GH‐secreting pituitary adenomas infrequently contain inactivating mutations of PRKAR1A and LOH of 17q23–24

Yamasaki, Hiroyuki; Mizusawa, Noriko; Saijo, Nagahiro; Yamada, Shozo; Sendo, Toshiaki; Itakura, Mitsuo; Yoshimoto, Katsuhiko

doi:10.1046/j.1365-2265.2003.01740.x

Cited by 43 publications

(31 citation statements)

References 30 publications

(47 reference statements)

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“…Subsequently, the same genetic defects have been detected in some sporadic endocrine tumors, such as adrenal and thyroid adenomas and carcinomas (16 -18). Conversely, a role of PKA R1A in the pathogenesis of pituitary tumors has been ruled out based on the absence of both gene mutations and loss of heterozygosity reported by previous studies and confirmed in the present series (15,19,20).…”

Section: Discussionsupporting

confidence: 58%

Proliferation of Transformed Somatotroph Cells Related to Low or Absent Expression of Protein Kinase A Regulatory Subunit 1A Protein

et al. 2004

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The two regulatory subunits (R1 and R2) of protein kinase A (PKA) are differentially expressed in cancer cell lines and exert diverse roles in growth control. Recently, mutations of the PKA regulatory subunit 1A gene (PRKAR1A) have been identified in patients with Carney complex. The aim of this study was to evaluate the expression of the PKA regulatory subunits R1A, R2A, and R2B in a series of 30 pituitary adenomas and the effects of subunit activation on cell proliferation. In these tumors, neither mutation of PRKAR1A nor loss of heterozygosity was identified. By realtime PCR, mRNA of the three subunits was detected in all of the tumors, R1A being the most represented in the majority of samples. By contrast, immunohistochemistry documented low or absent R1A levels in all tumors, whereas R2A and R2B were highly expressed, thus resulting in an unbalanced R1/R2 ratio. The low levels of R1A were, at least in part, due to proteasome-mediated degradation. The effect of the R1/R2 ratio on proliferation was assessed in GH3 cells, which showed a similar unbalanced pattern of R subunits expression, and in growth hormone-secreting adenomas. The R2-selective cAMP analog 8-Cl cAMP and R1A RNA silencing, stimulated cell proliferation and increased Cyclin D1 expression, respectively, in human and rat adenomatous somatotrophs. These data show that a low R1/R2 ratio promoted proliferation of transformed somatotrophs and are consistent with the Carney complex model in which R1A inactivating mutations further unbalance this ratio in favor of R2 subunits. These results suggest that low expression of R1A protein may favor cAMP-dependent proliferation of transformed somatotrophs.

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Section: Discussionsupporting

confidence: 58%

Proliferation of Transformed Somatotroph Cells Related to Low or Absent Expression of Protein Kinase A Regulatory Subunit 1A Protein

et al. 2004

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“…In studies reported in 1993, the incidence of gsp mutations in Japanese acromegalics was low as 9.3 and 4.4% (43,44); however, re-evaluation performed 10 years later by the same authors indicated that the corrected incidence was 53.1% (45).…”

Section: Gsp Mutations and Ck Staining Patternmentioning

confidence: 99%

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

Bakhtiar

Hirano

Arita

et al. 2010

European Journal of Endocrinology

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Objective: Somatotropinomae are classified as densely and sparsely granulated adenomae, which typically exhibit a perinuclear pattern (PP) and a dot pattern (DP) in cytokeratin (CK) immunostaining respectively. Some exhibit a mixed pattern (MP). We studied the relationship between these somatotropinoma subtypes and their clinico-pathological features. Methods: The study population consisted of 141 Japanese acromegalic patients. We evaluated their clinical presentation and their response to provocation tests with TRH and LHRH and to suppression (octreotide) test. Tumour tissues were subjected to immunostaining for CAM-5.2, MIB-1, CD34, E-cadherin (CDH1) and p53 (TP53). In 43 cases (30 non-DP and 13 DP), we analysed gsp mutations (constitutively activating mutations of the G s a protein that is encoded by GNAS gene). Results: The 141 adenomae were categorised into three subtypes based on their CK staining patterns; 30 (21.3%) exhibited DP, 83 (58.9%) exhibited PP, and 28 (19.9%) exhibited MP. Compared with the other subtypes, DP adenomae were significantly larger, and their E-cadherin expression and response to TRH, LHRH and octreotide challenge were lower. The postoperative cure rate tended to be lower in DP adenomae. gsp mutations were detected in 25 of 43 cases examined (58.1%); 20 of the 30 non-DP (66.7%) and 5 of the 13 DP tumours (38.5%) were affected by the mutation. Conclusion: DP somatotropinomae exhibit characteristic features. Compared with the non-DP subtypes, DP adenomae manifested a larger tumour size, a lower incidence of abnormal responses to TRH and LHRH challenge, a poor response to octreotide test and a lower expression of E-cadherin. gsp mutation was not exclusive for non-DP somatotropinomae.

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“…A reduced expression and/or function of the protein kinase A (PKA) regulatory subunit type Ia (PRKAR1A) due to loss-of-function mutations, leading to an abnormal cAMP pathway activation, causes GH-secreting pituitary adenomas in Carney complex, an autosomal dominant familial syndrome (19,20). To date, mutations of PRKAR1A gene have been rarely found in sporadic pituitary tumors (21,22), although a reduced PRKAR1A expression resulting from increased proteasomal degradation has been described in sporadic GH-secreting tumors (10). Reduced cAMP degradation caused by mutations in PDE11A and PDE8B, coding for members of the phosphodiesterase (PDE) family, have been involved in adrenocortical hyperplasia, adenomas, and cancer as well as in testicular germ cell tumors (23,24).…”

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confidence: 99%

Landscape of somatic mutations in sporadic GH-secreting pituitary adenomas

Ronchi¹,

Peverelli

Herterich

et al. 2016

European Journal of Endocrinology

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Context: Alterations in the cAMP signaling pathway are common in hormonally active endocrine tumors. Somatic mutations at GNAS are causative in 30-40% of GH-secreting adenomas. Recently, mutations affecting the USP8 and PRKACA gene have been reported in ACTH-secreting pituitary adenomas and cortisol-secreting adrenocortical adenomas respectively. However, the pathogenesis of many GH-secreting adenomas remains unclear. Aim: Comprehensive genetic characterization of sporadic GH-secreting adenomas and identification of new driver mutations. Design: Screening for somatic mutations was performed in 67 GH-secreting adenomas by targeted sequencing for GNAS, PRKACA, and USP8 mutations (nZ31) and next-generation exome sequencing (nZ36). Results: By targeted sequencing, known activating mutations in GNAS were detected in five cases (16.1%), while no somatic mutations were observed in both PRKACA and USP8. Whole-exome sequencing identified 132 protein-altering somatic mutations in 31/36 tumors with a median of three mutations per sample (range: 1-13). The only recurrent mutations have been observed in GNAS (31.4% of cases). However, seven genes involved in cAMP signaling pathway were affected in 14 of 36 samples and eight samples harbored variants in genes involved in the calcium signaling or metabolism. At the enrichment analysis, several altered genes resulted to be associated with developmental processes. No significant correlation between genetic alterations and the clinical data was observed. Conclusion: This study provides a comprehensive analysis of somatic mutations in a large series of GH-secreting adenomas. No novel recurrent genetic alterations have been observed, but the data suggest that beside cAMP pathway, calcium signaling might be involved in the pathogenesis of these tumors.

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GH‐secreting pituitary adenomas infrequently contain inactivating mutations of PRKAR1A and LOH of 17q23–24

Abstract: We reconfirm the important role of activating mutations of GNAS1 in GH-secreting adenomas, and conclude that PRKAR1A does not play a significant role in the tumourigenesis.

Cited by 43 publications

References 30 publications

Proliferation of Transformed Somatotroph Cells Related to Low or Absent Expression of Protein Kinase A Regulatory Subunit 1A Protein

Proliferation of Transformed Somatotroph Cells Related to Low or Absent Expression of Protein Kinase A Regulatory Subunit 1A Protein

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

Landscape of somatic mutations in sporadic GH-secreting pituitary adenomas

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