1. DNA damage and growth hormone hypersecretion in pituitary somatotroph adenomas.
- Author
-
Ben-Shlomo A, Deng N, Ding E, Yamamoto M, Mamelak A, Chesnokova V, Labadzhyan A, and Melmed S
- Subjects
- Animals, Cyclic AMP genetics, Cyclic AMP metabolism, Female, Humans, Male, Mice, Second Messenger Systems genetics, Adenoma genetics, Adenoma metabolism, Adenoma pathology, DNA Damage, DNA, Neoplasm genetics, DNA, Neoplasm metabolism, Growth Hormone-Secreting Pituitary Adenoma genetics, Growth Hormone-Secreting Pituitary Adenoma metabolism, Growth Hormone-Secreting Pituitary Adenoma pathology, Human Growth Hormone genetics, Human Growth Hormone metabolism, Neoplasm Proteins genetics, Neoplasm Proteins metabolism
- Abstract
Drivers of sporadic benign pituitary adenoma growth are largely unknown. Whole-exome sequencing of 159 prospectively resected pituitary adenomas showed that somatic copy number alteration (SCNA) rather than mutation is a hallmark of hormone-secreting adenomas and that SCNAs correlate with adenoma phenotype. Using single-gene SCNA pathway analysis, we observed that both cAMP and Fanconi anemia DNA damage repair pathways were affected by SCNAs in growth hormone-secreting (GH-secreting) somatotroph adenomas. As somatotroph differentiation and GH secretion are dependent on cAMP activation and we previously showed DNA damage, aneuploidy, and senescence in somatotroph adenomas, we studied links between cAMP signaling and DNA damage. Stimulation of cAMP in C57BL/6 mouse primary pituitary cultures using forskolin or a long-acting GH-releasing hormone (GHRH) analog increased GH production and DNA damage measured by H2AX phosphorylation and a comet assay. Octreotide, a somatostatin receptor ligand that targets somatotroph adenoma GH secretion in patients with acromegaly, inhibited cAMP and GH and reversed DNA damage induction. In vivo long-acting GHRH treatment also induced pituitary DNA damage in mice. We conclude that cAMP, which induces somatotroph proliferation and GH secretion, may concomitantly induce DNA damage, potentially linking hormone hypersecretion to SCNA and genome instability. These results elucidating somatotroph adenoma pathophysiology identify pathways for targeted treatment.
- Published
- 2020
- Full Text
- View/download PDF