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1.
Sci Adv ; 6(26): eaba3231, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32637605

RESUMO

Cancer risk is highly variable in carriers of the common TP53-R337H founder allele, possibly due to the influence of modifier genes. Whole-genome sequencing identified a variant in the tumor suppressor XAF1 (E134*/Glu134Ter/rs146752602) in a subset of R337H carriers. Haplotype-defining variants were verified in 203 patients with cancer, 582 relatives, and 42,438 newborns. The compound mutant haplotype was enriched in patients with cancer, conferring risk for sarcoma (P = 0.003) and subsequent malignancies (P = 0.006). Functional analyses demonstrated that wild-type XAF1 enhances transactivation of wild-type and hypomorphic TP53 variants, whereas XAF1-E134* is markedly attenuated in this activity. We propose that cosegregation of XAF1-E134* and TP53-R337H mutations leads to a more aggressive cancer phenotype than TP53-R337H alone, with implications for genetic counseling and clinical management of hypomorphic TP53 mutant carriers.

2.
J Clin Endocrinol Metab ; 105(8)2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32449514

RESUMO

CONTEXT: Objective response rate to mitotane in advanced adrenocortical carcinoma (ACC) is approximately 20%, and adverse drug effects are frequent. To date, there is no marker established that predicts treatment response. Mitotane has been shown to inhibit sterol-O-acyl transferase 1 (SOAT1), which leads to endoplasmic reticulum stress and cell death in ACC cells. OBJECTIVE: To investigate SOAT1 protein expression as a marker of treatment response to mitotane. PATIENTS: A total of 231 ACC patients treated with single-agent mitotane as adjuvant (n = 158) or advanced disease therapy (n = 73) from 12 ENSAT centers were included. SOAT1 protein expression was determined by immunohistochemistry on formalin-fixed paraffin-embedded specimens. SETTING: Retrospective study at 12 ACC referral centers. MAIN OUTCOME MEASURE: Recurrence-free survival (RFS), progression-free survival (PFS), and disease-specific survival (DSS). RESULTS: Sixty-one of 135 patients (45%) with adjuvant mitotane treatment had recurrences and 45/68 patients (66%) with mitotane treatment for advanced disease had progressive disease. After multivariate adjustment for sex, age, hormone secretion, tumor stage, and Ki67 index, RFS (hazard ratio [HR] = 1.07; 95% confidence interval [CI], 0.61-1.85; P = 0.82), and DSS (HR = 1.30; 95% CI, 0.58-2.93; P = 0.53) in adjuvantly treated ACC patients did not differ significantly between tumors with high and low SOAT1 expression. Similarly, in the advanced stage setting, PFS (HR = 1.34; 95% CI, 0.63-2.84; P = 0.45) and DSS (HR = 0.72; 95% CI, 0.31-1.70; P = 0.45) were comparable and response rates not significantly different. CONCLUSIONS: SOAT1 expression was not correlated with clinical endpoints RFS, PFS, and DSS in ACC patients with mitotane monotherapy. Other factors appear to be relevant for mitotane treatment response and ACC patient survival.

3.
Curr Opin Endocrinol Diabetes Obes ; 27(3): 177-186, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32304390

RESUMO

PURPOSE OF REVIEW: Adrenocortical tumor (ACT) is a rare disease with an annual worldwide incidence of 0.3-0.38/million children below 15 years old, and Brazilian population presents the highest incidence because of germline mutation in the TP53. Pediatric ACT is associated with virilizing features and hypercortisolism in most cases. Malignancy is defined when local invasion or metastasis is found, and it is associated with a poor prognosis. However, the correct and early diagnosis and treatment may impact on overall and disease-free survival. RECENT FINDINGS: A complete understanding of the disease and its singularities facilitates the assistance to the pediatric patient with ACT. The new insights about adrenal tumorigenesis have provided a better understanding of this disease. In this scenario, the era of molecular studies is leading to the refinement of the taxonomy, and it is offering the opportunity to discover new biomarkers and pathways of tumorigenesis, beyond the knowing ß-catenin, Insulin-like growth factor-II/IGF-IR, and the p53/Rb signaling. SUMMARY: The rarity of this disease makes it a real challenge. Here, we present a review focusing on clinical practice. A methodic approach aiming to clarify the diagnosis and a follow-up are suggested to guide physicians in the assistance of pediatrics patients, improving the prognosis.

4.
J Endocr Soc ; 3(9): 1682-1692, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31528828

RESUMO

Context: Von Hippel-Lindau (VHL) disease is an autosomal dominant syndrome caused by germline mutations in the VHL gene. Guidelines recommend pheochromocytoma (PHEO) biochemical screening should start at age 5 years. Objective: Genotype-phenotype correlations in VHL, focusing on PHEO penetrance in children, were studied. Design: We retrospectively evaluated 31 individuals (median age at diagnosis was 26 years) with diagnosed VHL disease. Results: PHEO was diagnosed in six children with VHL. A large PHEO (5 cm) was detected in a 4-year-old boy with p.Gly114Ser mutation. PHEO penetrance was 55% starting at age 4 years. VHL missense mutations were identified in 11 of 22 families (50%), frameshift mutations in four (18.2%), stop codon in three (13.6%), splicing site in two (9.1%), and large gene deletion in two (9.1%). The codon 167 (n = 10) was a hotspot for VHL mutations and was significantly associated with PHEO (90% vs. 38%; P = 0.007). PHEOs and pancreatic neuroendocrine tumors (PNETs) were strongly associated with VHL missense mutations compared with other mutations (89.5% vs. 0% and 73.7% vs. 16.7%; P = 0.0001 and 0.002, respectively). In contrast, pancreatic cysts (91.7% vs. 26.3%; P = 0.0001), renal cysts (66.7% vs. 26.3%; P = 0.027), and central nervous system hemangioblastomas (91.7% vs. 47.3%; P = 0.012) were more frequent in VHL with nonmissense mutations. Conclusion: VHL missense mutations were highly associated with PHEO and PNETs. Our data support that in children with VHL harboring missense mutations, biochemical screening for PHEO should be initiated at diagnosis.

5.
J Clin Endocrinol Metab ; 104(10): 4695-4702, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31216002

RESUMO

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.

6.
Clin Cancer Res ; 25(11): 3276-3288, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30770352

RESUMO

PURPOSE: Adrenocortical carcinoma (ACC) is a rare, aggressive malignancy with few therapies; however, patients with locoregional disease have variable outcomes. The Cancer Genome Atlas project on ACC (ACC-TCGA) identified that cancers of patients with homogeneously rapidly recurrent or fatal disease bear a unique CpG island hypermethylation phenotype, "CIMP-high." We sought to identify a biomarker that faithfully captures this subgroup.Experimental Design: We analyzed ACC-TCGA data to characterize differentially regulated biological processes, and identify a biomarker that is methylated and silenced exclusively in CIMP-high ACC. In an independent cohort of 114 adrenocortical tumors (80 treatment-naive primary ACC, 22 adrenocortical adenomas, and 12 non-naive/nonprimary ACC), we evaluated biomarker methylation by a restriction digest/qPCR-based approach, validated by targeted bisulfite sequencing. We evaluated expression of this biomarker and additional prognostic markers by qPCR. RESULTS: We show that CIMP-high ACC is characterized by upregulation of cell cycle and DNA damage response programs, and identify that hypermethylation and silencing of G0S2 distinguishes this subgroup. We confirmed G0S2 hypermethylation and silencing is exclusive to 40% of ACC, and independently predicts shorter disease-free and overall survival (median 14 and 17 months, respectively). Finally, G0S2 methylation combined with validated molecular markers (BUB1B-PINK1) stratifies ACC into three groups, with uniformly favorable, intermediate, and uniformly dismal outcomes. CONCLUSIONS: G0S2 hypermethylation is a hallmark of rapidly recurrent or fatal ACC, amenable to targeted assessment using routine molecular diagnostics. Assessing G0S2 methylation is straightforward, feasible for clinical decision-making, and will enable the direction of efficacious adjuvant therapies for patients with aggressive ACC.

7.
Clinics (Sao Paulo) ; 73(suppl 1): e756s, 2018 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-30540124

RESUMO

Malignancy must be considered in the management of adrenal lesions, including those incidentally identified on imaging studies. Adrenocortical carcinomas (ACCs) are rare tumors with an estimated annual incidence of 0.7-2 cases per year and a worldwide prevalence of 4-12 cases per million/year. However, a much higher incidence of these tumors (>15 times) has been demonstrated in south and southeastern Brazil. Most ACCs cause hypersecretion of steroids including glucocorticoids and androgens. ACC patients have a very poor prognosis with a 5-year overall survival (OS) below 30% in most series. Pheochromocytoma or paraganglioma (PPGL) is a metabolically active tumor originating from the chromaffin cells of the adrenal medulla. The incidence of PPGL is 0.2 to 0.9 cases per 100,000 individuals per year. Pheochromocytomas are present in approximately 4-7% of patients with adrenal incidentalomas. Classically, PPGL manifests as paroxysmal attacks of the following 4 symptoms: headaches, diaphoresis, palpitations, and severe hypertensive episodes. The diagnosis of malignant PPGL relies on the presence of local invasion or metastasis. In this review, we present the clinical and biochemical characteristics and pathogenesis of malignant primary lesions that affect the cortex and medulla of human adrenal glands.


Assuntos
Neoplasias do Córtex Suprarrenal/terapia , Neoplasias das Glândulas Suprarrenais/terapia , Carcinoma Adrenocortical/terapia , Paraganglioma/terapia , Feocromocitoma/terapia , Neoplasias do Córtex Suprarrenal/diagnóstico , Neoplasias do Córtex Suprarrenal/patologia , Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/patologia , Carcinoma Adrenocortical/diagnóstico , Carcinoma Adrenocortical/patologia , Antineoplásicos Hormonais/uso terapêutico , Humanos , Mitotano/uso terapêutico , Paraganglioma/diagnóstico , Paraganglioma/patologia , Feocromocitoma/diagnóstico , Feocromocitoma/patologia
8.
Mol Cell Endocrinol ; 460: 36-46, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-28676429

RESUMO

The participation of aberrant receptors and intra-adrenal ACTH in hyperplastic tissue are considered mechanisms that regulate hypercortisolism in PMAH. Additionally, germline ARMC5 mutations have been described as the most frequent genetic abnormality found in patients diagnosed with PMAH. Previous functional studies analyzed ARMC5 role using H295R cells. Therefore, we investigated the role of ARMC5 in cell cultures obtained from PMAH nodules containing steroidogenic cells, aberrant receptors and intra-adrenal ACTH. ARMC5 silencing in non-mutated PMAH cell cultures decreased steroidogenesis-related genes and increased CCNE1 mRNA expression and proliferative capacity without affecting cell viability. Additionally, ARMC5 overexpression induced cell death in PMAH mutated cell cultures, thereby decreasing cell viability. We confirmed the role of ARMC5 as an important pro-apoptotic protein involved in PMAH-related steroidogenesis. We also report for the first time the involvement of ARMC5 in controlling proliferation and regulating cell cycle in PMAH cell cultures; these effects need to be explored further.


Assuntos
Glândulas Suprarrenais/metabolismo , Glândulas Suprarrenais/patologia , Proteínas Supressoras de Tumor/metabolismo , Hormônio Adrenocorticotrópico/metabolismo , Hormônio Adrenocorticotrópico/farmacologia , Idoso , Proteínas do Domínio Armadillo , Células Cultivadas , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Inativação Gênica , Humanos , Hiperplasia , Gotículas Lipídicas/efeitos dos fármacos , Gotículas Lipídicas/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação/genética , Pró-Opiomelanocortina/metabolismo , Progesterona Redutase/genética , Progesterona Redutase/metabolismo , Receptor Tipo 2 de Melanocortina/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Análise de Sequência de DNA , Coloração e Rotulagem , Esteroide 17-alfa-Hidroxilase/genética , Esteroide 17-alfa-Hidroxilase/metabolismo , Proteínas Supressoras de Tumor/genética , Vasopressinas/farmacologia
9.
Clinics ; 73(supl.1): e756s, 2018. tab
Artigo em Inglês | LILACS-Express | ID: biblio-974949

RESUMO

Malignancy must be considered in the management of adrenal lesions, including those incidentally identified on imaging studies. Adrenocortical carcinomas (ACCs) are rare tumors with an estimated annual incidence of 0.7-2 cases per year and a worldwide prevalence of 4-12 cases per million/year. However, a much higher incidence of these tumors (>15 times) has been demonstrated in south and southeastern Brazil. Most ACCs cause hypersecretion of steroids including glucocorticoids and androgens. ACC patients have a very poor prognosis with a 5-year overall survival (OS) below 30% in most series. Pheochromocytoma or paraganglioma (PPGL) is a metabolically active tumor originating from the chromaffin cells of the adrenal medulla. The incidence of PPGL is 0.2 to 0.9 cases per 100,000 individuals per year. Pheochromocytomas are present in approximately 4-7% of patients with adrenal incidentalomas. Classically, PPGL manifests as paroxysmal attacks of the following 4 symptoms: headaches, diaphoresis, palpitations, and severe hypertensive episodes. The diagnosis of malignant PPGL relies on the presence of local invasion or metastasis. In this review, we present the clinical and biochemical characteristics and pathogenesis of malignant primary lesions that affect the cortex and medulla of human adrenal glands.

10.
Clinics (Sao Paulo) ; 72(6): 391-394, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28658440

RESUMO

OBJECTIVES:: Transcription Factor 21 represses steroidogenic factor 1, a nuclear receptor required for gonadal development, sex determination and the regulation of adrenogonadal steroidogenesis. The aim of this study was to investigate whether silencing or overexpression of the gene Transcription Factor 21 could modulate the gene and protein expression of steroidogenic factor 1 in adrenocortical tumors. METHODS:: We analyzed the gene expression of steroidogenic factor 1 using qPCR after silencing endogenous Transcription Factor 21 in pediatric adrenal adenoma-T7 cells through small interfering RNA. In addition, using overexpression of Transcription Factor 21 in human adrenocortical carcinoma cells, we analyzed the protein expression of steroidogenic factor 1 using Western blotting. RESULTS:: Transcription Factor 21 knockdown increased the mRNA expression of steroidogenic factor 1 by 5.97-fold in pediatric adrenal adenoma-T7 cells. Additionally, Transcription Factor 21 overexpression inhibited the protein expression of steroidogenic factor 1 by 0.41-fold and 0.64-fold in two different adult adrenocortical carcinoma cell cultures, H295R and T36, respectively. CONCLUSIONS:: Transcription Factor 21 is downregulated in adrenocortical carcinoma cells. Taken together, these findings support the hypothesis that Transcription Factor 21 is a regulator of steroidogenic factor 1 and is a tumor suppressor gene in pediatric and adult adrenocortical tumors.


Assuntos
Neoplasias do Córtex Suprarrenal/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Fator Esteroidogênico 1/metabolismo , Neoplasias do Córtex Suprarrenal/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Western Blotting , Linhagem Celular Tumoral , Regulação para Baixo , Humanos , Immunoblotting , Reação em Cadeia da Polimerase em Tempo Real , Fator Esteroidogênico 1/genética
11.
Oncotarget ; 6(26): 22724-33, 2015 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-26087193

RESUMO

Low DICER1 expression was associated with poor outcome in several cancers. Recently, hot-spot DICER1 mutations were found in ovarian tumors, and TARBP2 truncating mutations in tumor cell lines with microsatellite instability. In this study, we assessed DICER1 e TRBP protein expression in 154 adult adrenocortical tumors (75 adenomas and 79 carcinomas). Expression of DICER1 and TARBP2 gene was assessed in a subgroup of 61 tumors. Additionally, we investigated mutations in metal biding sites located at the RNase IIIb domain of DICER1 and in the exon 5 of TARBP2 in 61 tumors. A strong DICER1 expression was demonstrated in 32% of adenomas and in 51% of carcinomas (p = 0.028). Similarly, DICER1 gene overexpression was more frequent in carcinomas (60%) than in adenomas (23%, p = 0.006). But, among adrenocortical carcinomas, a weak DICER1 expression was significantly more frequent in metastatic than in non-metastatic adrenocortical carcinomas (66% vs. 31%; p = 0.002). Additionally, a weak DICER1 expression was significantly correlated with a reduced overall (p = 0.004) and disease-free (p = 0.005) survival. In the multivariate analysis, a weak DICER1 expression (p = 0.048) remained as independent predictor of recurrence. Regarding TARBP2 gene, its protein and gene expression did not correlate with histopathological and clinical parameters. No variant was identified in hot spot areas of DICER1 and TARBP2. In conclusion, a weak DICER1 protein expression was associated with reduced disease-free and overall survival and was a predictor of recurrence in adrenocortical carcinomas.


Assuntos
Neoplasias do Córtex Suprarrenal/metabolismo , Carcinoma Adrenocortical/metabolismo , RNA Helicases DEAD-box/biossíntese , Ribonuclease III/biossíntese , Adenoma/genética , Adenoma/metabolismo , Adenoma/patologia , Adolescente , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/genética , Carcinoma Adrenocortical/patologia , Adulto , Idoso , RNA Helicases DEAD-box/genética , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Ligação a RNA/biossíntese , Proteínas de Ligação a RNA/genética , Ribonuclease III/genética , Análise de Sobrevida , Resultado do Tratamento , Adulto Jovem
12.
Clin Endocrinol (Oxf) ; 82(4): 481-8, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25200669

RESUMO

OBJECTIVE: LIN28 control cells reprogramming and pluripotency mainly through miRNA regulation and has been overexpressed in many advanced cancers. In this study, we evaluated the prognostic role of LIN28 and its regulatory miRNAs in a large cohort of adrenocortical tumours (ACTs). PATIENTS AND METHODS: LIN28 protein expression was assessed in 266 adults ACTs (78 adenomas and 188 carcinomas) from Brazil and Germany. LIN28A and LIN28B gene expression was analysed in 59 ACTs (31 adenomas and 28 carcinomas) and copy number variation in 39 ACTs. In addition, we determined the expression of let-7 family, mir-9, mir-30 and mir-125 in 28 carcinomas. RESULTS: LIN28A gene was overexpressed in aggressive ACCs when compared with adenomas and nonaggressive ACCs, but no LIN28A copy number variation was found in ACTs. Unexpectedly, weak LIN28 protein expression was significantly associated with reduced disease-free survival in ACC patients (P = 0·01), but for overall survival only a trend was detectable (P = 0·117). In the multivariate analysis, only Ki67 index ≥10% (HR 4·6, P = 0·000) and weak LIN28 protein expression (HR 2·0, P = 0·03) were independent predictors of recurrence in ACC patients. Interestingly, mir-9 expression, a negative LIN28A/B regulator, was significantly higher in aggressive than in nonaggressive ACCs [2076 (from 36 to 9307) vs 133·4 (from 2·4 to 5193); P = 0·011] and was highly associated with reduced overall (P = 0·01) and disease-free survival (P = 0·01). However, mir-9 prognostic role should be further evaluated in a larger cohort. CONCLUSION: Weak LIN28 protein expression was associated with recurrence in ACCs. Additionally, overexpression of mir-9, a negative LIN28A regulator, was associated with poor outcome.


Assuntos
Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/metabolismo , Regulação Neoplásica da Expressão Gênica , MicroRNAs/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Adenoma/genética , Adenoma/metabolismo , Carcinoma Adrenocortical/genética , Carcinoma Adrenocortical/metabolismo , Adulto , Brasil , Estudos de Coortes , Variações do Número de Cópias de DNA , Intervalo Livre de Doença , Feminino , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Alemanha , Humanos , Antígeno Ki-67/metabolismo , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Prognóstico , Reação em Cadeia da Polimerase em Tempo Real , Resultado do Tratamento
13.
Eur J Endocrinol ; 171(3): 335-42, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24920291

RESUMO

OBJECTIVE: To date, no evidence of robust genotype-phenotype correlation or disease modifiers for multiple endocrine neoplasia type 1 (MEN1) syndrome has been described, leaving the highly variable clinical presentation of patients unaccounted for. DESIGN: As the CDKN1B (p27) gene causes MEN4 syndrome and it is transcriptionally regulated by the product of the MEN1 gene (menin), we sought to analyze whether p27 influences the phenotype of MEN1-mutated patients. The cohort consisted of 100 patients carrying germline MEN1 gene mutations and 855 population-matched control individuals. METHODS: Genotyping of the coding p27 c.326T>G (V109G) variant was performed by sequencing and restriction site digestion, and the genotypes were associated with clinical parameters by calculating odds ratios (ORs) and their 95% CIs using logistic regression. RESULTS: There were significant differences in p27 V109G allele frequencies between controls and MEN1-mutated patients (OR=2.55, P=0.019, CI=1.013-5.76). Among patients who are ≥30 years old carrying truncating MEN1 mutations, the T allele was strongly associated with susceptibility to tumors in multiple glands (three to four glands affected vs one to two glands affected; OR=18.33; P=0.002, CI=2.88-16.41). This finding remained significant after the Bonferroni's multiple testing correction, indicating a robust association. No correlations were observed with the development of MEN1-related tumors such as hyperparathyroidism, pituitary adenomas, and enteropancreatic and adrenocortical tumors. CONCLUSIONS: Our study suggests that the p27 tumor suppressor gene acts as a disease modifier for the MEN1 syndrome associated with MEN1 germline mutations. If confirmed in independent patient cohorts, this finding could facilitate the management of this clinically complex disease.


Assuntos
Inibidor de Quinase Dependente de Ciclina p27/genética , Estudos de Associação Genética/métodos , Variação Genética/genética , Mutação em Linhagem Germinativa/genética , Neoplasia Endócrina Múltipla Tipo 1/genética , Proteínas Proto-Oncogênicas/genética , Adolescente , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasia Endócrina Múltipla Tipo 1/diagnóstico , Adulto Jovem
14.
Endocr Relat Cancer ; 21(3): 395-404, 2014 06.
Artigo em Inglês | MEDLINE | ID: mdl-24532476

RESUMO

Germline mutations in p27(kip1) are associated with increased susceptibility to multiple endocrine neoplasias (MEN) both in rats and humans; however, the potential role of common polymorphisms of this gene in endocrine tumor susceptibility and tumorigenesis remains mostly unrecognized. To assess the risk associated with polymorphism rs2066827 (p27-V109G), we genotyped a large cohort of Brazilian patients with sporadic endocrine tumors (pituitary adenomas, n=252; pheochromocytomas, n=125; medullary thyroid carcinoma, n=51; and parathyroid adenomas, n=19) and 885 population-matched healthy controls and determined the odds ratios and 95% CIs. Significant associations were found for the group of patients with pituitary adenomas (P=0.01), particularly for those with ACTH-secreting pituitary adenomas (P=0.005). In contrast, no association was found with GH-secreting pituitary tumors alone or with the sporadic counterpart of MEN2-component neoplasias. Our in vitro analyses revealed increased colony formation and cell growth rate for an AtT20 corticotropin mouse cell line overexpressing the p27-V109G variant compared with cells transfected with the WT p27. However, the genotypic effects in genetic and in vitro approaches were divergent. In accordance with our genetic data showing specificity for ACTH-secreting pituitary tissues, the overexpression of p27-V109G in a GH3 somatotropin rat cell line resulted in no difference compared with the WT. Pituitary tumors are one of the major clinical components of syndromes associated with the p27 pathogenic mutations MENX and MEN4. Our genetic and in vitro data indicate that the common polymorphism rs2066827 may play a role in corticotropinoma susceptibility and tumorigenesis through a molecular mechanism not fully understood thus far.


Assuntos
Proliferação de Células , Inibidor de Quinase Dependente de Ciclina p27/genética , Mutação/genética , Neoplasias das Paratireoides/genética , Feocromocitoma/genética , Neoplasias Hipofisárias/genética , Neoplasias da Glândula Tireoide/genética , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/metabolismo , Neoplasias das Glândulas Suprarrenais/patologia , Adulto , Idoso , Animais , Apoptose , Western Blotting , Carcinoma Neuroendócrino , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Imunofluorescência , Humanos , Técnicas In Vitro , Masculino , Camundongos , Pessoa de Meia-Idade , Neoplasia Endócrina Múltipla/genética , Neoplasia Endócrina Múltipla/metabolismo , Neoplasia Endócrina Múltipla/patologia , Neoplasias das Paratireoides/metabolismo , Neoplasias das Paratireoides/patologia , Feocromocitoma/metabolismo , Feocromocitoma/patologia , Neoplasias Hipofisárias/metabolismo , Neoplasias Hipofisárias/patologia , Ratos , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia , Células Tumorais Cultivadas , Ensaio Tumoral de Célula-Tronco
15.
Clinics (Sao Paulo) ; 68(6): 887-91, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23778486

RESUMO

OBJECTIVE: The expression of transcription factors involved in early pituitary development, such as PROP1 and POU1F1, has been detected in pituitary adenoma tissues. In this study, we sought to characterize the transcriptional profiles of PROP1, POU1F1, and TBX19 in functioning and nonfunctioning pituitary adenomas in an attempt to identify their roles in tumorigenesis and hormone hypersecretion. METHODS: RT-qPCR analyses were performed to assess the transcriptional pattern of PROP1, POU1F1, TBX19, and hormone-producing genes in tissue samples of corticotrophinomas (n=10), somatotrophinomas (n=8), and nonfunctioning adenomas (n=6). RESULTS: Compared with normal pituitary tissue, POU1F1 was overexpressed in somatotrophinomas by 3-fold. PROP1 expression was 18-fold higher in corticotrophinomas, 10-fold higher in somatotrophinomas, and 3-fold higher in nonfunctioning adenomas. TBX19 expression was 27-fold higher in corticotrophinomas. Additionally, the level of TBX19 mRNA positively correlated with that of pro-opiomelanocortin (r=0.49, p=0.014). CONCLUSIONS: Our data demonstrate that PROP1 is overexpressed in pituitary adenomas, mainly in corticotrophinomas. Together with previously published data showing that patients who harbor PROP1 loss-of-function mutations present a progressive decline in corticotrope function, our results support a role for PROP1 in pituitary tumor development and in the maintenance of cell lineages committed to corticotrophic differentiation.


Assuntos
Adenoma Hipofisário Secretor de ACT/metabolismo , Adenoma/metabolismo , Proteínas de Homeodomínio/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas com Domínio T/metabolismo , Fator de Transcrição Pit-1/metabolismo , Adenoma Hipofisário Secretor de ACT/genética , Adenoma Hipofisário Secretor de ACT/patologia , Adenoma/genética , Adenoma/patologia , Adolescente , Adulto , Idoso , Diferenciação Celular , Feminino , Proteínas de Homeodomínio/genética , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Hipófise/metabolismo , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Proteínas com Domínio T/genética , Fator de Transcrição Pit-1/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Adulto Jovem
16.
Clinics ; 68(6): 887-891, jun. 2013. tab, graf
Artigo em Inglês | LILACS | ID: lil-676940

RESUMO

OBJECTIVE: The expression of transcription factors involved in early pituitary development, such as PROP1 and POU1F1, has been detected in pituitary adenoma tissues. In this study, we sought to characterize the transcriptional profiles of PROP1, POU1F1, and TBX19 in functioning and nonfunctioning pituitary adenomas in an attempt to identify their roles in tumorigenesis and hormone hypersecretion. METHODS: RT-qPCR analyses were performed to assess the transcriptional pattern of PROP1, POU1F1, TBX19, and hormone-producing genes in tissue samples of corticotrophinomas (n = 10), somatotrophinomas (n = 8), and nonfunctioning adenomas (n = 6). RESULTS: Compared with normal pituitary tissue, POU1F1 was overexpressed in somatotrophinomas by 3-fold. PROP1 expression was 18-fold higher in corticotrophinomas, 10-fold higher in somatotrophinomas, and 3-fold higher in nonfunctioning adenomas. TBX19 expression was 27-fold higher in corticotrophinomas. Additionally, the level of TBX19 mRNA positively correlated with that of pro-opiomelanocortin (r = 0.49, p = 0.014). CONCLUSIONS: Our data demonstrate that PROP1 is overexpressed in pituitary adenomas, mainly in corticotrophinomas. Together with previously published data showing that patients who harbor PROP1 loss-of-function mutations present a progressive decline in corticotrope function, our results support a role for PROP1 in pituitary tumor development and in the maintenance of cell lineages committed to corticotrophic differentiation. .


Assuntos
Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Adenoma Hipofisário Secretor de ACT/metabolismo , Adenoma/metabolismo , Proteínas de Homeodomínio/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas com Domínio T/metabolismo , Fator de Transcrição Pit-1/metabolismo , Adenoma Hipofisário Secretor de ACT/genética , Adenoma Hipofisário Secretor de ACT/patologia , Adenoma/genética , Adenoma/patologia , Diferenciação Celular , Proteínas de Homeodomínio/genética , Imuno-Histoquímica , Proteínas de Neoplasias/genética , Hipófise , Reação em Cadeia da Polimerase em Tempo Real , RNA Mensageiro/metabolismo , Proteínas com Domínio T/genética , Fator de Transcrição Pit-1/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
17.
Eur J Endocrinol ; 166(1): 61-7, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22048964

RESUMO

BACKGROUND: A recent microarray study identified a set of genes whose combined expression patterns were predictive of poor outcome in a cohort of adult adrenocortical tumors (ACTs). The difference between the expression values measured by qRT-PCR of DLGAP5 and PINK1 genes was the best molecular predictor of recurrence and malignancy. Among the adrenocortical carcinomas, the combined expression of BUB1B and PINK1 genes was the most reliable predictor of overall survival. The prognostic and molecular heterogeneity of ACTs raises the need to study the applicability of these molecular markers in other cohorts. OBJECTIVE: To validate the combined expression of BUB1B, DLGAP5, and PINK1 as outcome predictor in ACTs from a Brazilian cohort of adult and pediatric patients. PATIENTS AND METHODS: BUB1B, DLGAP5, and PINK1 expression was assessed by quantitative PCR in 53 ACTs from 52 patients - 24 pediatric and 28 adults (one pediatric patient presented a bilateral asynchronous ACT). RESULTS: DLGAP5-PINK1 and BUB1B-PINK1 were strong predictors of disease-free survival and overall survival, respectively, among adult patients with ACT. In the pediatric cohort, these molecular predictors were only marginally associated with disease-free survival but not with overall survival. CONCLUSION: This study confirms the prognostic value of the combined expression of BUB1B, DLGAP5, and PINK1 genes in a Brazilian group of adult ACTs. Among pediatric ACTs, other molecular predictors of outcome are required.


Assuntos
Neoplasias do Córtex Suprarrenal/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Adolescente , Neoplasias do Córtex Suprarrenal/genética , Biomarcadores Tumorais/metabolismo , Brasil , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Lactente , Recém-Nascido , Masculino , Proteínas de Neoplasias/genética , Proteínas Quinases/genética , Proteínas Serina-Treonina Quinases/genética
19.
Clinics (Sao Paulo) ; 65(4): 407-15, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20454499

RESUMO

OBJECTIVE: Non-pituitary tumors have been reported in a subset of patients harboring germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene. However, no detailed investigations of non-pituitary tumors of AIP-mutated patients have been reported so far. PATIENTS: We examined a MEN1- and p53-negative mother-daughter pair with acromegaly due to somatotropinoma. Subsequently, the mother developed a large virilizing adrenocortical carcinoma and a grade II B-cell non-Hodgkin's lymphoma. DESIGN: Mutational analysis was performed by automated sequencing. Loss-of-heterozygosity (LOH) analysis was carried out by sequencing and microsatellite analysis. AIP expression was assessed through quantitative PCR (qPCR) and immunohistochemistry. RESULTS: The functional inactivating mutation c.241C>T (R81X), which blocks the AIP protein from interacting with phosphodiesterase 4A (PDE4A), was identified in the heterozygous state in the leukocyte DNA of both patients. Analyzing the tumoral DNA revealed that the AIP wild-type allele was lost in the daughter's somatotropinoma and the mother's adrenocortical carcinoma. Both tumors displayed low AIP protein expression levels. Low AIP gene expression was confirmed by qPCR in the adrenocortical carcinoma. No evidence of LOH was observed in the DNA sample from the mother's B-cell lymphoma, and this tumor displayed normal AIP immunostaining. CONCLUSIONS: Our study presents the first molecular analysis of non-pituitary tumors in AIP-mutated patients. The finding of AIP inactivation in the adrenocortical tumor suggests that further investigation of the potential role of this recently identified tumor suppressor gene in non-pituitary tumors, mainly in those tumors in which the cAMP and the 11q13 locus are implicated, is likely to be worthwhile.


Assuntos
Acromegalia/genética , Adenoma/genética , Carcinoma Adrenocortical/genética , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias Hipofisárias/genética , Adenoma/metabolismo , Adolescente , Adulto , Feminino , Expressão Gênica , Genes p53 , Mutação em Linhagem Germinativa , Humanos , Perda de Heterozigosidade/genética , Neoplasia Endócrina Múltipla Tipo 1/genética , Neoplasias Hipofisárias/metabolismo , Reação em Cadeia da Polimerase
20.
J Clin Endocrinol Metab ; 95(3): 1458-62, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20080844

RESUMO

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.


Assuntos
Neoplasias do Córtex Suprarrenal/genética , Adenoma Adrenocortical/genética , Carcinoma Adrenocortical/genética , Amplificação de Genes/genética , Fator Esteroidogênico 1/genética , Adulto , Fatores Etários , Distribuição de Qui-Quadrado , Criança , Pré-Escolar , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise Serial de Tecidos
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