PIT-1/SF-1-positive pituitary tumors in patients with acromegaly: transcriptomic perspective

Neuroendocrine pituitary tumors (PitNETs) are classified based on clinical manifestation and expression of pituitary cell lineage-specific transcription factors (TFs) and hormones. A subtype of tumors in patients with acromegaly was found to express PIT-1 and SF-1 TFs, two markers of distinct pituitary cell lineages. These tumors have been described as multilineage or "somatogonadotoph" tumors. The aim of our study was to clarify their identity and cell type origin using extensive transcriptomic analysis. For this purpose, we analyzed the RNA sequencing (RNAseq) data from 546 PitNETs (including 193 tumors of patient with acromegaly) and single cell RNAseq data from somatotroph and gonadotroph tumors and normal pituitary tissue. Somatrotroph PitNETs co-expressing PIT-1 and SF-1 TFs were identified in each of the analyzed RNAseq dataset. Their transcriptomic profile and pituitary TF activity closely resembled those of other somatotroph tumors, while differing substantially from gonadotroph PitNETs, though they retained NR5A1 (SF-1) activity and expressed some SF-1-regulated genes (e.g., LHB and GNHRH). Notably, SF-1 appeared to regulate a slightly different set of genes in double positive somatotroph PitNETs and gonadotroph tumors. Analysis of scRNAseq data revealed a subcluster of normal gonadotroph cells expressing POU1F1 (PIT-1), but tumor cells from PIT-1/SF-1 PitNETs did not resemble this normal gonadotroph cell subtype. Genes expression profiles of three subtypes of somatotroph tumors were distinguished through analyses of both bulk- and scRNAseq data. From transcriptomic perspective - based on gene co-regulation and pituitary TF activity - PitNETs of patients with acromegaly that co-express PIT-1 and SF-1 represent a subtype of PIT-1 lineage tumors, and the molecular data do not support classifying them as multilineage tumors.