RESUMEN
INTRODUCTION: AMPK (AMP-activated protein kinase) is an enzyme that acts as a metabolic sensor and regulates multiple pathways via phosphorylating proteins in metabolic and proliferative pathways. The aim of this work was to study the activated cellular AMPK (phosphorylated-AMPK at Thr172, pAMPK) levels in pituitary tumor samples from patients with sporadic and familial acromegaly, as well as in samples from normal human pituitary gland. METHODS: We studied pituitary adenoma tissue from patients with sporadic somatotroph adenomas, familial acromegaly with heterozygote germline variants in the aryl hydrocarbon receptor interacting protein (AIP) gene (p.Q164*, p.R304* and p.F269_H275dup) and autopsy from normal pituitary glands without structural alterations. RESULTS: Cellular levels of pAMPK were significantly higher in patients with sporadic acromegaly compared to normal pituitary glands (p < 0.0001). Tissues samples from patients with germline AIP mutations also showed higher cellular levels of pAMPK compared to normal pituitary glands. We did not observe a significant difference in cellular levels of pAMPK according to the cytokeratin (CAM5.2) pattern (sparsely or densely granulated) for tumor samples of sporadic acromegaly. CONCLUSION: Our data show, for the first time in human cells, an increase of cellular levels of pAMPK in sporadic somatotropinomas, regardless of cytokeratin pattern, as well as in GH-secreting adenomas from patients with germline AIP mutations.
Asunto(s)
Proteínas Quinasas Activadas por AMP , Adenoma , Adenoma Hipofisario Secretor de Hormona del Crecimiento , Humanos , Proteínas Quinasas Activadas por AMP/metabolismo , Proteínas Quinasas Activadas por AMP/genética , Masculino , Adenoma Hipofisario Secretor de Hormona del Crecimiento/genética , Adenoma Hipofisario Secretor de Hormona del Crecimiento/metabolismo , Adenoma Hipofisario Secretor de Hormona del Crecimiento/patología , Femenino , Persona de Mediana Edad , Adulto , Adenoma/genética , Adenoma/patología , Adenoma/metabolismo , Adenoma/enzimología , Acromegalia/genética , Acromegalia/patología , Acromegalia/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Anciano , Neoplasias Hipofisarias/genética , Neoplasias Hipofisarias/patología , Neoplasias Hipofisarias/metabolismo , Neoplasias Hipofisarias/enzimología , Fosforilación , Hipófisis/metabolismo , Hipófisis/patología , Regulación Neoplásica de la Expresión GénicaRESUMEN
It is usually considered that only 5% of all pituitary neuroendocrine tumours are due to inheritable causes. Since this estimate was reported, however, multiple genetic defects driving syndromic and nonsyndromic somatotrophinomas have been unveiled. This heterogeneous genetic background results in overlapping phenotypes of GH excess. Genetic tests should be part of the approach to patients with acromegaly and gigantism because they can refine the clinical diagnoses, opening the possibility to tailor the clinical conduct to each patient. Even more, genetic testing and clinical screening of at-risk individuals have a positive impact on disease outcomes, by allowing for the timely detection and treatment of somatotrophinomas at early stages. Future research should focus on determining the actual frequency of novel genetic drivers of somatotrophinomas in the general population, developing up-to-date disease-specific multi-gene panels for clinical use, and finding strategies to improve access to modern genetic testing worldwide.
Asunto(s)
Acromegalia , Pruebas Genéticas , Gigantismo , Humanos , Acromegalia/genética , Acromegalia/diagnóstico , Acromegalia/terapia , Gigantismo/genética , Gigantismo/diagnóstico , Neoplasias Hipofisarias/genética , Neoplasias Hipofisarias/diagnóstico , Adenoma Hipofisario Secretor de Hormona del Crecimiento/genética , Adenoma Hipofisario Secretor de Hormona del Crecimiento/diagnóstico , Adenoma Hipofisario Secretor de Hormona del Crecimiento/terapiaRESUMEN
Objective: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome characterized by its clinical variability and complexity in diagnosis and treatment. We performed both clinical and molecular descriptions of four families with MEN1 in a follow-up at a tertiary center in Brasília. Methods: From a preliminary review of approximately 500 medical records of patients with pituitary neuroendocrine tumor (PitNET) from the database of the Neuroendocrinology Outpatient Clinic of the University Hospital of Brasília, a total of 135 patients met the criteria of at least two affected family members. From this cohort, we have identified 34 families: only four with a phenotype of MEN1 and the other 30 families with the phenotype of familial isolated pituitary adenoma (FIPA). Eleven patients with a clinical diagnosis of MEN1 from these four families were selected. Results: Variants in MEN1 gene were identified in all families. One individual from each family underwent genetic testing using targeted high-throughput sequencing (HTS). All patients had primary hyperparathyroidism (PHPT), and the second most common manifestation was PitNET. One individual had well-differentiated liposarcoma, which has been previously reported in a single case of MEN1. Three variants previously described in the database and a novel variant in exon 2 have been found. Conclusions: The study allowed the genotypic and phenotypic characterization of families with MEN1 in a follow-up at a tertiary center in Brasília.
Asunto(s)
Adenoma Hipofisario Secretor de Hormona del Crecimiento , Neoplasia Endocrina Múltiple Tipo 1 , Tumores Neuroendocrinos , Neoplasias Hipofisarias , Humanos , Neoplasia Endocrina Múltiple Tipo 1/diagnóstico , Neoplasia Endocrina Múltiple Tipo 1/genética , Neoplasia Endocrina Múltiple Tipo 1/patología , Brasil/epidemiología , Adenoma Hipofisario Secretor de Hormona del Crecimiento/genética , Neoplasias Hipofisarias/diagnóstico , Neoplasias Hipofisarias/genética , Neoplasias Hipofisarias/patologíaRESUMEN
Currently, the first-generation somatostatin receptor ligands (fg-SRLs), octreotide LAR and lanreotide autogel, are the mainstays of acromegaly treatment and achieve biochemical control in approximately 40% of patients and tumor shrinkage in over 60% of patients. Pasireotide, a second-generation SRL, shows higher efficacy with respect to both biochemical control and tumor shrinkage but has a worse safety profile. In this review, we discuss the future perspectives of currently available SRLs, focusing on the use of biomarkers of response and precision medicine, new formulations of these SRLs and new drugs, which are under development. Precision medicine, which is based on biomarkers of response to treatment, will help guide the decision-making process by allowing physicians to choose the appropriate drug for each patient and improving response rates. New formulations of available SRLs, such as oral, subcutaneous depot, and nasal octreotide, may improve patients' adherence to treatment and quality of life since there will be more options available that better suit each patient. Finally, new drugs, such as paltusotine, somatropin, ONO-5788, and ONO-ST-468, may improve treatment adherence and present higher efficacy than currently available drugs.
Asunto(s)
Acromegalia/tratamiento farmacológico , Antineoplásicos Hormonales/administración & dosificación , Adenoma Hipofisario Secretor de Hormona del Crecimiento/tratamiento farmacológico , Receptores de Somatostatina/metabolismo , Acromegalia/sangre , Acromegalia/etiología , Antineoplásicos Hormonales/efectos adversos , Biomarcadores de Tumor/sangre , Adenoma Hipofisario Secretor de Hormona del Crecimiento/sangre , Adenoma Hipofisario Secretor de Hormona del Crecimiento/complicaciones , Adenoma Hipofisario Secretor de Hormona del Crecimiento/genética , Humanos , Octreótido/administración & dosificación , Octreótido/efectos adversos , Péptidos Cíclicos/administración & dosificación , Péptidos Cíclicos/efectos adversos , Medicina de Precisión/métodos , Medicina de Precisión/tendencias , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , Somatostatina/administración & dosificación , Somatostatina/efectos adversos , Somatostatina/análogos & derivados , Resultado del TratamientoRESUMEN
INTRODUCTION: Gigantism is a rare pediatric disease characterized by increased production of growth hormone (GH) before epiphyseal closure, that manifests clinically as tall stature, musculoskeletal abnormalities, and multiple comorbidities. MATERIALS AND METHODS: Case series of 6 male patients with gigantism evaluated at the Endocrinology Service of Hospital de San José (Bogotá, Colombia) between 2010 and 2016. RESULTS: All patients had macroadenomas and their mean final height was 2.01 m. The mean age at diagnosis was 16 years, and the most common symptoms were headache (66%) and hyperhidrosis (66%). All patients had acral changes, and one had visual impairment secondary to compression of the optic chiasm. All patients underwent surgery, and 5 (83%) required additional therapy for biochemical control, including radiotherapy (n = 4, 66%), somatostatin analogues (n = 5, 83%), cabergoline (n = 3, 50%), and pegvisomant (n = 2, 33%). Three patients (50%) achieved complete biochemical control, while 2 patients showed IGF-1 normalization with pegvisomant. Two patients were genetically related and presented a mutation in the aryl hydrocarbon receptor-interacting protein (AIP) gene (pathogenic variant, c.504G>A in exon 4, p.Trp168*), fulfilling the diagnostic criteria of familial isolated pituitary adenoma. CONCLUSIONS: This is the largest case series of patients with gigantism described to date in Colombia. Transsphenoidal surgery was the first-choice procedure, but additional pharmacological therapy was usually required. Mutations in the AIP gene should be considered in familial cases of GH-producing adenomas.
Asunto(s)
Adenoma/terapia , Gigantismo/terapia , Neoplasias Hipofisarias/terapia , Adenoma/diagnóstico , Adolescente , Colombia , Estudios de Seguimiento , Gigantismo/diagnóstico , Hormona del Crecimiento/sangre , Adenoma Hipofisario Secretor de Hormona del Crecimiento/genética , Humanos , Factor I del Crecimiento Similar a la Insulina/análisis , Péptidos y Proteínas de Señalización Intracelular/genética , Masculino , Mutación/genética , Linaje , Neoplasias Hipofisarias/diagnóstico , Estudios Retrospectivos , Distribución por Sexo , Resultado del Tratamiento , Adulto JovenRESUMEN
ABSTRACT Introduction Gigantism is a rare pediatric disease characterized by increased production of growth hormone (GH) before epiphyseal closure, that manifests clinically as tall stature, musculoskeletal abnormalities, and multiple comorbidities. Materials and methods Case series of 6 male patients with gigantism evaluated at the Endocrinology Service of Hospital de San José (Bogotá, Colombia) between 2010 and 2016. Results All patients had macroadenomas and their mean final height was 2.01 m. The mean age at diagnosis was 16 years, and the most common symptoms were headache (66%) and hyperhidrosis (66%). All patients had acral changes, and one had visual impairment secondary to compression of the optic chiasm. All patients underwent surgery, and 5 (83%) required additional therapy for biochemical control, including radiotherapy (n = 4, 66%), somatostatin analogues (n = 5, 83%), cabergoline (n = 3, 50%), and pegvisomant (n = 2, 33%). Three patients (50%) achieved complete biochemical control, while 2 patients showed IGF-1 normalization with pegvisomant. Two patients were genetically related and presented a mutation in the aryl hydrocarbon receptor-interacting protein (AIP) gene (pathogenic variant, c.504G>A in exon 4, p.Trp168*), fulfilling the diagnostic criteria of familial isolated pituitary adenoma. Conclusions This is the largest case series of patients with gigantism described to date in Colombia. Transsphenoidal surgery was the first-choice procedure, but additional pharmacological therapy was usually required. Mutations in the AIP gene should be considered in familial cases of GH-producing adenomas.
Asunto(s)
Humanos , Masculino , Adolescente , Adulto Joven , Neoplasias Hipofisarias/terapia , Adenoma/terapia , Gigantismo/terapia , Linaje , Neoplasias Hipofisarias/diagnóstico , Factor I del Crecimiento Similar a la Insulina/análisis , Hormona del Crecimiento/sangre , Adenoma/diagnóstico , Estudios Retrospectivos , Estudios de Seguimiento , Resultado del Tratamiento , Distribución por Sexo , Colombia , Péptidos y Proteínas de Señalización Intracelular/genética , Adenoma Hipofisario Secretor de Hormona del Crecimiento/genética , Gigantismo/diagnóstico , Mutación/genéticaRESUMEN
Filamin-A (FLNA) plays a crucial role in somatostatin receptor (sst) subtype-2 signaling in somatotropinomas. Our objective was to investigate the in vivo association between FLNA and sst2 expression, sst5 expression, dopamine receptor subtype-2 (D2) expression, somatostatin receptor ligand (SRL) responsiveness and tumor invasiveness in somatotropinomas. Quantitative real-time PCR was used to evaluate the absolute mRNA copy numbers of FLNA/sst2/sst5/D2 in 96 somatotropinomas. FLNA, sst2 and sst5 protein expression levels were also evaluated using immunohistochemistry. The Knosp-Steiner criteria were used to evaluate tumor invasiveness. Median FLNA, sst2, sst5 and D2 copy numbers were 4,244, 731, 156 and 3,989, respectively. Thirty-one of the 35 available tumors (89%) were immune positive for FLNA in the cytoplasm and membrane but not in the nucleus. FLNA and sst5 expression were positively correlated at the mRNA and protein levels (p < 0.001 and p = 0.033, respectively). FLNA was positively correlated with sst2 mRNA in patients who were responsive to SRL (p = 0.014, R = 0.659). No association was found between FLNA and tumor invasiveness. Our findings show that in somatotropinomas FLNA expression positively correlated with in vivo sst5 and D2 expression. Notably, FLNA was only correlated with sst2 in patients who were controlled with SRL. FLNA was not associated with tumor invasiveness.
Asunto(s)
Acromegalia/genética , Adenoma/tratamiento farmacológico , Antineoplásicos/administración & dosificación , Filaminas/genética , Adenoma Hipofisario Secretor de Hormona del Crecimiento/tratamiento farmacológico , Receptores de Dopamina D2/genética , Receptores de Somatostatina/genética , Acromegalia/etiología , Acromegalia/metabolismo , Adenoma/complicaciones , Adenoma/genética , Adenoma/metabolismo , Adolescente , Adulto , Anciano , Antineoplásicos/uso terapéutico , Membrana Celular/genética , Membrana Celular/metabolismo , Núcleo Celular/genética , Núcleo Celular/metabolismo , Citoplasma/genética , Citoplasma/metabolismo , Femenino , Filaminas/metabolismo , Adenoma Hipofisario Secretor de Hormona del Crecimiento/complicaciones , Adenoma Hipofisario Secretor de Hormona del Crecimiento/genética , Adenoma Hipofisario Secretor de Hormona del Crecimiento/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Octreótido/administración & dosificación , Octreótido/uso terapéutico , Péptidos Cíclicos/administración & dosificación , Péptidos Cíclicos/uso terapéutico , Receptores de Dopamina D2/metabolismo , Receptores de Somatostatina/metabolismo , Somatostatina/administración & dosificación , Somatostatina/análogos & derivados , Somatostatina/uso terapéutico , Carga Tumoral , Adulto JovenRESUMEN
OBJECTIVES: This study analyzed the KISS1 c.-145delA (rs5780218) promoter polymorphism in a cohort of patients with growth hormone secreting pituitary adenoma (somatotropinoma) and controls, to investigate its role in the incidence of acromegaly and to assess patient/tumor characteristics. Material and methods rs5780218 allelic and genotypic distributions were compared between 49 somatotropinoma patients and 167 healthy controls. rs5780218 was also assessed in relation to patient characteristics and tumor aggressiveness, as characterized by tumor invasion and resistance to conventional therapy. The relationship between KISS1 mRNA expression and the rs5780218 genotype was also assessed in available pituitary tumor samples. RESULTS: The homozygous -/- variant genotype was associated with high rates of somatotropinoma (P<0.01), but not with tumor invasiveness, patient characteristics or hormonal remission. KISS1 mRNA expression was much lower in somatotropinomas carrying the deleted allele than in homozygous wild type AA. CONCLUSIONS: In this pilot study, the rs5780218 promoter polymorphism was evaluated in pituitary adenoma, and showed a possible association with the incidence of somatotropinoma but not with tumor progression.
Asunto(s)
Adenoma/genética , Adenoma Hipofisario Secretor de Hormona del Crecimiento/genética , Kisspeptinas/genética , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas/genética , Adenoma/epidemiología , Adenoma/patología , Adulto , Estudios de Casos y Controles , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Adenoma Hipofisario Secretor de Hormona del Crecimiento/epidemiología , Adenoma Hipofisario Secretor de Hormona del Crecimiento/patología , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Proyectos Piloto , Polimorfismo de Nucleótido Simple/fisiología , Factores de Riesgo , Adulto JovenRESUMEN
Genetic and functional aberrations of guanine nucleotide-binding protein, alpha stimulating (GNAS), aryl hydrocarbon receptor interacting protein (AIP), and pituitary tumor transforming gene (PTTG) are among the most prominent events in pituitary tumorigenesis. A cohort of Brazilian patients with somatotropinomas (n=41) and non-functioning pituitary adenomas (NFPA, n=21) from a single tertiary-referral center were evaluated for GNAS and AIP mutations and gene expression of AIP and PTTG. Results were compared to the clinical and biological (Ki67 and p53 expression) characteristics of tumors and their response to therapy, if applicable. Genetic analysis revealed that 27% of somatotropinomas and 4.8% of NFPA harbored GNAS mutations (P=0.05). However, no differences were observed in clinical characteristics, tumor extension, response to somatostatin analog therapy, hormonal/surgical remission rates, Ki67 index, and p53 expression between mutated and non-mutated somatotropinomas patients. PTTG overexpression (RQ mean=10.6, min=4.39, max=11.9) and AIP underexpression (RQ mean=0.56, min=0.46-max=0.92) were found in virtually all cases without a statistically significant relationship with clinical and biological tumor features. No patients exhibited somatic or germline pathogenic AIP mutations. In conclusion, mutations in GNAS and abnormal PTTG and AIP expression had no impact on tumor features and treatment outcomes in this cohort. Our data support some previous studies and point to the need for further investigations, probably involving epigenetic and transcriptome analysis, to improve our understanding of pituitary tumor behavior.
Asunto(s)
Adenoma/genética , Mutación de Línea Germinal/genética , Adenoma Hipofisario Secretor de Hormona del Crecimiento/genética , Neoplasias Hipofisarias/genética , Adenoma/patología , Adulto , Brasil , Carcinogénesis , Transformación Celular Neoplásica , Estudios de Cohortes , ADN de Neoplasias , Femenino , Marcadores Genéticos , Adenoma Hipofisario Secretor de Hormona del Crecimiento/patología , Humanos , Péptidos y Proteínas de Señalización Intracelular , Masculino , Persona de Mediana Edad , Hipófisis/patología , Neoplasias Hipofisarias/patologíaRESUMEN
Type 4 phosphodiesterases (PDE4s) of the large PDE enzyme superfamily have unique specificity for cAMP and may, therefore, be relevant for somatotroph tumorigenesis. Somatotroph adenomas typically overexpress PDEs probably as part of a compensatory mechanism to reduce cAMP levels. The rat PDE4A5 isoform (human homolog PDE4A4) interacts with the AIP protein, coded by a tumour suppressor gene mutated in a subgroup of familial isolated pituitary adenomas (FIPAs). PDE4A8 is the closest related isoform of PDE4A4. We aimed to evaluate the expression of both PDE4A4 and PDE4A8 in GH cells of AIP-mutated adenomas and compare their expression with that in GH cells from sporadic AIP-mutation negative GH-secreting adenomas, where we had shown previously that both PDE4A4 and PDE4A8 isoforms had been over-expressed. Confocal immunofluorescence analysis showed that both PDE4A8 and PDE4A4 had lower expression in AIP-mutated somatotropinoma samples compared to sporadic GH-secreting tumours (Pâ¯<â¯0.0001 for both). Based on the association of low PDE4A4 and PDE4A8 expression with germline AIP-mutations positive samples we suggest that lack of AIP hinders the upregulation of PDE4A8 and PDE4A4 protein seen in sporadic somatotrophinomas. These data point to a unique disturbance of the cAMP-PDE pathway in AIP-mutation positive adenomas, which may help to explain their well-described poor response to somatostatin analogues.
Asunto(s)
Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Adenoma Hipofisario Secretor de Hormona del Crecimiento/enzimología , Adenoma Hipofisario Secretor de Hormona del Crecimiento/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Mutación/genética , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Sirtuins 1-7 (SIRT) are a highly conserved family of histone deacetylases involved in the regulation of longevity that have a considerable impact in transcription, DNA repair regulation, telomeric stability, cell senescence and apoptosis. In the present study, SIRT1-7 mRNA levels were evaluated in 37 somatotropinomas and 31 nonfunctioning pituitary adenomas (NFPAs) using qPCR and relation to tumor size, invasiveness and Ki-67 proliferative index was made. Overexpression of SIRT1 was observed in 86.5% of somatotropinomas versus 41.9% of NFPAs (P < 0.01). SIRT3 was more underexpressed in NFPAs than somatotropinomas (77.4 and 40.5%, respectively, P < 0.01) as well as SIRT4 and SIRT7. Despite the lack of association between sirtuins and invasiveness or Ki-67 index, SIRT1 and SIRT3 expressions were related to tumor size. Mean of the largest diameter was smaller in adenomas with SIRT1 overexpression than with normal expression (P < 0.01) and SIRT3 underexpression was associated with larger tumors (P < 0.01). In conclusion, a pronounced difference in sirtuins expression was identified between pituitary adenomas, suggesting that these genes are potential markers of pituitary adenomas and could be employed in the characterization of somatotropinomas and NFPAs. The role of sirtuins in pathogenesis of pituitary tumors merits further investigation and possibly will provide new molecular insight about their progression.
Asunto(s)
Adenoma/metabolismo , Neoplasias Hipofisarias/metabolismo , Sirtuinas/metabolismo , Adenoma/genética , Adenoma/patología , Adulto , Femenino , Adenoma Hipofisario Secretor de Hormona del Crecimiento/genética , Adenoma Hipofisario Secretor de Hormona del Crecimiento/metabolismo , Adenoma Hipofisario Secretor de Hormona del Crecimiento/patología , Histona Desacetilasas/genética , Histona Desacetilasas/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Neoplasias Hipofisarias/genética , Neoplasias Hipofisarias/patología , Sirtuina 1/genética , Sirtuina 1/metabolismo , Sirtuina 2/genética , Sirtuina 2/metabolismo , Sirtuina 3/genética , Sirtuina 3/metabolismo , Sirtuinas/genéticaRESUMEN
Genetic and functional aberrations of guanine nucleotide-binding protein, alpha stimulating (GNAS), aryl hydrocarbon receptor interacting protein (AIP), and pituitary tumor transforming gene (PTTG) are among the most prominent events in pituitary tumorigenesis. A cohort of Brazilian patients with somatotropinomas (n=41) and non-functioning pituitary adenomas (NFPA, n=21) from a single tertiary-referral center were evaluated for GNAS and AIP mutations and gene expression of AIP and PTTG. Results were compared to the clinical and biological (Ki67 and p53 expression) characteristics of tumors and their response to therapy, if applicable. Genetic analysis revealed that 27% of somatotropinomas and 4.8% of NFPA harbored GNAS mutations (P=0.05). However, no differences were observed in clinical characteristics, tumor extension, response to somatostatin analog therapy, hormonal/surgical remission rates, Ki67 index, and p53 expression between mutated and non-mutated somatotropinomas patients. PTTG overexpression (RQ mean=10.6, min=4.39, max=11.9) and AIP underexpression (RQ mean=0.56, min=0.46-max=0.92) were found in virtually all cases without a statistically significant relationship with clinical and biological tumor features. No patients exhibited somatic or germline pathogenic AIP mutations. In conclusion, mutations in GNAS and abnormal PTTG and AIP expression had no impact on tumor features and treatment outcomes in this cohort. Our data support some previous studies and point to the need for further investigations, probably involving epigenetic and transcriptome analysis, to improve our understanding of pituitary tumor behavior.
Asunto(s)
Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Neoplasias Hipofisarias/genética , Adenoma/genética , Mutación de Línea Germinal/genética , Adenoma Hipofisario Secretor de Hormona del Crecimiento/genética , Hipófisis/patología , Neoplasias Hipofisarias/patología , Brasil , ADN de Neoplasias , Marcadores Genéticos , Adenoma/patología , Transformación Celular Neoplásica , Estudios de Cohortes , Péptidos y Proteínas de Señalización Intracelular , Adenoma Hipofisario Secretor de Hormona del Crecimiento/patología , CarcinogénesisRESUMEN
INTRODUCTION: Pituitary adenomas (PA) occur mainly as sporadic disease, but familial syndromes are found in approximately 5% of cases. Identification of these syndromes is important in order to diagnose individuals at risk at an earlier stage. AIMS: To evaluate the frequency of familial PA in a reference outpatient clinic devoted to PA treatment and to identify family members suspected to have pituitary disease. METHODS: Patients with PA were interviewed with respect to the presence of family members with diagnosis of PA or with signs or symptoms suggestive of them. The family members who had a clinical picture suggestive of pituitary disease were further evaluated in an attempt to identify new PA cases. In families with familial disease, the AIP gene was sequenced. RESULTS: 262 patients were evaluated and familial syndrome was found in 13 (5%). Ten (3.8%) patients had familial isolated PA (FIPA) and three (1.2%) had multiple endocrine neoplasia type 1. After evaluation of family members' symptomatology, 110 were considered suspected of having pituitary disease, but only 24 participated in the study. Of these 24, 1 was diagnosed with a corticotropinoma. AIP mutations were found in 20% of FIPA families. CONCLUSION: We found a frequency of familial PA similar to that previously described, as well as a similar frequency of AIP mutations among FIPA families. An active search of the affected family members was able to identify one case of Cushing´s disease. Patients should be aware of pituitary disease's clinical picture to identify possibly affected family members.
Asunto(s)
Predisposición Genética a la Enfermedad , Adenoma Hipofisario Secretor de Hormona del Crecimiento/epidemiología , Péptidos y Proteínas de Señalización Intracelular/genética , Mutación , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/epidemiología , Neoplasias Hipofisarias/epidemiología , Adulto , Anciano , Anciano de 80 o más Años , Instituciones de Atención Ambulatoria , Estudios Transversales , Femenino , Estudios de Seguimiento , Adenoma Hipofisario Secretor de Hormona del Crecimiento/genética , Adenoma Hipofisario Secretor de Hormona del Crecimiento/patología , Humanos , Patrón de Herencia , Masculino , Persona de Mediana Edad , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/genética , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/patología , Neoplasias Hipofisarias/genética , Neoplasias Hipofisarias/patología , Pronóstico , Estándares de Referencia , Síndrome , Adulto JovenRESUMEN
Acromegaly is caused by a somatotropinoma in the vast majority of the cases. These are monoclonal tumors that can occur sporadically or rarely in a familial setting. In the last few years, novel familial syndromes have been described and recent studies explored the landscape of somatic mutations in sporadic somatotropinomas. This short review concentrates on the current knowledge of the genetic basis of both familial and sporadic acromegaly.
Asunto(s)
Acromegalia/genética , Acromegalia/etiología , Femenino , Antecedentes Genéticos , Adenoma Hipofisario Secretor de Hormona del Crecimiento/complicaciones , Adenoma Hipofisario Secretor de Hormona del Crecimiento/genética , Humanos , Masculino , Mutación/genéticaRESUMEN
Familial isolated pituitary adenoma (FIPA) is a rare genetic disorder. In a subset of FIPA families AIP germline mutations have been reported, but in most FIPA cases the exact genetic defect remains unknown. The present study aimed to determine the genetic basis of FIPA in a Brazilian family. Three siblings presented with isolated prolactin genes. Further mutation screening was performed using whole-exome sequencing and all likely causative mutations were validated by Sanger sequencing. In silico analysis and secreting pituitary adenoma diagnosed through clinical, biochemical and imaging testing. Sanger sequencing was used to genotype candidate prolactinoma-mutated additional predictive algorithms were applied to prioritize likely pathogenic variants. No mutations in the coding and flanking intronic regions in the MEN1, AIP and PRLR genes were detected. Whole-exome sequencing of three affected siblings revealed novel, predicted damaging, heterozygous variants in three different genes: RXRG, REXO4 and TH. In conclusion, the RXRG and TH possibly pathogenic variants may be associated with isolated prolactinoma in the studied family. The possible contribution of these genes to additional FIPA families should be explored.
Asunto(s)
Adenoma/genética , Mutación de Línea Germinal , Adenoma Hipofisario Secretor de Hormona del Crecimiento/genética , Prolactinoma/genética , Receptor gamma X Retinoide/genética , Tirosina 3-Monooxigenasa/genética , Adulto , Simulación por Computador , Análisis Mutacional de ADN , Exoma , Femenino , Predisposición Genética a la Enfermedad , Humanos , Péptidos y Proteínas de Señalización Intracelular/química , Péptidos y Proteínas de Señalización Intracelular/genética , Masculino , Linaje , Proteínas Proto-Oncogénicas/química , Proteínas Proto-Oncogénicas/genética , Receptores de Prolactina/química , Receptores de Prolactina/genética , Receptor gamma X Retinoide/química , Tirosina 3-Monooxigenasa/químicaRESUMEN
Although aryl hydrocarbon receptor-interacting protein (AIP) mutations are rare in sporadic acromegaly, their prevalence among young patients is nonnegligible. The objectives of this study were to evaluate the frequency of AIP mutations in a cohort of Mexican patients with acromegaly with disease onset before the age of 30 and to search for molecular abnormalities in the AIP gene in teeth obtained from the "Tampico Giant". Peripheral blood DNA from 71 patients with acromegaly (51 females) with disease onset <30 years was analysed (median age of disease onset of 23 years) and correlated with clinical, biochemical and imaging characteristics. Sequencing was also carried out in DNA extracted from teeth of the Tampico Giant. Five patients (7 %) harboured heterozygous, germline mutations of the AIP gene. In two of them (a 9-year-old girl with gigantism and a young man with symptoms of GH excess since age 14) the c.910C>T (p.Arg304Ter), well-known truncating mutation was identified; in one of these two cases and her identical twin sister, the mutation proved to be a de novo event, since neither of their parents were found to be carriers. In the remaining three patients, new mutations were identified: a frameshift mutation (c.976_977insC, p.Gly326AfsTer), an in-frame deletion (c.872_877del, p.Val291_Leu292del) and a nonsense mutation (c.868A > T, p.Lys290Ter), which are predicted to be pathogenic based on in silico analysis. Patients with AIP mutations tended to have an earlier onset of acromegaly and harboured larger and more invasive tumours. A previously described genetic variant of unknown significance (c.869C > T, p.Ala299Val) was identified in DNA from the Tampico Giant. The prevalence of AIP mutations in young Mexican patients with acromegaly is similar to that of European cohorts. Our results support the need for genetic evaluation of patients with early onset acromegaly.
Asunto(s)
Acromegalia/genética , Gigantismo/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Adenoma/genética , Adolescente , Adulto , Femenino , Frecuencia de los Genes , Adenoma Hipofisario Secretor de Hormona del Crecimiento/genética , Humanos , Masculino , México , Mutación , Adulto JovenRESUMEN
BACKGROUND: Acromegaly is associated with significant morbidity and increased mortality, but has a variable severity phenotype. The presence of the exon 3-deleted isoform of the growth hormone receptor (d3-GHR) may influence the disease phenotype and treatment outcomes, including the frequency of biochemical discordance after medical treatment. AIMS: The objective of this study was to analyze the influence of the d3-GHR isoform on clinical and biochemical characteristics and in the treatment outcomes of Brazilian multiethnic acromegaly patients. METHODS: We retrospectively analyzed our acromegaly outpatient clinic databank and collected demographic, clinical, biochemical and treatment outcome data from those patients who agreed to participate in the study. A blood sample was collected from all patients, the DNA was extracted and the GHR isoforms were evaluated by PCR, with the full length (fl)-GHR represented by a 935-bp fragment and the d3-GHR represented by a 532-bp fragment. RESULTS: A total of 121 patients were included. Fifty-six patients (46.3 %) were full-length homozygous (fl/fl), 48 (39.7 %) were heterozygous (fl/d3) and 17 (14.0 %) were d3-GHR homozygous (d3/d3). There was no difference between patients homozygous for the fl isoform and those harboring at least one d3-GHR allele in the demographic, clinical and biochemical data or in the treatment outcomes, including somatostatin receptor ligands (SRL) monotherapy, combination therapy with SRL and cabergoline and pegvisomant treatment. There was also no difference between the groups for the frequency of GH and IGF-I discordance after medical treatment. CONCLUSION: GHR exon 3 genotyping appears to have no clinical significance, at least in Brazilian acromegaly patients.
Asunto(s)
Acromegalia/genética , Adenoma/genética , Etnicidad/genética , Adenoma Hipofisario Secretor de Hormona del Crecimiento/genética , Receptores de Somatotropina/genética , Eliminación de Secuencia/genética , Acromegalia/metabolismo , Adenoma/metabolismo , Adulto , Secuencia de Bases , Brasil , Exones/genética , Femenino , Adenoma Hipofisario Secretor de Hormona del Crecimiento/metabolismo , Hormona de Crecimiento Humana/metabolismo , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Análisis de Secuencia de ADNRESUMEN
INTRODUCTION: There are few data regarding ZAC1 expression in clinically non-functioning pituitary adenomas (NFPA). Because somatotropinomas and NFPA behave differently with respect to tumor shrinkage during somatostatin analogs (SA) therapy, we sought to compare the ZAC1 and somatostatin receptor (sstr) types 1, 2, 3 and 5 mRNA expression in these two pituitary adenoma subtypes and in normal human pituitaries. METHODS: ZAC1 and SSTR mRNA expression levels were evaluated using real-time RT-PCR (TaqMan) in 20 NFPA and compared with the expression levels in 23 somatotropinomas and five normal pituitaries. The NFPA invasiveness was evaluated using magnetic resonance imaging with Hardy's modified criteria. Ki-67 and p53 were evaluated using immunohistochemistry. RESULTS: A total of 20 patients with NFPA [6 males, median age 56 years (range: 30-78)], 23 with acromegaly [12 males, median age 43 years (range: 24-57)] and five normal pituitaries [4 males, median age 48 years (range: 36-54)] were included. Four of the patients (20%) had Hardy's grade 2 tumors; all of the others had Hardy's grade 3 tumors. The Ki-67 median expression was 2.35 (range: 0.2-9.23), and only four of the tumors (20%) were positive for p53. The ZAC1 mRNA expression was significantly lower in NFPA than in somatotropinomas and in normal pituitaries (p<0.001 for both), as well as the SSTR2 (p=0.001 and 0.01, respectively). The SSTR3 expression was higher in the NFPA than in the somatotropinomas and in the normal pituitaries (p=0.03 and 0.02, respectively). No correlation was found between the ZAC1 mRNA expression and the tumor invasiveness, Ki-67 and p53. CONCLUSION: ZAC1 and SSTR2 are underexpressed and SSTR3 is overexpressed in NFPA compared to those in somatotropinomas and in normal pituitaries, which might explain the lack of tumor shrinkage that is observed in response to commercially available SA therapy in patients with NFPA.
Asunto(s)
Adenoma/genética , Proteínas de Ciclo Celular/genética , Regulación Neoplásica de la Expresión Génica , Adenoma Hipofisario Secretor de Hormona del Crecimiento/genética , Neoplasias Hipofisarias/genética , Receptores de Somatostatina/genética , Factores de Transcripción/genética , Proteínas Supresoras de Tumor/genética , Adenoma/tratamiento farmacológico , Adenoma/metabolismo , Adenoma/patología , Adulto , Anciano , Estudios de Casos y Controles , Proteínas de Ciclo Celular/metabolismo , Femenino , Adenoma Hipofisario Secretor de Hormona del Crecimiento/tratamiento farmacológico , Adenoma Hipofisario Secretor de Hormona del Crecimiento/metabolismo , Adenoma Hipofisario Secretor de Hormona del Crecimiento/patología , Humanos , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Masculino , Persona de Mediana Edad , Hipófisis/efectos de los fármacos , Hipófisis/metabolismo , Hipófisis/patología , Neoplasias Hipofisarias/tratamiento farmacológico , Neoplasias Hipofisarias/metabolismo , Neoplasias Hipofisarias/patología , Receptores de Somatostatina/metabolismo , Somatostatina/análogos & derivados , Somatostatina/uso terapéutico , Factores de Transcripción/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Supresoras de Tumor/metabolismoRESUMEN
Pituitary adenomas are common tumors of the adenohypophysis which can cause considerable morbidity, due to excessive hormonal secretion or compression and local invasion of surrounding structures. The vast majority of pituitary adenomas occur sporadically. Altered gene expression is commonly detected but somatic mutations, epigenetic changes and abnormal microRNAs have also been described. Occurrence of GNAS mutations at a postzygotic stage lead to McCune-Albright syndrome (MAS), a disease causing endocrine hyperfunction and tumors in several organs, including the pituitary. Familial pituitary adenomas occur as part of a syndrome affecting other organs, such as in MEN1 or Carney complex, or occur with pituitary adenomas only as in familial isolated pituitary adenoma (FIPA). FIPA, an autosomal-dominant disease with variable penetrance, is explained in 20% of patients by germline mutations in the tumor suppressor aryl hydrocarbon receptor interacting protein(AIP), while no gene abnormality has been identified to date in the majority of the FIPA families. AIP mutation-positive patients have a characteristic clinical phenotype with usually young- or childhood-onset growth hormone (GH) and/or prolactin (PRL)-secreting adenomas and can be seen in cases with no apparent family history as well. Understanding the tumorigenic process in AIP-positive and AIP-negative FIPA patients could result in better diagnostic and treatment options for both familial and sporadic cases.
Asunto(s)
Adenoma/genética , Neoplasias Hipofisarias/genética , Adulto , Animales , Cromograninas , Femenino , Displasia Fibrosa Poliostótica/genética , Subunidades alfa de la Proteína de Unión al GTP Gs/genética , Adenoma Hipofisario Secretor de Hormona del Crecimiento/genética , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Masculino , Modelos Animales , Neoplasia Endocrina Múltiple Tipo 1/genética , Hipófisis/metabolismoRESUMEN
Acromegaly is a chronic disease with increased morbidity and mortality, where usually multiple treatment modalities are used. The somatostatin analogs (SSAs) are the mainstay of medical therapy but, in many patients, including those with a germline mutation in the aryl hydrocarbon receptor-interacting protein (AIP) gene, disease activity cannot be controlled with these drugs. Previous data have suggested the involvement of the tumor-suppressor gene ZAC1 in the mechanism of action of SSAs, and more recent findings suggested that SSAs could regulate AIP, which in turn can stimulate ZAC1, therefore suggesting the existence of a SSA-AIP-ZAC1-somatostatin effect pathway. The current review discusses these novel observations, highlighting their significance in the treatment of sporadic and familial somatotroph adenomas.