Genomic Differences Between Corticotroph and Ectopic ACTH-Producing NETs

We aimed to identify and compare key molecular alterations underlying adrenocorticotropin (ACTH)-producing neuroendocrine tumors (NETs) in Cushing's disease and ectopic ACTH syndrome. Whole-exome sequencing was performed on 34 pituitary ACTH-secreting NETs (corticotroph tumors: 30 microadenomas and 4 macroadenomas) and 8 ectopic ACTH-producing NETs of lung, pancreatic, and renal origin. Somatic point mutations, copy-number alterations, and loss of heterozygosity (LOH) were compared between corticotroph and ectopic ACTH-producing NETs. Corticotroph tumors demonstrated significantly more gene deletions and LOH events compared with ectopic ACTH-producing NETs (median 1687 and 2573.5 affected genes in corticotroph tumors, respectively). In corticotroph tumors recurrent subtelomeric deletions and LOH on chromosome 19 affecting FAM98C, RASGRP4, RYR1, MAP4K1, and EIF3K were observed. Notably, TERT deletion was detected in 94% of corticotroph tumors versus only 12.5% ectopic ACTH-producing NETs. In contrast, ectopic ACTH-producing NETs frequently exhibited chromosomal duplications on chromosomes 17 and 21, enriched for keratin-associated protein gene clusters. Recurrent somatic point mutations were identified in BRAF, CACNA1I, KLHL20, MCCC2, LRP1, TCP11X2, USP8, and USP48 genes, explaining the molecular basis of disease in 20 of 34 corticotroph tumors and 2 of 6 lung ACTH-producing NETs (LRP1 R1497Q and CACNA1I S639T). These findings indicate that corticotroph tumors predominantly demonstrated deletions and LOH involving subtelomeric genes, whereas ectopic ACTH-producing tumors more commonly exhibited chromosomal duplications. Potentially relevant somatic mutations were detected in 59% of corticotroph tumors and in 33% of lung ACTH-producing NETs. In conclusion, ACTH-producing NETs of pituitary versus other localizations demonstrate significantly different genetic alterations despite similar clinical and secretory phenotypes.