Expression patterns and prognostic relevance of subtype-specific transcription factors in surgically resected small cell lung cancer

ǂan ǂinternational multicenter study

Zsolt Megyesfalvi (Author), Nandor Barany (Author), Andras Lantos (Author), Zsuzsanna Valko (Author), Orsolya Pipek (Author), Christian Lang (Author), Viktoria Laszlo (Author), Balazs Dome (Author), Anna Schwendenwein (Author), Felicitas Oberndorfer (Author), Sandor Paku (Author), Bence Ferencz (Author), Izidor Kern (Author), Mile Kovačević (Author)

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.

Keywords

molekularni podtipi;napovedni pomen;vzorec izražanja;nevroendokrini podtipi;molecular subtypes;prognostic relevance;expression pattern;neuroendocrine subtypes;

Data

Language:	English
Year of publishing:	2022
Typology:	1.01 - Original Scientific Article
Publisher:	John Wiley &Sons
UDC:	616
COBISS:	107358467
ISSN:	1096-9896
Views:	98
Downloads:	185
Average score:	0 (0 votes)
Metadata:

Other data

Secondary keywords:	Carcinoma, non-small-cell lung;Immunohistochemistry;Nedrobnocelični karcinom pljuč;Imunohistokemija;
Source comment:	Nasl. z nasl. zaslona; Soavtorja iz Slovenije: Izidor Kern, Mile Kovačević; Opis vira z dne 11. 5. 2022;
Pages:	str. [1-28]
Volume:	ǂVol. ǂ257
Issue:	ǂiss. ǂ
Chronology:	2022
DOI:	10.1002/path.5922
ID:	15437289