Whole-Genome Sequencing of Growth Hormone (GH)-Secreting Pituitary Adenomas

Välimäki, Niko; Demi̇r, Hande; Pitkänen, Esa; Kaasinen, Eevi; Karppinen, Atte; Kivipelto, Leena; Schalin‐Jäntti, Camilla; Aaltonen, Lauri A.; Karhu, Auli

doi:10.1210/jc.2015-3129

Cited by 90 publications

(102 citation statements)

References 43 publications

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“…Furthermore, a number of genes associated with the Ca 2C signaling (see Table 2) were altered. These findings are in agreement with another recent study on whole-genome alterations in 12 GH-secreting adenomas (37). This is consistent with the notion that binding of growth hormone-releasing hormone to its receptor activates not only the stimulatory subunit a of the G-protein (Ga-S, cAMP-dependent pathways) but also Ga-I, Gb, and Gg, leading to release of intracellular free Ca 2C , which then further triggers secretion of GH (44,45).…”

Section: Discussionsupporting

confidence: 94%

“…This finding is consistent with the low mitotic activity of pituitary tumors and with previous small studies on both non-functioning (nZ7) (43) and GH-secreting pituitary adenomas (nZ12) (37). Moreover, no recurrent somatic mutations have been observed, except the known alterations at the GNAS gene, similarly to a previous report on a small series of GH-secreting adenomas (37). In particular, no somatic mutations have been also detected at the gene GPR101, probably due to the low reported frequency of this mutations (11/248 cases) (33), and, at both the exome sequencing and the targeted sequencing, we did not find any mutations of the PRKACA and USP8 genes.…”

Section: Discussionsupporting

confidence: 92%

“…By whole-exome sequencing, only a limited number of genetic alterations have been detected in the 36 evaluated samples. This finding is consistent with the low mitotic activity of pituitary tumors and with previous small studies on both non-functioning (nZ7) (43) and GH-secreting pituitary adenomas (nZ12) (37). Moreover, no recurrent somatic mutations have been observed, except the known alterations at the GNAS gene, similarly to a previous report on a small series of GH-secreting adenomas (37).…”

Section: Discussionsupporting

confidence: 92%

“…No further genetic alterations were found in more than one sample in this series. Even comparing the list of the mutated genes with that of a recent paper on whole-genome sequencing in 12 GH-secreting adenomas (37), no additional recurrent somatic genetic alterations were observed.…”

Section: European Journal Of Endocrinologymentioning

confidence: 81%

“…Dominant mutations in the deubiquitinase USP8 gene that promote activation of EGFR signaling have been also found in adrenocorticotropin (ACTH)-secreting pituitary adenomas by exome sequencing (36). Finally, germline mutations of genes such as the aryl hydrocarbon receptor-interacting protein (AIP), the menin (MEN1), and the p27 (CDKN1B) have been reported in genetic syndromes associated with acromegaly (i.e., familialisolated pituitary adenoma and multiple endocrine neoplasia type 1 and 4) and in a low percentage of young acromegalic patients (37).…”

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confidence: 99%

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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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Section: Discussionsupporting

confidence: 94%

Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 92%

Section: European Journal Of Endocrinologymentioning

confidence: 81%

mentioning

confidence: 99%

See 3 more Smart Citations

Landscape of somatic mutations in sporadic GH-secreting pituitary adenomas

Ronchi¹,

Peverelli

Herterich

et al. 2016

European Journal of Endocrinology

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Genetics of Pituitary Adenoma

Fukuoka

2017

Encyclopedia of Life Sciences

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Genetic changes of pituitary have been investigated during several decades and have been identified as germ line mutations, including MEN1 , PRKAR1A , AIP , CDKN1B and SDHx genes, and somatic mutations including GNAS and PIK3CA genes. In addition to these genetic changes, further novel genes were recently identified related to childhood pituitary tumours including DICER1 and GPR101 . And somatic USP8 gene mutations were found in 35–62% of Cushing disease by next‐generation sequencing technique. Furthermore, Genome‐wide association study of pituitary adenomas and whole‐genome sequencing of GH ‐secreting adenomas were reported. From the studies of genetically engineered animals which develop pituitary adenomas, predominant genes related to cell cycle ( Rb , p27 , p18 , PTTG1 , HMGAs , MEN1 and Cdk4 ) and cAMP signalling ( Prkar1a , D2r , Ghrhr and Aip ) have been identified. Key Concepts Genetic changes in human pituitary adenomas are identified predominantly from germ line mutations of hereditary syndromes. Some genes related to germ line mutations were also identified in somatic mutations. Recent developments of somatic mutations using next‐generation sequencing are updated. Genetically engineered animal models of pituitary adenomas are summarised. Further epigenetic and proteomic analyses are important in pituitary adenomas.

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Genetics of Pituitary Tumours

Loughrey

Korbonits

2019

Experientia Supplementum

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Whole-Genome Sequencing of Growth Hormone (GH)-Secreting Pituitary Adenomas

Cited by 90 publications

References 43 publications

Landscape of somatic mutations in sporadic GH-secreting pituitary adenomas

Landscape of somatic mutations in sporadic GH-secreting pituitary adenomas

Genetics of Pituitary Adenoma

Genetics of Pituitary Tumours

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