![]() The study revealed infrequent recurrent single nucleotide mutations or small insertions/deletions, with the exception of 29% of somatotroph adenomas that harbored activating mutations of GNAS ( 9). describe the results of whole-exome sequencing of 159 pituitary adenomas, the largest series reported so far. In this issue of the JCI, Ben-Shlomo et al. Specific mutations include those of GRP101, an orphan G protein–coupled receptor ( 4), GNAS, the gene encoding the Gsα subunit of the heterotrimeric G protein that activates the enzyme adenylyl cyclase, which catalyzes the conversion of ATP to cAMP ( 5, 6), PKRAR1A, a regulatory subunit of protein kinase A ( 7), as well as inactivating mutations of AIP, the aryl hydrocarbon receptor–interacting protein ( 8). Salient examples are reflected in patients who develop acromegaly as a result of neuroendocrine tumors that ectopically secrete GH-releasing hormone (GHRH) ( 3) or because of germline or somatic mutations of canonical signaling effectors in the cAMP pathway. There is compelling evidence that constitutive activation of cAMP signaling plays an important role in driving somatotroph adenoma growth and GH secretion. Growth hormone–secreting (GH-secreting) pituitary (somatotroph) adenomas, which give rise to acromegaly or gigantism, represent up to 15% of all pituitary neoplasms. The accepted definition of pituitary malignancy, however, is restricted to tumors that metastasize craniospinally or to distant sites, and these are exceedingly rare (<0.1/100,000 population) ( 2). More aggressive tumors can invade surrounding structures and frequently recur after surgical resection. They are often identified incidentally, are almost invariably benign, and are confined to the sella turcica ( 1). Pituitary adenomas have a prevalence of approximately 1 in 1000 persons and constitute approximately 15% of all brain tumors. These results elucidating somatotroph adenoma pathophysiology identify pathways for targeted treatment. 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. In vivo long-acting GHRH treatment also induced pituitary DNA damage in mice. Octreotide, a somatostatin receptor ligand that targets somatotroph adenoma GH secretion in patients with acromegaly, inhibited cAMP and GH and reversed DNA damage induction. 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. 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. 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. 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. Drivers of sporadic benign pituitary adenoma growth are largely unknown.
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