Characteristics of gsp-positive growth hormone-secreting pituitary tumors in Korean acromegalic patients

Abstract

A subset of human growth hormone (GH)-secreting pituitary tumors contains the gsp oncogene that encodes an activation mutation of the alpha-subunit of the stimulatory GTP-binding protein (G(S) alpha). This study was undertaken to investigate the frequency of the gsp oncogene in GH-secreting pituitary tumors in Korean acromegalic patients and to elucidate the clinical characteristics of these patients to endocrine testing. Direct polymerase chain reaction sequencing revealed the gsp oncogene mutation in 9 out of 21 tumors (43%) at amino acid 201 of the G(S) alpha protein. A single nucleotide mutation in the tumors carrying the gsp oncogene was observed, which replaced an arginine (CGT) in the normal protein with cysteine (TGT) in eight tumors and serine (AGT) in one tumor. The patients with the gsp oncogene mutation (group 1) were older (54 +/- 10 vs 41 +/- 11 years, p = 0.0085) than those without the mutation (group 2). Sex, tumor size and grade, basal GH and prolactin levels, the GH response to oral glucose loading, the GH fluctuation and the paradoxical response to thyrotropin-releasing hormone or gonadotropin-releasing hormone did not differ between the groups. The gsp oncogene was found mostly in somatotroph adenomas. The octreotide-induced GH suppression was significantly higher in group 1 than in group 2 (95 +/- 5% vs 81 +/- 17%, p = 0.0335). The GH response to bromocriptine did not differ between the groups. These results suggest that the G(S) alpha mutations of GH-secreting tumor are observed in Korean acromegalic patients with similar frequency to those of western countries. The patients with gsp oncogene are likely to be older than those without the oncogene, and show excellent response of GH suppression to octreotide.

Relationship between cytokeratin staining patterns and clinico-pathological features in somatotropinomae

“…Physiologically, TRH receptors act via the inositol 1,4,5-triphosphate pathway to release TSH and PRL (32,33). However, ectopically expressed TRH receptors cross-couple with cAMP and regulate GH secretion by somatotroph cells (34), and the abnormal GH response is more frequently observed in adenomae with gsp mutation than those without the mutation (35) as is in our series. As gsp mutation was more frequently encountered in non-DP adenomae in this study, it is thus rational to expect TRH receptor prevailed more frequently in DG GHomae than in SG ones (31).…”

Somatostatin receptors subtypes 2 and 5, dopamine receptor type 2 expression and gsp status as predictors of octreotide LAR® responsiveness in acromegaly

“…Although this analysis was not done in patient #2, the fact that patient #1 is gsp positive increases her chance to be successfully controlled with octreotide LAR ® . In fact, several studies explored SA responsiveness in the light of gsp status and it seems that gsp positive patients are better responders (20)(21)(22)(23)(24)(25)(26), although there is some controversy in the literature (18).…”

“…Immunohistochemical detection of somatostatin receptor subtype 2 (SSTR2) correlates positively with percent GH reduction on acute test and IGF-I after 6 months of treatment (18,19). When molecular analysis of the ressected tumor is possible, the presence of the gsp oncogene seems to be indicative of a good response to SA treatment (20)(21)(22)(23)(24)(25)(26). Despite the fact that most studies suggest that gsp-positive adenomas respond better to octreotide LAR ® compared to gsp-negative tumors, a recent study failed to fi nd differences in octreotide LAR ® sensitivity according to gsp status (18).…”

AIP and the somatostatin system in pituitary tumours

“…The recurrent somatic mutations in GNAS gene coding for the α-subunit of the stimulatory G protein Gs, commonly named gsp mutation, have been associated with particular clinical characteristics: smaller and less invading densely granulated tumours, normally appearing in older patients (Landis et al 1990, Spada et al 1990, Faglia et al 1996, Yang et al 1996, Barlier et al 1998, Kim et al 2001, Freda et al 2007). The implication of gsp mutation in SSA response has been widely discussed (Larkin et al 2013); nevertheless, a recent meta-analysis revealed that GNAS-positive patients have an approximately 10% greater reduction in GH levels in response to an acute octreotide suppression test (Efstathiadou et al 2015).…”