journal of Pathology
volume
257
issue
5
pages
13 pages
publisher
John Wiley & Sons Inc.
external identifiers
  • scopus:85130578460
  • pmid:35489038
ISSN
0022-3417
DOI
10.1002/path.5922
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
id
faf38cfe-d716-4c27-a886-02947864930a
date added to LUP
2022-08-18 13:14:49
date last changed
2024-06-27 07:38:01
@article{faf38cfe-d716-4c27-a886-02947864930a,
  abstract     = {{<p>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.</p>}},
  author       = {{Megyesfalvi, Zsolt and Barany, Nandor and Lantos, Andras and Valko, Zsuzsanna and Pipek, Orsolya and Lang, Christian and Schwendenwein, Anna and Oberndorfer, Felicitas and Paku, Sandor and Ferencz, Bence and Dezso, Katalin and Fillinger, Janos and Lohinai, Zoltan and Moldvay, Judit and Galffy, Gabriella and Szeitz, Beata and Rezeli, Melinda and Rivard, Christopher and Hirsch, Fred R. and Brcic, Luka and Popper, Helmut and Kern, Izidor and Kovacevic, Mile and Skarda, Jozef and Mittak, Marcel and Marko-Varga, Gyorgy and Bogos, Krisztina and Renyi-Vamos, Ferenc and Hoda, Mir Alireza and Klikovits, Thomas and Hoetzenecker, Konrad and Schelch, Karin and Laszlo, Viktoria and Dome, Balazs}},
  issn         = {{0022-3417}},
  keywords     = {{ASCL1; expression pattern; immunohistochemistry; molecular subtypes; NEUROD1; neuroendocrine subtypes; POU2F3; prognostic relevance; small cell lung cancer; YAP1}},
  language     = {{eng}},
  number       = {{5}},
  pages        = {{674--686}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Journal of Pathology}},
  title        = {{Expression patterns and prognostic relevance of subtype-specific transcription factors in surgically resected small-cell lung cancer : an international multicenter study}},
  url          = {{http://dx.doi.org/10.1002/path.5922}},
  doi          = {{10.1002/path.5922}},
  volume       = {{257}},
  year         = {{2022}},
}