Differential expression of POMC-processing genes in corticotroph tumors

Corticotroph tumors (CTs) derive from the TBX19 lineage and are functioning (FCTs) or nonfunctioning (NFCTs). In FCTs, the main pathogenic variants are found in USP8, enhancing proopiomelanocortin (POMC) transcription through epidermal growth factor receptor (EGFR) signaling, resulting in a higher secretion index compared with wild type (WT). POMC is cleaved by prohormone convertase 1/3, encoded by proprotein convertase subtilisin/kexin type 1 gene (PCSK1), into ACTH. PCSK1 is inhibited by PCSK1N, which in turn is inhibited by transcription factor paired box 6 (PAX6). We aimed to compare gene expressions involved in POMC processing among NFCTs, USP8+ FCTs, and WT FCTs.

Fresh CTs were collected to quantify TBX19, POMC, EGFR, PCSK1, PCSK1N, and PAX6 by polymerase chain reaction. Sanger sequencing was performed to detect USP8 variants. ACTH levels were normalized to tumor diameter to calculate the secretion index.

We included 42 NFCTs, 13 WT FCTs, and 11 USP8+ FCTs. NFCTs had lower TBX19, POMC, and PAX6 compared with both FCT groups, but similar PCSK1N. TBX19 correlated positively with POMC (R = +0.460; P = 0.002) and PAX6 (R = +0.327; P = 0.030). USP8+ FCTs had a higher secretion index (P = 0.019), higher PCSK1 (P = 0.037), and also lower PCSK1N (P = 0.041), compared with WT, despite similar TBX19 and POMC. Secretion index only correlated with PCSK1N (R = -0.469; P = 0.021).

In NFCTs, low TBX19 may contribute to their nonfunctioning phenotype. In FCTs, USP8+ and WT displayed similar POMC levels, but downstream POMC, USP8+ had a higher PCSK1 and lower PCSK1N, which may account for their comparatively increased secretory activity.