Comprehensive genomic and transcriptomic profiling (WES, WGS, RNA-seq) of 54 relapsed and 27 treatment-naive SCLC samples, including 26 patient-matched paired samples, to characterize the molecular landscape at relapse versus diagnosis.
Relapsed SCLC was marked by platinum and APOBEC mutational signatures, MYC/MYCL/MYCN amplifications, and immune evasion mechanisms (CD24 amplification, IDO1 overexpression, HLA-E upregulation, increased M2 macrophages); neoantigen burden was high but similar at both timepoints (median 86 treatment-naive vs. 90 relapsed, p=0.8), and retained intron splicing events were significantly enriched in treatment-naive samples affecting DNA repair, WNT, and MYC pathway genes.
Relatively small sample size (54 relapsed, 27 treatment-naive), not all samples had matched pairs or all three sequencing modalities applied, limiting statistical power and direct longitudinal comparisons.
Clinicians should be aware that relapsed SCLC harbors distinct immune evasion features and splicing aberrations not prominent at diagnosis, suggesting that therapeutic strategies targeting the splicing machinery, WNT signaling, or immune checkpoints (beyond standard PD-L1 axis) may be worth exploring in clinical trials.
