RESUMEN

Primary aldosteronism (PA) is the most common form of secondary arterial hypertension, with a prevalence of approximately 20% in patients with resistant hypertension. In the last decade, somatic pathogenic variants in KCNJ5, CACNA1D, ATP1A1 and ATP2B3 genes, which are involved in maintaining intracellular ionic homeostasis and cell membrane potential, were described in aldosterone-producing adenomas (aldosteronomas). All variants in these genes lead to the activation of calcium signaling, the major trigger for aldosterone production. Genetic causes of familial hyperaldosteronism have been expanded through the report of germline pathogenic variants in KCNJ5, CACNA1H and CLCN2 genes. Moreover, PDE2A and PDE3B variants were associated with bilateral PA and increased the spectrum of genetic etiologies of PA. Of great importance, the genetic investigation of adrenal lesions guided by the CYP11B2 staining strongly changed the landscape of somatic genetic findings of PA. Furthermore, CYP11B2 staining allowed the better characterization of the aldosterone-producing adrenal lesions in unilateral PA. Aldosterone production may occur from multiple sources, such as solitary aldosteronoma or aldosterone-producing nodule (classical histopathology) or clusters of autonomous aldosterone-producing cells without apparent neoplasia denominated aldosterone-producing micronodules (non-classical histopathology). Interestingly, KCNJ5 mutational status and classical histopathology of unilateral PA (aldosteronoma) have emerged as relevant predictors of clinical and biochemical outcome, respectively. In this review, we summarize the most recent advances in the pathogenesis of PA and discuss their impact on clinical outcome.

Asunto(s)

Adenoma Corticosuprarrenal , Hiperaldosteronismo , Hipertensión , Adenoma Corticosuprarrenal/complicaciones , Adenoma Corticosuprarrenal/genética , Adenoma Corticosuprarrenal/metabolismo , Aldosterona/metabolismo , Citocromo P-450 CYP11B2/genética , Citocromo P-450 CYP11B2/metabolismo , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/genética , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/metabolismo , Humanos , Hiperaldosteronismo/complicaciones , Hiperaldosteronismo/genética , Hipertensión/etiología , ATPasa Intercambiadora de Sodio-Potasio/genética , ATPasa Intercambiadora de Sodio-Potasio/metabolismo

RESUMEN

CONTEXT: Primary aldosteronism (PA) is the most common cause of endocrine hypertension (HT). HT remission (defined as blood pressure <140/90 mm Hg without antihypertensive drugs) has been reported in approximately 50% of patients with unilateral PA after adrenalectomy. HT duration and severity are predictors of blood pressure response, but the prognostic role of somatic KCNJ5 mutations is unclear. OBJECTIVE: To determine clinical and molecular features associated with HT remission after adrenalectomy in patients with unilateral PA. METHODS: We retrospectively evaluated 100 patients with PA (60 women; median age at diagnosis 48 years with a median follow-up of 26 months). Anatomopathological analysis revealed 90 aldosterone-producing adenomas, 1 carcinoma, and 9 unilateral adrenal hyperplasias. All patients had biochemical cure after unilateral adrenalectomy. KCNJ5 gene was sequenced in 76 cases. RESULTS: KCNJ5 mutations were identified in 33 of 76 (43.4%) tumors: p.Gly151Arg (n = 17), p.Leu168Arg (n = 15), and p.Glu145Gln (n = 1). HT remission was reported in 37 of 100 (37%) patients. Among patients with HT remission, 73% were women (P = 0.04), 48.6% used more than three antihypertensive medications (P = 0.0001), and 64.9% had HT duration <10 years (P = 0.0015) compared with those without HT remission. Somatic KCNJ5 mutations were associated with female sex (P = 0.004), larger nodules (P = 0.001), and HT remission (P = 0.0001). In multivariate analysis, only a somatic KCNJ5 mutation was an independent predictor of HT remission after adrenalectomy (P = 0.004). CONCLUSION: The presence of a KCNJ5 somatic mutation is an independent predictor of HT remission after unilateral adrenalectomy in patients with unilateral PA.

Asunto(s)

Adrenalectomía , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/genética , Hiperaldosteronismo/cirugía , Hipertensión/diagnóstico , Hipertensión/cirugía , Neoplasias de la Corteza Suprarrenal/complicaciones , Neoplasias de la Corteza Suprarrenal/diagnóstico , Neoplasias de la Corteza Suprarrenal/genética , Neoplasias de la Corteza Suprarrenal/cirugía , Adrenalectomía/efectos adversos , Adenoma Corticosuprarrenal/complicaciones , Adenoma Corticosuprarrenal/diagnóstico , Adenoma Corticosuprarrenal/genética , Adenoma Corticosuprarrenal/cirugía , Adulto , Femenino , Estudios de Seguimiento , Humanos , Hiperaldosteronismo/complicaciones , Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/genética , Hipertensión/genética , Masculino , Persona de Mediana Edad , Mutación , Pronóstico , Inducción de Remisión , Estudios Retrospectivos

Asunto(s)

Neoplasias de la Corteza Suprarrenal/diagnóstico , Adenoma Corticosuprarrenal/diagnóstico , Hiperaldosteronismo/diagnóstico , Neoplasias de la Corteza Suprarrenal/genética , Adenoma Corticosuprarrenal/genética , Humanos , Hiperaldosteronismo/genética , Hipertensión/etiología

RESUMEN

DAX1 transcription factor is a key determinant of adrenogonadal development, acting as a repressor of SF1 targets in steroidogenesis. It was recently demonstrated that DAX1 regulates pluripotency and differentiation in murine embryonic stem cells. In this study, we investigated DAX1 expression in adrenocortical tumors (ACTs) and correlated it with SF1 expression and clinical parameters. DAX1 and SF1 protein expression were assessed in 104 ACTs from 34 children (25 clinically benign and 9 malignant) and 70 adults (40 adenomas and 30 carcinomas). DAX1 gene expression was studied in 49 ACTs by quantitative real-time PCR. A strong DAX1 protein expression was demonstrated in 74% (25 out of 34) and 24% (17 out of 70) of pediatric and adult ACTs, respectively (χ(2)=10.1, p=0.002). In the pediatric group, ACTs with a strong DAX1 expression were diagnosed at earlier ages than ACTs with weak expression [median 1.2 (range, 0.5-4.5) vs. 2.2 (0.9-9.4), p=0.038]. DAX1 expression was not associated with functional status in ACTs. Interestingly, a positive correlation was observed between DAX1 and SF1 protein expression in both pediatric and adult ACTs (r=0.55 for each group separately; p<0.0001). In addition, DAX1 gene expression was significantly correlated with SF1 gene expression (p<0.0001, r=0.54). In conclusion, DAX1 strong protein expression was more frequent in pediatric than in adult ACTs. Additionally, DAX1 and SF1 expression positively correlated in ACTs, suggesting that these transcription factors might cooperate in adrenocortical tumorigenesis.

Asunto(s)

Neoplasias de la Corteza Suprarrenal/metabolismo , Carcinogénesis/metabolismo , Receptor Nuclear Huérfano DAX-1/metabolismo , Factor Esteroidogénico 1/metabolismo , Neoplasias de la Corteza Suprarrenal/genética , Adenoma Corticosuprarrenal/genética , Adenoma Corticosuprarrenal/metabolismo , Carcinoma Corticosuprarrenal/genética , Carcinoma Corticosuprarrenal/metabolismo , Adulto , Carcinogénesis/genética , Niño , Preescolar , Receptor Nuclear Huérfano DAX-1/genética , Femenino , Expresión Génica , Humanos , Lactante , Masculino , Persona de Mediana Edad , Factor Esteroidogénico 1/genética

RESUMEN

Adrenocortical tumours (ACT), which include adenomas, carcinomas and adrenal hyperplasia, may be associated with genetic syndromes, such as Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome, multiple endocrine neoplasia type 1, familial adenomatous polyposis and Carney complex. Genetic defects have been found to be responsible for the disease in most of these syndromes, allowing genetic counselling to affected patients and family members. Here, we summarize the clinical criteria of these hereditary syndromes and briefly describe the genetic alterations related to them. In addition, we discuss the involvement of various genetic defects in the development of sporadic adrenocortical tumours.

Asunto(s)

Neoplasias de la Corteza Suprarrenal/genética , Hiperplasia Suprarrenal Congénita/genética , Adenoma Corticosuprarrenal/genética , Síndrome de Beckwith-Wiedemann/genética , Complejo de Carney/genética , Humanos , Síndrome de Li-Fraumeni/genética , Modelos Biológicos , Neoplasia Endocrina Múltiple Tipo 1/genética , Síndromes Neoplásicos Hereditarios/genética

RESUMEN

Tumores do córtex adrenal (TCA) são mais frequentes em crianças, mas podem ocorrer em qualquer faixa etária. São classificados como funcionantes, não funcionantes (predominam no adulto), e mistos. O diagnóstico é baseado na avaliação clínica, hormonal e exames de imagem. Em crianças, o método de escolha para diferenciar entre benigno ou maligno é a classificação baseada no estadiamento do tumor. Alguns marcadores moleculares merecem destaque: além de mutações inativadoras no gene supressor tumoral TP53, há evidências de envolvimento do IGF2 em 90 por cento de TAC malignos, e mutações no éxon 3 do gene CTNNB1 foram encontradas em 6 por cento dos TAC pediátricos. Além disso, microRNAs podem atuar como reguladores negativos da expressão gênica e participar da tumorigênese adrenocortical. Métodos para análise da expressão gênica permitem identificar TCA com prognóstico bom ou ruim, e espera-se que esses estudos possam facilitar o desenvolvimento de drogas para tratar pacientes de acordo com as vias de sinalização específicas que estiverem alteradas.

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Adrenocortical tumors (ACT) are more frequent during childhood, but they can appear at any age. ACTs can be classified in functioning, nonfunctioning (mainly observed in adults) and mixed. The diagnosis is based on clinical, biochemical findings and imaging. In children, in order to classify ACT as benign or malignant, tumor staging classification is recommended. Regarding molecular markers some studies should be taken into account: besides TP53 mutations, previous studies have also provided evidences of IGF2 involvement in 90 percent of the malignant ACT. Mutations altering exon 3 of CTNNB1 gene have been found in 6 percent of childhood ACTs. In addition, microRNAs can act as negative regulators of gene expression by targeting mRNA controlling cell growth, differentiation and apoptosis and have been implicated in adrenal tumorigenesis. High-throughput methods to analyze genome-wide expression have been developed over the last decade and identified a subset of tumors with good or poor prognosis. In the future, these studies can provide the basis of specific drug development, which can treat patients according to specific altered signaling pathway.

Asunto(s)

Niño , Humanos , Neoplasias de la Corteza Suprarrenal/diagnóstico , Adenoma Corticosuprarrenal/diagnóstico , Carcinoma Corticosuprarrenal/diagnóstico , Neoplasias de la Corteza Suprarrenal/genética , Adenoma Corticosuprarrenal/genética , Carcinoma Corticosuprarrenal/genética , Regulación Neoplásica de la Expresión Génica/genética , Mutación/genética , Biomarcadores de Tumor/genética , beta Catenina/genética

RESUMEN

Adrenocortical tumors (ACT) are more frequent during childhood, but they can appear at any age. ACTs can be classified in functioning, nonfunctioning (mainly observed in adults) and mixed. The diagnosis is based on clinical, biochemical findings and imaging. In children, in order to classify ACT as benign or malignant, tumor staging classification is recommended. Regarding molecular markers some studies should be taken into account: besides TP53 mutations, previous studies have also provided evidences of IGF2 involvement in 90% of the malignant ACT. Mutations altering exon 3 of CTNNB1 gene have been found in 6% of childhood ACTs. In addition, microRNAs can act as negative regulators of gene expression by targeting mRNA controlling cell growth, differentiation and apoptosis and have been implicated in adrenal tumorigenesis. High-throughput methods to analyze genome-wide expression have been developed over the last decade and identified a subset of tumors with good or poor prognosis. In the future, these studies can provide the basis of specific drug development, which can treat patients according to specific altered signaling pathway.

Asunto(s)

Neoplasias de la Corteza Suprarrenal/diagnóstico , Adenoma Corticosuprarrenal/diagnóstico , Carcinoma Corticosuprarrenal/diagnóstico , Neoplasias de la Corteza Suprarrenal/genética , Adenoma Corticosuprarrenal/genética , Carcinoma Corticosuprarrenal/genética , Biomarcadores de Tumor/genética , Niño , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Mutación/genética , beta Catenina/genética

RESUMEN

BACKGROUND: Steroidogenic factor 1 (SF-1) is a key determinant of endocrine development and function of adrenal cortex. SF-1 overexpression and gene amplification were previously demonstrated in a small group of pediatric adrenocortical tumors. OBJECTIVE: Our objective was to determine the frequency of SF-1 protein expression and gene amplification in a large cohort of pediatric and adult adrenocortical tumors. PATIENTS: SF-1 protein expression was assessed in a cohort of 103 adrenocortical tumors from 36 children and 67 adults, whereas gene amplification was studied in 38 adrenocortical tumors (17 from children). METHODS: Tissue microarray, multiplex ligation-dependent probe amplification, and quantitative real-time PCR were used. RESULTS: A strong nuclear SF-1 expression was detected by tissue microarray in 56% (20 of 36) and 19% (13 of 67) of the pediatric and adult adrenocortical tumors, respectively (P = 0.0004). Increased SF-1 copy number was identified in 47% (eight of 17) and 10% (two of 21) of the pediatric and adult adrenocortical tumors, respectively (P = 0.02). All adrenocortical tumors with SF-1 gene amplification showed a strong SF-1 staining, whereas most of the tumors (61%) without SF-1 amplification displayed a weak or negative staining (P = 0.0008). Interestingly, a strong SF-1 staining was identified in five (29%) pediatric adrenocortical tumors without SF-1 amplification. The frequency of SF-1 overexpression and gene amplification was similar in adrenocortical adenomas and carcinomas. CONCLUSION: We demonstrated a higher frequency of SF-1 overexpression and gene amplification in pediatric than in adult adrenocortical tumors, suggesting an important role of SF-1 in pediatric adrenocortical tumorigenesis.

Asunto(s)

Neoplasias de la Corteza Suprarrenal/genética , Adenoma Corticosuprarrenal/genética , Carcinoma Corticosuprarrenal/genética , Amplificación de Genes/genética , Factor Esteroidogénico 1/genética , Adulto , Factores de Edad , Distribución de Chi-Cuadrado , Niño , Preescolar , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de Matrices Tisulares

RESUMEN

Glucose-dependent insulinotropic peptide receptor (GIPR) and LHCGR are G-protein-coupled receptors with a wide tissue expression pattern. Aberrant expression of these receptors has rarely been demonstrated in adult sporadic adrenocortical tumors with a lack of data on pediatric tumors. We quantified the GIPR and LHCGR expression in a large cohort of 55 patients (25 children and 30 adults) with functioning and non-functioning sporadic adrenocortical tumors. Thirty-eight tumors were classified as adenomas whereas 17 were carcinomas. GIPR and LHCGR expression were analyzed by real-time PCR and normal human pancreatic and testicular tissue samples were used as positive controls. Mean expression values were determined by fold increase in comparison with a normal adrenal pool. GIPR mRNA levels were significantly higher in adrenocortical carcinomas than in adenomas from both pediatric and adult groups. LHCGR expression was similar in both carcinomas and adenomas from the pediatric group but significantly lower in carcinomas than in adenomas from the adult group (median 0.06 and 2.3 respectively, P<0.001). GIPR was detected by immunohistochemistry in both pediatric and adult tumors. Staining and real-time PCR results correlated positively only when GIPR mRNA levels were increased at least two-fold in comparison with normal adrenal expression levels. In conclusion, GIPR overexpression was observed in pediatric and adult adrenocortical tumors and very low levels of LHCGR expression were found in all adult adrenocortical carcinomas.

Asunto(s)

Neoplasias de la Corteza Suprarrenal/genética , Adenoma Corticosuprarrenal/genética , Carcinoma Corticosuprarrenal/genética , Regulación Neoplásica de la Expresión Génica/genética , Receptores de la Hormona Gastrointestinal/genética , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Expresión Génica , Humanos , Lactante , Masculino , Persona de Mediana Edad , Receptores de HL/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa