Epigenomic profiling of neuroendocrine lung cancers identifies a classical-neuroendocrine ASCL1/NKX2-1 subtype and a...

Heterogeneity of neuroendocrine (NE) differentiation in pulmonary high-grade NE carcinoma, mainly small-cell lung cancer (SCLC), has been recently explored based on the expression of lineage transcription factors such as ASCL1, NEUROD1 and POU2F3. However, molecular classification based on these factors remains incomplete, and NE differentiation in lung cancers is more heterogeneous than previously appreciated. Here, we investigated the heterogeneity of NE differentiation using epigenomic profiling across a range of lung cancers with NE components, predominantly large-cell neuroendocrine carcinoma (LCNEC).

We analyzed super-enhancer profiles of 24 formalin-fixed paraffin-embedded tumor tissues from patients with primary lung cancers containing LCNEC components. Associations between epigenomic profiles and NE factors were examined. The functional role of SOX11 was assessed by transcriptomic analysis following CRISPR-Cas9-mediated deletion, as well as by analysis of human LCNEC/SCLC tumor and organoid datasets.

We identified a classical NE subtype characterized by high expression of ASCL1 and NKX2-1, along with high positivity for canonical NE markers. In addition, we identified a unique differentiation axis characterized by a neural transcription factor SOX11. Transcriptomic analyses revealed loss of neuronal gene signatures accompanied by induction of immune response-associated genes. Consistent with these findings, analysis of the human LCNEC/SCLC data showed enrichment of neuronal genes among those positively correlated with SOX11 expression and immune-associated genes among those negatively correlated. Furthermore, SOX11 was associated with reduced expression of immune-related genes, including MHC class I components.

Our epigenomic profiling identifies a classical ASCL1/NKX2-1 subtype and a SOX11-associated axis linked to tumor immunogenicity in NE lung cancers.