Drivers of sporadic benign pituitary adenoma growth are largely unknown. Whole exome sequencing of 159 prospectively resected pituitary adenomas showed somatic copy number alteration (SCNA) rather than mutation is a hallmark of hormone-secreting adenomas and that SCNA correlate with adenoma phenotype. Using single-gene SCNA pathway analysis, we observed cAMP and Fanconi anemia DNA damage repair pathways both affected by SCNA in growth hormone (GH)-secreting somatotroph adenomas. As somatotroph differentiation and GH secretion is 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 long-acting GH releasing hormone (GHRH) analogue increased GH production and DNA damage measured by phosphorylated H2AX and 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 mouse pituitary DNA damage. 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 treatment targeting.
Anat Ben-Shlomo, Nan Deng, Evelyn Ding, Masaaki Yamamoto, Adam Mamelak, Vera Chesnokova, Artak Labadzhyan, Shlomo Melmed