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SHR Neuro Cancer Cardio Lipid Metab Microb

Megyesfalvi, Z; Barany, N; Lantos, A; Valko, Z; Pipek, O; Lang, C; Schwendenwein, A; Oberndorfer, F; Paku, S; Ferencz, B; Dezso, K; Fillinger, J; Lohinai, Z; Moldvay, J; Galffy, G; Szeitz, B; Rezeli, M; Rivard, C; Hirsch, FR; Brcic, L; Popper, H; Kern, I; Kovacevic, M; Skarda, J; Mittak, M; Marko-Varga, G; Bogos, K; Renyi-Vamos, F; Hoda, MA; Klikovits, T; Hoetzenecker, K; Schelch, K; Laszlo, V; Dome, B.
Expression patterns and prognostic relevance of subtype-specific transcription factors in surgically resected small-cell lung cancer: an international multicenter study.
J Pathol. 2022; 257(5):674-686 Doi: 10.1002/path.5922 [OPEN ACCESS]
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Co-authors Med Uni Graz: Brcic Luka; Popper Helmuth
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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 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.
Find related publications in this database (using NLM MeSH Indexing): Basic Helix-Loop-Helix Transcription Factors - genetics, metabolism; Cell Line, Tumor - administration & dosage; Gene Expression Regulation, Neoplastic - administration & dosage; Humans - administration & dosage; Lung Neoplasms - genetics, metabolism, surgery; Prognosis - administration & dosage; Proteomics - administration & dosage; Small Cell Lung Carcinoma - genetics, metabolism, surgery; Transcription Factors - genetics, metabolism
Find related publications in this database (Keywords): small cell lung cancer; molecular subtypes; prognostic relevance; expression pattern; immunohistochemistry; ASCL1; NEUROD1; YAP1; neuroendocrine subtypes