MARIA CANDIDA BARISSON VILLARES FRAGOSO
Projetos de Pesquisa
Unidades Organizacionais
Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas, Faculdade de Medicina - Médico
Instituto Central, Hospital das Clínicas, Faculdade de Medicina
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina - Líder
Instituto Central, Hospital das Clínicas, Faculdade de Medicina
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina - Líder
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- Editorial: Molecular -genetic causes underlying primary adrenal insufficiency: Current insights into diagnosis and treatment(2022) V, Maria Candida B. Fragoso; BACHEGA, Tania A. S. S.; DAIN, Liliana
- The Role of gsp Mutations on the Development of Adrenocortical Tumors and Adrenal Hyperplasia(2016) FRAGOSO, Maria Candida Barisson Villares; WANICHI, Ingrid Quevedo; CAVALCANTE, Isadora Pontes; MARIANI, Beatriz Marinho de PaulaSomatic GNAS point mutations, commonly known as gsp mutations, are involved in the pathogenesis of McCune-Albright syndrome (MAS) and have also been described in autonomous hormone-producing tumors, such as somatotropinoma, corticotrophoma, thyroid cancer, ovarian and testicular Leydig cell tumors, and primary macronodular adrenocortical hyperplasia (PMAH) (1-3). The involvement of gsp mutations in adrenal tumors was first described by Lyons et al. Since then, several studies have detected the presence of gsp mutations in adrenal tumors, but none of them could explain its presence along or the mechanism that leads to tumor formation and hormone hypersecretion. As a result, the molecular pathogenesis of the majority of sporadic adrenocortical tumors remains unclear (3). PMAH has also been reported with gsp somatic mutations in a few cases. Fragoso et al. identified two distinct gsp somatic mutations affecting arginine residues on codon 201 of GNAS in a few patients with PMAH who lacked any features or manifestations of MAS. Followed by this discovery, other studies have continued looking for gsp mutations based on strong prior evidence demonstrating that increased cAMP signaling is sufficient for cell proliferation and cortisol production (2, 4). With consideration for the previously reported findings, we conjecture that although somatic activating mutations in GNAS are a rare molecular event, these mutations could probably be sufficient to induce the development of macronodule hyperplasia and variable cortisol secretion. In this manuscript, we revised the presence of gsp mutations associated with adrenal cortical tumors and hyperplasia.
- Transcriptome analysis showed a Differential signature between invasive and non-invasive corticotrophinomas(2017) ARAUJO, Leonardo Jose Tadeu de; LERARIO, Antonio Marcondes; CASTRO, Margaret de; MARTINS, Clarissa Silva; BRONSTEIN, Marcello Delano; MACHADO, Marcio Carlos; TRARBACH, Ericka Barbosa; FRAGOSO, Maria Candida Barisson VillaresACTH-dependent hypercortisolism caused by a pituitary adenoma [Cushing's disease (CD)] is the most common cause of endogenous Cushing's syndrome. CD is often associated with several morbidities, including hypertension, diabetes, osteoporosis/bone fractures, secondary infections, and increased cardiovascular mortality. While the majority (approximate to 80%) of the corticotrophinomas visible on pituitary magnetic resonance imaging are microadenomas (MICs, <10 mm of diameter), some tumors are macroadenomas (MACs, >= 10 mm) with increased growth potential and invasiveness, exceptionally exhibiting malignant demeanor. In addition, larger and invasive MACs are associated with a significant increased risk of local complications, such as hypopituitarism and visual defects. Given the clinical and molecular heterogeneity of corticotrophinomas, the aim of this study was to investigate the pattern of genetic differential expression between MIC and MAC, including the invasiveness grade as a criterion for categorizing these tumors. In this study, were included tumor samples from patients with clinical, laboratorial, radiological, and histopathological diagnosis of hypercortisolism due to an ACTH-producing pituitary adenoma. Differential gene expression was studied using an Affymetrix microarray platform in 12 corticotrophinomas, classified as non-invasive MIC (n = 4) and MAC (n = 5), and invasive MAC (n = 3), according to modified Hardy criteria. Somatic mutations in USP8 were also investigated, but none of the patients exhibited USP8 variants. Differential expression analysis demonstrated that non-invasive MIC and MAC have a similar genetic signature, while invasive MACs exhibited a differential expression profile. Among the genes differentially expressed, we highlighted CCND2, ZNF676, DAPK1, and TIMP2, and their differential expression was validated through quantitative real-time PCR in another cohort of 15 non-invasive and 3 invasive cortocotrophinomas. We also identified potential biological pathways associated with growth and invasiveness, TGF-beta and G protein signaling pathways, DNA damage response pathway, and pathways associated with focal adhesion. Our study revealed a differential pattern of genetic signature in a subgroup of MAC, supporting a genetic influence on corticotrophinomas in patients with CD.
- Allelic Variants of ARMC5 in Patients With Adrenal Incidentalomas and in Patients With Cushing's Syndrome Associated With Bilateral Adrenal Nodules(2020) MARIANI, Beatriz Marinho de Paula; NISHI, Mirian Yumie; WANICHI, Ingrid Quevedo; BRONDANI, Vania Balderrama; LACOMBE, Amanda Meneses Ferreira; CHARCHAR, Helaine; PEREIRA, Maria Adelaide Albergaria; SROUGI, Victor; TANNO, Fabio Yoshiaki; CECCATO, Filippo; REGAZZO, Daniela; BARBOT, Mattia; OCCHI, Gianluca; ALBIGER, Nora Maria Elvira; VIEIRA-CORREA, Marcelo; KATER, Claudio Elias; SCARONI, Carla; CHAMBO, Jose Luis; ZERBINI, Maria Claudia Nogueira; MENDONCA, Berenice B.; ALMEIDA, Madson Q.; FRAGOSO, Maria Candida Barisson VillaresObjective: Germline ARMC5 mutations are considered to be the main genetic cause of primary macronodular adrenal hyperplasia (PMAH). PMAH is associated with high variability of cortisol secretion caused from subclinical hypercortisolism to overt Cushing's syndrome (CS), in general due to bilateral adrenal nodules and rarely could also be due to non-synchronic unilateral adrenal nodules. The frequency of adrenal incidentalomas (AI) associated with PMAH is unknown. This study evaluated germline allelic variants of ARMC5 in patients with bilateral and unilateral AI and in patients with overt CS associated with bilateral adrenal nodules. Methods: We performed a retrospective multicenter study involving 123 patients with AI (64 bilateral; 59 unilateral). We also analyzed 20 patients with ACTH pituitary independent overt CS associated with bilateral adrenal nodules. All patients underwent germline genotyping analysis of ARMC5; abdominal CT and were classified as normal, possible or autonomous cortisol secretion, according to the low doses of dexamethasone suppression test. Results: We identified only one pathogenic allelic variant among the patients with bilateral AI. We did not identify any pathogenic allelic variants of ARMC5 in patients with unilateral AI. Thirteen out of 20 patients (65%) with overt CS and bilateral adrenal nodules were carriers of pathogenic germline ARMC5 allelic variants, all previously described. The germline ARMC5 mutation was observed in only one patient with bilateral AI; it was associated with autonomous cortisol secretion and showed to be a familial form. Conclusion: The rarity of germline ARMC5 mutations in AI points to other molecular mechanisms involved in this common adrenal disorder and should be investigated. In contrast, patients with overt Cushing's syndrome and bilateral adrenal nodules had the presence of ARMC5 mutations that were with high prevalence and similar to the literature. Therefore, we recommend the genetic analysis of ARMC5 for patients with established Cushing's syndrome and bilateral adrenal nodules rather than patients with unilateral AI.
- TCF21/POD-1, a Transcritional Regulator of SF-1/NR5A1, as a Potential Prognosis Marker in Adult and Pediatric Adrenocortical Tumors(2018) PASSAIA, Barbara dos Santos; DIAS, Matheus Henrique; KREMER, Jean Lucas; ANTONINI, Sonir Roberto Rauber; ALMEIDA, Madson Queiroz de; FRAGOSO, Maria Candida Barisson Villares; LOTFI, Claudimara Ferini PaciccoWith recent progress in understanding the pathogenesis of adrenocortical tumors (ACTs), identification of molecular markers to predict their prognosis has become possible. Transcription factor 21 (TCF21)/podocyte-expressed 1 (POD1) is a transcriptional regulatory protein expressed in mesenchymal cells at sites of epithelial-mesenchymal transition during the development of different systems. Adult carcinomas express less TCF21 than adenomas, in addition, the KEGG pathway analysis has shown that BUB1B, among others genes, is negatively correlated with TCF21 expression. The difference between BUB1B and PTEN-induced putative kinase 1 (PINK1) expression has been described previously to be associated with survival in adult but not in pediatric carcinomas. Here, we analyzed the gene expression of TCF21, BUB1B, PINK1, and NR5A1 in adult and pediatric ACTs. We found a negative correlation between the relative expression levels of TCF21 and BUB1B in adult ACTs, but the relative expression levels of TCF21, BUB1B, PINK1, and NR5A1 were similar in childhood ACTs. In addition, we propose using the subtracted expression levels of the TCF21/POD-1 genes as a predictor of overall survival (OS) in adult carcinomas and TCF21-NR5A1 as a predictor of malignancy for pediatric tumors in patients aged <5 years. These results require further validation in different cohorts of both adult and pediatric samples. Finally, we observed that the OS for patients aged <5 years was markedly favorable compared with that for patients >5 years as well as adult patients with carcinoma. In summary, we propose TCF21/POD-1 as a new prognostic marker in adult and pediatric ACTs.
- Choroidal and Retinal Abnormalities by Optical Coherence Tomography in Endogenous Cushing's Syndrome(2016) ABALEM, Maria Fernanda; MACHADO, Marcio Carlos; SANTOS, Helen Nazareth Veloso Dos; GARCIA, Rafael; HELAL JR., John; CARRICONDO, Pedro Carlos; PIMENTEL, Sergio Luis Gianotti; MONTEIRO, Mario Luiz Ribeiro; QIAN, Cynthia X.; BRONSTEIN, Marcello Delano; FRAGOSO, Maria Candida Villares BarissonContext: Cortisol has been suggested as a risk factor for choroidal thickening, which may lead to retinal changes. Objective: To compare choroidal thickness measurements using optical coherence tomography (OCT) in patients with endogenous active Cushings syndrome (CS) and to evaluate the occurrence of retinal abnormalities in the same group of patients. Design: Cross-sectional study. Setting: Outpatient clinic. Patients: Eleven female patients with CS in hypercortisolism state as determined by the presence of at least two abnormal measurements from urinary cortisol 24 h, no suppression of cortisol with low dose dexamethasone suppression test, and nocturnal salivary cortisol levels and 12 healthy controls. Methods: Choroidal and retinal morphology was assessed using OCT. Main outcome measures: Choroidal thickness measurements and the presence of retinal changes. Results: The mean subfoveal choroidal thickness was 372.96 +/- 73.14 m in the patients with CS and 255.63 +/- 50.70 mu m in the control group (p < 0.001). One patient (9.09%) presented with central serous chorioretinopathy and one patient (9.09%) with pachychoroid pigment epitheliopathy. Conclusion: Choroidal thickness is increased in the eyes of patients with active CS compared to healthy and matched control. Also, 18.18% of patients presented with macular changes, possibly secondary to choroidal thickening. While further studies are necessary to confirm our findings, excess corticosteroid levels seem to have a significant effect on the choroid and might be associated with secondary retinal diseases.
- Transcriptome Analysis Showed a Differential Signature Between Invasive and Non-invasive Corticotrophinomas (vol 8, 55, 2017)(2019) ARAUJO, Leonardo Jose Tadeu de; LERARIO, Antonio Marcondes; CASTRO, Margaret de; MARTINS, Clarissa Silva; BRONSTEIN, Marcello Delano; MACHADO, Marcio Carlos; TRARBACH, Ericka Barbosa; FRAGOSO, Maria Candida Barisson Villares