Hepatocyte nuclear factor 4 alpha defines a distinct subtype of lung carcinoid with therapeutic potential targeting...

Lung neuroendocrine neoplasms (NENs) range from low-grade carcinoids to high-grade aggressive neuroendocrine carcinomas (NECs). While studies have identified molecular subtypes of NEC driven by lineage-defining transcription factors, the molecular classification of lung carcinoids (LCs) remains poorly understood. Here, we investigated the molecular and clinicopathological characteristics of LC, focusing on hepatocyte nuclear factor 4α (HNF4α), a transcription factor expressed in certain NECs. Using a publicly available transcriptomic dataset comprising 30 carcinoid tumors, we identified a distinct HNF4A-high LC subtype, in which HNF4A expression was almost mutually exclusive with NK2 Homeobox 1 (NKX2-1), which encodes thyroid transcription factor-1 (TTF-1), and Achaete-Scute family BHLH transcription factor 1 (ASCL1), showing a trend toward central/endobronchial locations. Immunohistochemical analysis of 15 surgically resected LCs revealed that HNF4α-positive LCs accounted for 46.7% (7/15) and HNF4α-negative LCs and tumorlets were mostly TTF-1-positive. RNA sequencing of representative HNF4α-positive and -negative cases demonstrated that the HNF4α-positive subtype possesses a distinctive molecular signature. Differentially expressed genes identified across two independent transcriptome datasets revealed that HNF4α-positive/HNF4A-high and HNF4α-negative/HNF4A-low LCs were enriched for genes related to the digestive and pulmonary neuroendocrine systems, respectively, suggesting distinct cells of origin. Furthermore, somatostatin receptor 2 (SSTR2) was significantly upregulated in the HNF4α-positive/HNF4A-high subtype, as validated by immunohistochemistry. Taken together, HNF4α-positive LC represents a unique subtype characterized by a specific neuroendocrine phenotype, mutually exclusive with TTF-1 and ASCL1 expression, and SSTR2 may serve as a potential therapeutic target for this subtype.