ANTONIO MARCONDES LERARIO

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LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina

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Autor e Coautores FMUSP-HC Normalizados: MADSON QUEIROZ DE ALMEIDA ×

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Agora exibindo 1 - 10 de 28
  • conferenceObject
    Metabolic Reprograming in Adrenocortical Tumors in Children: A Promising New Pathway in the Biology of This Disease
    (2016) ZERBINI, Maria; PINHEIRO, Celine; GRANJA, Sara; LONGATTO, Adhemar; FARIA, Andre M.; FRAGOSO, Maria C. V.; LOVISOLO, Silvana M.; LERARIO, Antonop M.; ALMEIDA, Madson Q.; BALTAZAR, Fatima
  • article 17 Citação(ões) na Scopus
    Phosphodiesterase 2A and 3B variants are associated with primary aldosteronism
    (2021) RASSI-CRUZ, Marcela; MARIA, Andrea G.; FAUCZ, Fabio R.; LONDON, Edra; VILELA, Leticia A. P.; SANTANA, Lucas S.; BENEDETTI, Anna Flavia F.; GOLDBAUM, Tatiana S.; TANNO, Fabio Y.; SROUGI, Vitor; CHAMBO, Jose L.; PEREIRA, Maria Adelaide A.; CAVALCANTE, Aline C. B. S.; CARNEVALE, Francisco C.; PILAN, Bruna; BORTOLOTTO, Luiz A.; DRAGER, Luciano F.; LERARIO, Antonio M.; LATRONICO, Ana Claudia; V, Maria Candida B. Fragoso; MENDONCA, Berenice B.; ZERBINI, Maria Claudia N.; STRATAKIS, Constantine A.; ALMEIDA, Madson Q.
    Familial primary aldosteronism (PA) is rare and mostly diagnosed in early-onset hypertension (HT). However, 'sporadic' bilateral adrenal hyperplasia (BAH) is the most frequent cause of PA and remains without genetic etiology in most cases. Our aim was to investigate new genetic defects associated with BAH and PA. We performed whole-exome sequencing (paired blood and adrenal tissue) in six patients with PA caused by BAH that underwent unilateral adrenalectomy. Additionally, we conducted functional studies in adrenal hyperplastic tissue and transfected cells to confirm the pathogenicity of the identified genetic variants. Rare germline variants in phosphodiesterase 2A (PDE2A) and 3B (PDE3B) genes were identified in three patients. The PDE2A heterozygous variant (p.Ile629Val) was identified in a patient with BAH and early-onset HT at 13 years of age. Two PDE3B heterozygous variants (p.Arg217Gln and p.Gly392Val) were identified in patients with BAH and HT diagnosed at 18 and 33 years of age, respectively. A strong PDE2A staining was found in all cases of BAH in zona glomerulosa and/or micronodules (that were also positive for CYP11B2). PKA activity in frozen tissue was significantly higher in BAH from patients harboring PDE2A and PDE3B variants. PDE2A and PDE3B variants significantly reduced protein expression in mutant transfected cells compared to WT. Interestingly, PDE2A and PDE3B variants increased SGK1 and SCNN1G/ENaCg at mRNA or protein levels. In conclusion, PDE2A and PDE3B variants were associated with PA caused by BAH. These novel genetic findings expand the spectrum of gene tic etiologies of PA.
  • conferenceObject
    Gene and Protein Expression Analysis of GLUT1 and HK2 in Primary Macronodular Adrenocortical Hyperplasia with High 18F-FDG Uptake in PET/CT
    (2014) CAVALCANTE, Isadora Pontes; ALENCAR, Guilherme Asmar; MARIANI, Beatriz M. P.; MURAD, Andre Faria; ALMEIDA, Madson Q.; BUCHPIGUEL, Carlos Alberto; LERARIO, Antonio M.; ZERBINI, Maria Claudia N.; MENDONCA, Berenice B.; FRAGOSO, Maria Candida B. V.
  • article 9 Citação(ões) na Scopus
    Clinical and molecular aspects of a pediatric metachronous adrenocortical tumor
    (2011) LIMA, Lorena de Oliveira; LERARIO, Antonio Marcondes; ALENCAR, Guilherme Asmar; BRITO, Luciana Pinto; ALMEIDA, Madson Queiroz; DOMENICE, Sorahia; LATRONICO, Ana Claudia; MENDONCA, Berenice Bilharinho; FRAGOSO, Maria Candida Barrison Villares
    The occurrence of metachronous adrenocortical carcinoma has rarely been described. We report a case of a child with virilizing adrenocortical metachronous tumors that, despite several metastases, presented long-term survival (15 years). We analyzed in this tumor IGF2, IGF1R and FGFR4 gene expression, and evaluated the presence of p.R337H germline p53 mutation and somatic CTNNB1 mutation. IGF2 gene was over-expressed in both left (Weiss score 5) and right (Weiss 7) adrenocortical tumors. IGF1R expression levels were higher in the right adrenocortical tumor. FGFR4 over-expression was also detected in the right adrenocortical tumor. In addition, this patient harbors the germline p.R337H p53 mutation and loss of heterozygosity (LOH) was detected in the tumors. No somatic CTNNB1 mutations were found in both tumors. In conclusion, we demonstrated in this unusual case the over-expression of growth signaling pathways, which are molecular mechanisms previously related to adrenocortical tumorigenesis. Furthermore, the absence of somatic CTNNB1 mutations, which is a molecular marker of poor prognosis in adults, might be related to the long-term survival of this patient. Arq Bras Endocrinol Metab. 2011;55(1) 72-7
  • article 48 Citação(ões) na Scopus
    Targeted Assessment of G0S2 Methylation Identifies a Rapidly Recurrent, Routinely Fatal Molecular Subtype of Adrenocortical Carcinoma
    (2019) MOHAN, Dipika R.; LERARIO, Antonio Marcondes; ELSE, Tobias; MUKHERJEE, Bhramar; ALMEIDA, Madson Q.; VINCE, Michelle; REGE, Juilee; MARIANI, Beatriz M. P.; ZERBINI, Maria Claudia N.; MENDONCA, Berenice B.; LATRONICO, Ana Claudia; MARIE, Suely K. N.; RAINEY, William E.; GIORDANO, Thomas J.; V, Maria Candida B. Fragoso; HAMMER, Gary D.
    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 andDNAdamage 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.
  • conferenceObject
    Metabolic Reprograming in Adrenocortical Tumors in Children: A Promising New Pathway in the Biology of This Disease
    (2016) ZERBINI, Maria; PINHEIRO, Celine; GRANJA, Sara; LONGATTO, Adhemar; FARIA, Andre M.; FRAGOSO, Maria C. V.; LOVISOLO, Silvana M.; LERARIO, Antonop M.; ALMEIDA, Madson Q.; BALTAZAR, Fatima
  • conferenceObject
    Development of Virilizing Adrenocortical Carcinoma during Pregnancy: Case Report
    (2014) NAKAGUMA, Marilena; MINANNI, Carlos Andre; MIRANDA, Mirela Costa de; LERARIO, Antonio M.; MENDONCA, Berenice B.; LATRONICO, Ana Claudia; ALMEIDA, Madson Q.; FRAGOSO, Maria Candida B. V.
  • article 9 Citação(ões) na Scopus
    DAX1 Overexpression in Pediatric Adrenocortical Tumors: A Synergic Role with SF1 in Tumorigenesis
    (2015) SOUSA, G. R. V. de; SOARES, I. C.; FARIA, A. M.; DOMINGUES, V. B.; WAKAMATSU, A.; LERARIO, A. M.; ALVES, V. A. F.; ZERBINI, M. C. N.; MENDONCA, B. B.; FRAGOSO, M. C. B. V.; LATRONICO, A. C.; ALMEIDA, M. Q.
    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 ((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.
  • article 26 Citação(ões) na Scopus
    Expression of LIN28 and its regulatory microRNAs in adult adrenocortical cancer
    (2015) FARIA, Andre M.; SBIERA, Silviu; RIBEIRO, Tamaya C.; SOARES, Ibere C.; MARIANI, Beatriz M. P.; FREIRE, Daniel S.; SOUSA, Gabriela R. V. de; LERARIO, Antonio M.; RONCHI, Cristina L.; DEUTSCHBEIN, Timo; WAKAMATSU, Alda; ALVES, Venancio A. F.; ZERBINI, Maria Claudia N.; MENDONCA, Berenice B.; FRAGOSO, Maria Candida B. V.; LATRONICO, Ana Claudia; FASSNACHT, Martin; ALMEIDA, Madson Q.
    ObjectiveLIN28 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 methodsLIN28 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. ResultsLIN28A 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=001), but for overall survival only a trend was detectable (P=0117). In the multivariate analysis, only Ki67 index 10% (HR 46, P=0000) and weak LIN28 protein expression (HR 20, P=003) 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 1334 (from 24 to 5193); P=0011] and was highly associated with reduced overall (P=001) and disease-free survival (P=001). However, mir-9 prognostic role should be further evaluated in a larger cohort. ConclusionWeak LIN28 protein expression was associated with recurrence in ACCs. Additionally, overexpression of mir-9, a negative LIN28A regulator, was associated with poor outcome.
  • article 76 Citação(ões) na Scopus
    Comprehensive Pan-Genomic Characterization of Adrenocortical Carcinoma (vol 29, pg 723, 2016)
    (2016) ZHENG, Siyuan; CHERNIACK, Andrew D.; DEWAL, Ninad; MOFFITT, Richard A.; DANILOVA, Ludmila; MURRAY, Bradley A.; LERARIO, Antonio M.; ELSE, Tobias; KNIJNENBURG, Theo A.; CIRIELLO, Giovanni; KIM, Seungchan; ASSIE, Guillaume; MOROZOVA, Olena; AKBANI, Rehan; SHIH, Juliann; HOADLEY, Katherine A.; CHOUEIRI, Toni K.; WALDMANN, Jens; METE, Ozgur; ROBERTSON, A. Gordon; WU, Hsin-Ta; RAPHAEL, Benjamin J.; SHAO, Lina; MEYERSON, Matthew; DEMEURE, Michael J.; BEUSCHLEIN, Felix; GILL, Anthony J.; SIDHU, Stan B.; ALMEIDA, Madson Q.; FRAGOSO, Maria C. B. V.; COPE, Leslie M.; KEBEBEW, Electron; HABRA, Mouhammed A.; WHITSETT, Timothy G.; BUSSEY, Kimberly J.; RAINEY, William E.; ASA, Sylvia L.; BERTHERAT, Jerome; FASSNACHT, Martin; WHEELER, David A.; HAMMER, Gary D.; GIORDANO, Thomas J.; VERHAAK, Roel G. W.