Expression patterns and prognostic relevance of subtype-specific transcription factors in surgically resected small-cell lung cancer: an international multicenter study.
ASCL1
NEUROD1
POU2F3
YAP1
expression pattern
immunohistochemistry
molecular subtypes
neuroendocrine subtypes
prognostic relevance
small cell lung cancer
Journal
The Journal of pathology
ISSN: 1096-9896
Titre abrégé: J Pathol
Pays: England
ID NLM: 0204634
Informations de publication
Date de publication:
08 2022
08 2022
Historique:
revised:
10
04
2022
received:
07
10
2021
accepted:
27
04
2022
pubmed:
1
5
2022
medline:
2
8
2022
entrez:
30
4
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35489038
doi: 10.1002/path.5922
pmc: PMC9541929
doi:
Substances chimiques
Basic Helix-Loop-Helix Transcription Factors
0
Transcription Factors
0
Types de publication
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
674-686Subventions
Organisme : Austrian Science Fund FWF
ID : I 3522
Pays : Austria
Informations de 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.
Références
J Natl Compr Canc Netw. 2018 Oct;16(10):1171-1182
pubmed: 30323087
Cancer Discov. 2012 Sep;2(9):798-811
pubmed: 22961666
Sci Transl Med. 2015 Aug 26;7(302):302ra136
pubmed: 26311731
Cancer Res. 1985 Jun;45(6):2924-30
pubmed: 2985258
Cancer Cell. 2020 Jul 13;38(1):60-78.e12
pubmed: 32473656
Oncologist. 2019 Nov;24(11):e1172-e1179
pubmed: 31068386
Cancer Res. 1985 Jun;45(6):2913-23
pubmed: 2985257
Cancer Cell. 2021 Mar 8;39(3):346-360.e7
pubmed: 33482121
Lancet Oncol. 2016 Dec;17(12):e542-e551
pubmed: 27924752
J Clin Oncol. 2006 Jan 1;24(1):70-6
pubmed: 16382115
Cancer Sci. 2016 Oct;107(10):1527-1538
pubmed: 27418196
J Clin Pathol. 2017 Nov;70(11):988-993
pubmed: 28596153
Cell Rep. 2016 Aug 2;16(5):1259-1272
pubmed: 27452466
Cancer Cell. 2017 Feb 13;31(2):270-285
pubmed: 28089889
ESMO Open. 2018 Apr 27;3(3):e000366
pubmed: 29719730
J Thorac Dis. 2017 Nov;9(Suppl 15):S1474-S1483
pubmed: 29201450
Am J Surg Pathol. 2002 Sep;26(9):1184-97
pubmed: 12218575
Cold Spring Harb Perspect Med. 2021 Apr 1;11(4):
pubmed: 32513672
Oncogene. 2014 Jul 17;33(29):3776-83
pubmed: 24037524
Ann Thorac Surg. 1999 Aug;68(2):343-7; discussion 348
pubmed: 10475393
Transl Lung Cancer Res. 2018 Feb;7(1):32-49
pubmed: 29535911
Nat Cancer. 2020 Apr;1(4):437-451
pubmed: 35121965
Biopreserv Biobank. 2013 Apr;11(2):101-6
pubmed: 24845430
Pathol Res Pract. 2021 Mar;219:153341
pubmed: 33581550
Am J Pathol. 1994 Nov;145(5):1036-40
pubmed: 7977636
Mol Ther Oncolytics. 2021 Feb 06;20:470-483
pubmed: 33718595
J Proteome Res. 2021 Jan 1;20(1):1027-1039
pubmed: 33301673
J Thorac Oncol. 2017 Feb;12(2):334-346
pubmed: 27998793
J Thorac Oncol. 2014 Mar;9(3):273-84
pubmed: 24518085
Nat Rev Cancer. 2019 May;19(5):289-297
pubmed: 30926931
Genes Dev. 2018 Jul 1;32(13-14):915-928
pubmed: 29945888
Diagnostics (Basel). 2020 Nov 13;10(11):
pubmed: 33202998
Nat Rev Dis Primers. 2021 Jan 14;7(1):3
pubmed: 33446664
J Thorac Oncol. 2020 Dec;15(12):1823-1835
pubmed: 33011388
Nat Rev Cancer. 2017 Dec;17(12):725-737
pubmed: 29077690
Clin Lung Cancer. 2016 Sep;17(5):325-333
pubmed: 27397481
Biomark Res. 2020 Aug 26;8:34
pubmed: 32864131
Mol Oncol. 2020 Sep;14(9):1947-1965
pubmed: 32506804
J Thorac Oncol. 2022 Jan;17(1):141-153
pubmed: 34534680
Trends Pharmacol Sci. 2021 Mar;42(3):166-182
pubmed: 33422376
Proteomics Clin Appl. 2018 Nov;12(6):e1800015
pubmed: 29888431
Lab Invest. 1986 Aug;55(2):244-8
pubmed: 3525985
Nature. 2015 Aug 6;524(7563):47-53
pubmed: 26168399
Front Oncol. 2022 Mar 02;12:779276
pubmed: 35311069
Lung Cancer. 1996 Aug;15(1):31-40
pubmed: 8865121
Oncotarget. 2017 Aug 28;8(43):73745-73756
pubmed: 29088741
Transl Lung Cancer Res. 2016 Aug;5(4):363-6
pubmed: 27650513
Histopathology. 2019 Apr;74(5):792-794
pubmed: 30431185
Nat Commun. 2019 Jul 19;10(1):3201
pubmed: 31324758
Mod Pathol. 2012 Jan;25 Suppl 1:S18-30
pubmed: 22214967