Abstract
We aimed to identify somatic genetic alterations in pure growth hormone (GH)-secreting pituitary adenomas without GNAS variants. Patients with GH-secreting pituitary adenoma who underwent transsphenoidal adenomectomy at Severance Hospital, Yonsei University College of Medicine were recruited. Somatic genetic alterations were profiled by whole-exome sequencing (WES) and targeted resequencing. WES was performed using DNA from nine GH-secreting pituitary tumors and corresponding blood samples. Absence of GNAS variant was confirmed by Sanger sequencing. For targeted resequencing of 140 fixed tissues, 48 WES-derived candidate genes and 7 GH-secreting pituitary adenoma-associated genes were included. Forty-eight genes with 59 somatic variants were identified by WES. In targeted resequencing, variants in 26 recurrent genes, including MAST4, PRIM2, TNN, STARD9, DNAH11, DOCK4, GPR98, BCHE, DARS, CUBN, NGDN, PLXND1, UNC5B, and COL22A1, were identified, but variants in previously reported genes were not detected. BCHE, DARS, NGDN, and UNC5B variants were associated with increased GH-secreting pituitary tumor biochemical activity, which was confirmed in vitro. Although recurrent point variants were rare, several somatic variants were identified in sporadic pure GH-secreting pituitary adenomas. Several somatic variants may affect pathways involved in the tumorigenesis and biochemical activities of GH-secreting pituitary adenomas.
Highlights
Growth hormone (GH)-secreting pituitary adenoma is the most common cause of acromegaly, which is associated with high mortality caused by cardiovascular disease, metabolic disorders, and malignancies[1,2,3]
We aimed to identify the somatic variants that may be associated with clinical differences in patients with growth hormone (GH)-secreting pituitary adenoma
We identified novel somatic variants associated with pure GH-secreting pituitary adenoma from patients with neither GNAS variants nor a family history
Summary
Growth hormone (GH)-secreting pituitary adenoma is the most common cause of acromegaly, which is associated with high mortality caused by cardiovascular disease, metabolic disorders, and malignancies[1,2,3]. Hormone analysis Report been studied in several sporadic pituitary adenomas by exome s equencing[11,12,13]. Few variants, such as the USP8 variant in Cushing’s disease, have been identified by exome sequencing. We performed somatic variant profiling based on whole-exome sequencing (WES) and targeted resequencing analysis in a large and well-characterized collection of 50 of 140 patients with acromegaly with pure GHexpressing pituitary adenomas without GNAS variants (Fig. 1). We aimed to identify the somatic variants that may be associated with clinical differences in patients with GH-secreting pituitary adenoma
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