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Comprehensive analysis of transcription factor-based molecular subtypes and their correlation to clinical outcomes in small-cell lung cancer

Authors
 Sehhoon Park  ;  Tae Hee Hong  ;  Soohyun Hwang  ;  Simon Heeke  ;  Carl M Gay  ;  Jiyeon Kim  ;  Hyun-Ae Jung  ;  Jong-Mu Sun  ;  Jin Seok Ahn  ;  Myung-Ju Ahn  ;  Jong Ho Cho  ;  Yong Soo Choi  ;  Jhingook Kim  ;  Young Mog Shim  ;  Hong Kwan Kim  ;  Lauren Averett Byers 4  ;  John V Heymach  ;  Yoon-La Choi  ;  Se-Hoon Lee  ;  Keunchil Park 
Citation
 EBIOMEDICINE, Vol.102 : 105062, 2024-04 
Journal Title
EBIOMEDICINE
Issue Date
2024-04
MeSH
Biomarkers, Tumor / genetics ; Biomarkers, Tumor / metabolism ; Female ; Humans ; Lung Neoplasms* / genetics ; Lung Neoplasms* / therapy ; Male ; Prognosis ; Small Cell Lung Carcinoma* / genetics ; Small Cell Lung Carcinoma* / therapy ; Transcription Factors / genetics
Keywords
ASCL1 ; Molecular subtype ; NEUROD1 ; POU2F3 ; Small cell lung cancer
Abstract
Background: Recent studies have reported the predictive and prognostic value of novel transcriptional factor-based molecular subtypes in small-cell lung cancer (SCLC). We conducted an in-depth analysis pairing multi-omics data with immunohistochemistry (IHC) to elucidate the underlying characteristics associated with differences in clinical outcomes between subtypes. Methods: IHC (n = 252), target exome sequencing (n = 422), and whole transcriptome sequencing (WTS, n = 189) data generated from 427 patients (86.4% males, 13.6% females) with SCLC were comprehensively analysed. The differences in the mutation profile, gene expression profile, and inflammed signatures were analysed according to the IHC-based molecular subtype. Findings: IHC-based molecular subtyping, comprised of 90 limited-disease (35.7%) and 162 extensive-disease (64.3%), revealed a high incidence of ASCL1 subtype (IHC-A, 56.3%) followed by ASCL1/NEUROD1 co-expressed (IHC-AN, 17.9%), NEUROD1 (IHC-N, 12.3%), POU2F3 (IHC-P, 9.1%), triple-negative (IHC-TN, 4.4%) subtypes. IHC-based subtype showing high concordance with WTS-based subtyping and non-negative matrix factorization (NMF) clusterization method. IHC-AN subtype resembled IHC-A (rather than IHC-N) in terms of both gene expression profiles and clinical outcomes. Favourable median overall survival was observed in IHC-A (15.2 months) compared to IHC-N (8.0 months, adjusted HR 2.3, 95% CI 1.4–3.9, p = 0.002) and IHC-P (8.3 months, adjusted HR 1.7, 95% CI 0.9–3.2, p = 0.076). Inflamed tumours made up 25% of cases (including 53% of IHC-P, 26% of IHC-A, 17% of IHC-AN, but only 11% of IHC-N). Consistent with recent findings, inflamed tumours were more likely to benefit from first-line immunotherapy treatment than non-inflamed phenotype (p = 0.002). Interpretation: This study provides fundamental data, including the incidence and basic demographics of molecular subtypes of SCLC using both IHC and WTS from a comparably large, real-world Asian/non-Western patient cohort, showing high concordance with the previous NMF-based SCLC model. In addition, we revealed underlying biological pathway activities, immunogenicity, and treatment outcomes based on molecular subtype, possibly related to the difference in clinical outcomes, including immunotherapy response. Funding: This work was supported by AstraZeneca, Future Medicine 2030 Project of the Samsung Medical Center [grant number SMX1240011], the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) [grant number 2020R1C1C1010626] and the 7th AstraZeneca-KHIDI (Korea Health Industry Development Institute) oncology research program. © 2024 The Authors
Files in This Item:
T202402708.pdf Download
DOI
10.1016/j.ebiom.2024.105062
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Thoracic and Cardiovascular Surgery (흉부외과학교실) > 1. Journal Papers
Yonsei Authors
Hong, Tae Hee(홍태희)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/199205
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