Molecular subtype expression and genomic profiling differ between surgically resected pure and combined small cell lung carcinoma

Abstract

A new molecular subtype classification method has been proposed for small cell lung carcinoma (SCLC). However, little is known about the differences between the pure (P-SCLC) and combined subtypes (C-SCLC). We aimed to compare the molecular subtype expression and genomic profiling in terms of clinical relevance between the two groups. 154 surgically resected SCLCs were analyzed for protein expression of four subtypes (ASCL1, NEUROD1, POU2F3, and YAP1) and two predictive markers (DLL3 and MYC) by immunohistochemistry (IHC). We also performed whole exome sequencing of 60 samples to examine genomic profiles. A total of 113 patients with P-SCLC and 41 with C-SCLC were included. In P-SCLC and C-SCLC, the expression of these markers was 78.8% and 41.5%, 98.2% and 97.6%, 42.5% and 51.2%, 38.9% and 85.4%, 85.0% and 68.3%, and 24.8% and 34.1%, respectively. ASCL1 and DLL3 were highly expressed in P-SCLC (p=0.000 and p=0.021, respectively), and YAP1 expression was significantly enriched in C-SCLC (p=0.000). NGS results, including 45P-SCLCs and 15C-SCLCs, indicated that EGFR gene mutations were mostly observed in C-SCLCs (p=0.000). C-SCLC showed higher CNA burden and wGII than P-SCLC (p<0.01 and p<0.05); conversely, P-SCLC had higher TMB burden and SDI (p<0.05 and p<0.05). YAP1 expression was associated with poor prognosis in P-SCLC but with favorable prognosis in C-SCLC. P-SCLC and C-SCLC are heterogeneous diseases characterized by different molecular subtype expressions and genomic profiles. Our data provide a basis for adopting histological subtype-based treatments, and further prospective studies are required to confirm our conclusions.