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Neuroendocrinology and Pituitary

SAT-077 - Frequent TERT Loss and Subtelomeric Instability Distinguish Pituitary from Ectopic ACTH-Secreting Tumors.

Saturday, June 13, 2026
9:30 AM - 4:30 PM CT
Location: ENDOExpo; Poster Floor


Objective: To compare somatic mutation profiles, copy-number variations (CNVs), and loss of heterozygosity (LOH) patterns in pituitary and ectopic ACTH-secreting neuroendocrine tumors and to identify molecular mechanisms underlying their distinct biological behavior.
Materials and methods: Whole-exome sequencing was performed on 42 ACTH-secreting tumors, specifically 34 corticotroph and 8 ectopic ACTH-producing neuroendocrine tumors of pulmonary, pancreatic, and renal origin. Somatic point mutations, CNVs, and LOH events were systematically analyzed using validated bioinformatic pipelines and compared between corticotroph and ectopic tumors.

Results: Corticotroph tumors demonstrated significantly higher genomic instability, exhibiting a 2.6-fold increase in gene deletions and a 2.5-fold increase in LOH events compared with ectopic tumors. Genomic losses predominantly affected subtelomeric regions and frequently involved deletion of the telomerase reverse transcriptase (TERT) gene, which was detected in 94% of corticotroph tumors but in only 12.5% of ectopic tumors. These alterations were accompanied by enrichment of genes involved in telomere organization and alternative telomere maintenance pathways. In addition, corticotroph tumors showed recurrent LOH clusters on chromosome 19 affecting genes related to immune regulation and intracellular signaling.
In contrast, ectopic ACTH-producing tumors displayed fewer deletions and LOH events but demonstrated characteristic chromosomal duplications on chromosomes 17 and 21, enriched for keratin-associated protein gene clusters, suggesting a distinct pattern of chromosomal remodeling.
Recurrent somatic point mutations in USP8, USP48, BRAF, TCP11X2, LRP1, KLHL20, and CACNA1I explained the molecular basis of disease in 20 of 34 (58%) corticotroph tumors and in 2 of 6 (33%) lung-derived ectopic tumors, harboring variants only in LRP1 and KLHL20, highlighting marked molecular heterogeneity between these tumor types.

Conclusions: Pituitary and ectopic ACTH-secreting tumors exhibit fundamentally different genomic architectures. Corticotroph tumors are characterized by pronounced subtelomeric instability, frequent TERT loss, and extensive LOH, pointing to telomerase deficiency as a potential biological mechanism underlying their typically indolent growth behavior. In contrast, ectopic tumors demonstrate alternative chromosomal remodeling dominated by gene duplications. These findings expand current understanding of ACTH-secreting tumor biology and may support future molecular stratification and personalized therapeutic approaches.

*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*