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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 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 (2022) Expression patterns and prognostic relevance of subtype‐specific transcription factors in surgically resected small‐cell lung cancer: an international multicenter study. The Journal of Pathology, 257 (5). pp. 674-686. ISSN 0022-3417

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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.

Item Type: Article
Uncontrolled Keywords: small cell lung cancer; molecular subtypes; prognostic relevance; expression pattern; immunohistochemistry; ASCL1; NEUROD1; POU2F3; YAP1; neuroendocrine subtypes
Subjects: R Medicine / orvostudomány > R1 Medicine (General) / orvostudomány általában
Depositing User: Dr. Zsolt Megyesfalvi
Date Deposited: 29 Sep 2024 01:03
Last Modified: 29 Sep 2024 01:03
URI: https://real.mtak.hu/id/eprint/206303

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