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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
Author(s) -
Megyesfalvi Zsolt,
Barany Nandor,
Lantos Andras,
Valko Zsuzsanna,
Pipek Orsolya,
Lang Christian,
Schwendenwein Anna,
Oberndorfer Felicitas,
Paku Sandor,
Ferencz Bence,
Dezso Katalin,
Fillinger Janos,
Lohinai Zoltan,
Moldvay Judit,
Galffy Gabriella,
Szeitz Beata,
Rezeli Melinda,
Rivard Christopher,
Hirsch Fred R,
Brcic Luka,
Popper Helmut,
Kern Izidor,
Kovacevic Mile,
Skarda Jozef,
Mittak Marcel,
MarkoVarga Gyorgy,
Bogos Krisztina,
RenyiVamos Ferenc,
Hoda Mir Alireza,
Klikovits Thomas,
Hoetzenecker Konrad,
Schelch Karin,
Laszlo Viktoria,
Dome Balazs
Publication year - 2022
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.5922
Subject(s) - yap1 , immunohistochemistry , biology , cancer research , oncology , transcription factor , univariate analysis , lung cancer , medicine , pathology , multivariate analysis , immunology , gene , genetics
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.