Aims A new molecular subtype classification was proposed for small-cell lung carcinoma (SCLC). We aimed to further validate the classification in various SCLC patient samples using immunohistochemistry (IHC) to highlight its clinical significance.
Methods We analysed the protein expression of four subtype (achaete-scute family BHLH transcription factor 1 (ASCL1), neuronal differentiation 1 (NEUROD1), POU class 2 homeobox 3 (POU2F3) and Yes1-associated transcriptional regulator (YAP1)) and two predictive markers (delta-like ligand 3 (DLL3) and MYC) using IHC in 216 specimens from 195 SCLC patients, including 21 pairs of resected biopsy tumours. Associations among molecular subtypes, clinicopathological features and prognostic implications were also explored.
Results The ASCL1, NEUROD1, POU2F3, YAP1, DLL3 and MYC-positive expression rates were 70.3%, 56.9%, 14.9%, 19.0%, 75.4% and 22.6%, respectively. DLL3 expression had positive and negative associations with that of ASCL1 and POU2F3/YAP1, respectively, whereas MYC had the opposite effect. Strong associations of ASCL1 (Ρ=0.8603, p<0.0001), NEUROD1 (Ρ=0.8326, p<0.0001), POU2F3 (Ρ=0.6950, p<0.0001) and YAP1 (Ρ=0.7466, p<0.0001) expressions were detected between paired resected biopsy tumours. In addition to SCLC-A (ASCL1-dominant), SCLC-N (NEUROD1-dominant) and SCLC-P (POU2F3-dominant), unsupervised hierarchical cluster analyses identified a fourth, quadruple-negative SCLC subtype (SCLC-QN) characterised by the low expression of all four subtype-specific proteins, and 55.4% (n=108), 27.2% (n=53), 11.8% (n=23) and 5.6% (n=11) were categorised as SCLC-A, SCLC-N, SCLC-P and SCLC-QN, respectively. Significant enrichment of SCLC-P in the combined SCLC cohort was observed, and adenocarcinoma was more prevalent in SCLC-A, while large-cell neuroendocrine carcinoma was more commonly seen in SCLC-P. No survival difference was found among molecular subtypes.
Conclusions Our results provide clinical insights into the diagnostic, prognostic and predictive significance of SCLC molecular subtype classifications.
- Lung Neoplasms
- Biomarkers, Tumor
Data availability statement
Data are available upon reasonable request. All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials.
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Handling editor Vikram Deshpande.
YZ and SL contributed equally.
Contributors Conceptualisation: YZ, HW and DL; methodology: SL, WR, JW and LM; investigation: YZ and KC; validation: YZ and SL; resources: YZ and DL; writing—original draft preparation: YZ and SL; writing—review and editing: MZ and DL; supervision: MZ and DL; funding acquisition: YZ, SL and MZ; Guarantor: DL.
Funding This study was supported by the General Program of National Natural Science Foundation of China (82073247), Science Foundation of Peking University Cancer Hospital (PY202303), Beijing Municipal Administration of Hospitals Incubating Program (PX2019038) and Beijing Youth Program for Outstanding Talents (2018000021469G262).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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