DNA damage and growth hormone hypersecretion in pituitary somatotroph adenomas.

The Journal of Clinical Investigation
Anat Ben-ShlomoShlomo Melmed

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 induc...Continue Reading

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Citations

Nov 19, 2020·Pituitary·Zhenqing WeiRenzhi Wang
Feb 13, 2021·Frontiers in Endocrinology·Mengqi ChangRenzhi Wang
Feb 20, 2021·Journal of the Endocrine Society·Ken HoShlomo Melmed
Sep 29, 2020·The Journal of Clinical Investigation·James A Fagin, John H Petrini
May 22, 2021·Cellular and Molecular Life Sciences : CMLS·Jose Mario Gonzalez-Meljem, Juan Pedro Martinez-Barbera
May 22, 2021·Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc·Sylvia L AsaUNKNOWN Attendees of the 15th Meeting of the International Pituitary Pathology Club, Istanbul October 2019
Aug 29, 2021·Toxicological Sciences : an Official Journal of the Society of Toxicology·Rachel V L GonzalezLori T Raetzman

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Methods Mentioned

BETA
surgical resection
Assay
PCR
ELISA
electrophoresis

Software Mentioned

R Project for Statistical Computing
GATK
- Alignment ( BWA )
ANNOVAR
Illumina
ImageJ
Bedtools
Burrows
Integrative Genomics Viewer
ANASpec

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