MARIA CLAUDIA NOGUEIRA ZERBINI
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Patologia, Faculdade de Medicina - Docente
LIM/14 - Laboratório de Investigação em Patologia Hepática, Hospital das Clínicas, Faculdade de Medicina
LIM/14 - Laboratório de Investigação em Patologia Hepática, Hospital das Clínicas, Faculdade de Medicina
20 resultados
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- KCNJ5 Somatic Mutation Is a Predictor of Hypertension Remission After Adrenalectomy for Unilateral Primary Aldosteronism(2019) VILELA, Leticia A. P.; RASSI-CRUZ, Marcela; GUIMARAES, Augusto G.; MOISES, Caio C. S.; FREITAS, Thais C.; ALENCAR, Natalia P.; PETENUCI, Janaina; GOLDBAUM, Tatiana S.; MACIEL, Ana Alice W.; PEREIRA, Maria Adelaide A.; V, Giovanio Silva; PIO-ABREU, Andrea; ZERBINI, Maria Claudia N.; CAVALCANTE, Aline C. B. S.; CARNEVALE, Francisco C.; PILAN, Bruna; YAMAUCHI, Fernando; SROUGI, Vitor; TANNO, Fabio Y.; CHAMBO, Jose L.; LATRONICO, Ana Claudia; MENDONCA, Berenice B.; V, Maria Candida B. Fragoso; BORTOLOTTO, Luiz A.; DRAGER, Luciano F.; ALMEIDA, Madson Q.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.GIu145GIn (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.
- Genetic and clinical aspects of paediatric pheochromocytomas and paragangliomas(2021) PETENUCI, Janaina; GUIMARAES, Augusto G.; FAGUNDES, Gustavo F. C.; BENEDETTI, Anna Flavia F.; AFONSO, Ana Caroline F.; PEREIRA, Maria Adelaide A.; ZERBINI, Maria Claudia N.; SIQUEIRA, Sheila; YAMAUCHI, Fernando; SOARES, Silvia C.; SROUGI, Victor; TANNO, Fabio Y.; CHAMBO, Jose L.; I, Roberto Lopes; DENES, Francisco T.; HOFF, Ana O.; LATRONICO, Ana Claudia; MENDONCA, Berenice B.; V, Maria Candida B. Fragoso; ALMEIDA, Madson Q.Objective Few and conflicting reports have characterized the genetics of paediatric pheochromocytomas and paragangliomas (PPGLs). This study aimed to investigate the clinical and genetic features of Brazilian children with PPGL. Patients and Methods This study included 25 children (52% girls) with PPGL. The median age at diagnosis was 15 years (4-19). The median time of follow-up was 145 months. The genetic investigation was performed by Sanger DNA sequencing, multiplex ligation-dependent probe amplification and/or target next-generation sequencing panel. Results Of the 25 children with PPGL, 11 (44%), 4 (16%), 2 (8%), 1 (4%) and 7 (28%) had germline VHL pathogenic variants, SDHB, SDHD, RET and negative genetic investigation, respectively. Children with germline VHL missense pathogenic variants were younger than those with SDHB or SDHD genetic defects [median (range), 12 (4-16) vs. 15.5 (14-19) years; P = .027]. Moreover, 10 of 11 cases with VHL pathogenic variants had bilateral pheochromocytoma (six asynchronous and four synchronous). All children with germline SDHB pathogenic variants presented with abdominal paraganglioma (one of them malignant). The two cases with SDHD pathogenic variants presented with head and neck paraganglioma. Among the cases without a genetic diagnosis, 6 and 2 had pheochromocytoma and paraganglioma, respectively. Furthermore, metastatic PPGL was diagnosed in four (16%) of 25 PPGL. Conclusions Most of the paediatric PPGL were hereditary and multifocal. The majority of the affected genes belong to pseudohypoxic cluster 1, with VHL being the most frequently mutated. Therefore, our findings impact surgical management and surveillance of children with PPGL.
- Retrospective Analysis of Prognostic Factors in Pediatric Patients with Adrenocortical Tumor from Unique Tertiary Center with Long-Term Follow-Up(2022) BACHEGA, Fernanda S.; V, Caio Suartz; ALMEIDA, Madson Q.; BRONDANI, Vania B.; CHARCHAR, Helaine L. S.; LACOMBE, Amanda M. F.; MARTINS-FILHO, Sebastiao N.; SOARES, Ibere C.; ZERBINI, Maria Claudia N.; DENES, Francisco T.; MENDONCA, Berenice; I, Roberto Lopes; LATRONICO, Ana Claudia; V, Maria Candida B. FragosoPediatric adrenocortical tumors (PACTs) represent rare causes of malignancies. However, the south/southeast regions of Brazil are known to have a high incidence of PACTs because of the founder effect associated with a germline pathogenic variant of tumor suppressor gene TP53. We aimed to retrospectively analyze the types of variables among hormone production, radiological imaging, tumor staging, histological and genetic features that were associated with the occurrence of malignancy in 95 patients (71% females) with PACTs from a unique center. The worst prognosis was associated with those aged > 3 years (p < 0.05), high serum levels of 11-desoxicortisol (p < 0.001), tumor weight >= 200 g (p < 0.001), tumor size >= 5 cm (p < 0.05), Weiss score >= 5 (p < 0.05), Wieneke index >= 3 (p < 0.001) and Ki67 >= 15% (p < 0.05). Furthermore, patients with MacFarlane stage IV had an overall survival rate almost two times shorter than patients with other stages (p < 0.001). Additionally, the subtractions of BUB1B-PINK1 (<6.95) expression (p < 0.05) and IGF-IR overexpression (p = 0.0001) were associated with malignant behavior. These results helped identify patients who are likely to have an aggressive course; further multicenter prospective studies are required to confirm our results. In conclusion, PACTs with these patterns of prognostic factors could be treated using an adjuvant approach that may improve the overall survival in such patients.
- SDHB large deletions are associated with absence of MIBG uptake in metastatic lesions of malignant paragangliomas(2021) PETENUCI, Janaina; FAGUNDES, Gustavo F. C.; BENEDETTI, Anna Flavia F.; GUIMARAES, Augusto G.; AFONSO, Ana Caroline F.; MOTA, Flavia T.; MAGALHAES, Aurea Luiza F.; COURA-FILHO, George B.; ZERBINI, Maria Claudia N.; SIQUEIRA, Sheila; MONTENEGRO, Fabio L. M.; SROUGI, Victor; TANNO, Fabio Y.; CHAMBO, Jose Luis; FERRARI, Marcela S. S.; BEZERRA NETO, Joao Evangelista; PEREIRA, Maria Adelaide A.; LATRONICO, Ana Claudia; FRAGOSO, Maria Candida B. V.; MENDONCA, Berenice B.; HOFF, Ana O.; ALMEIDA, Madson Q.
- 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.
- 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.
- 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.
- Clinical spectrum of Li-Fraumeni syndrome/Li-Fraumeni-like syndrome in Brazilian individuals with the TP53 p.R337H mutation(2019) FERREIRA, Amanda Meneses; BRONDANI, Vania Balderrama; HELENA, Vanessa Petry; CHARCHAR, Helaine Laiz Silva; ZERBINI, Maria Claudia Nogueira; LEITE, Luiz Antonio Senna; HOFF, Ana Oliveira; LATRONICO, Ana Claudia; MENDONCA, Berenice Bilharinho; DIZ, Maria Del Pilar Estevez; ALMEIDA, Madson Queiroz de; FRAGOSO, Maria Candida Barisson VillaresBackground: The TP53 p.R337H germline mutation is highly prevalent among children with adrenocortical tumors (ACTs) from South and Southeast Brazil. However, the prevalence of other tumors of the Li-Fraumeni syndrome (LFS) and Li-Fraumeni-like syndrome (LFL) spectrum, the clinical outcomes and the potential tumor occurrence in relatives carrying this distinct TP53 mutation were not fully investigated. Patients and Methods: We investigated tumor profile data and outcomes of individuals and their close relatives with the TP53 p.R337H germline mutation. A questionnaire and the Toronto protocol were used for evaluation of asymptomatic carriers of this TP53 mutation. Results: The cohort of this study comprised 51 patients from 46 different families; 67% were female. All but one harbored the TP53 p.R337H mutation in heterozygous state; only one child was homozygous for this variant. Maternal allele inheritance occurred in 72% of the cases (p = 0,002). In pediatric group, ACT was the most common primary tumor at the diagnosis (55%; median age = 2 years). No patient of the pediatric group who initially presented with ACT developed a second primary tumor and 11% (n= 3) died due to complications related to the primary tumor (median follow-up time of 81.5 months, range = 3-378 months). In adult group, the main tumors at diagnosis were: adrenocortical carcinoma (ACC) (23%; median age= 29.5 years), breast cancer (12%; median age = 38.5 years), soft tissue sarcoma (8%; median age = 50.3 years) and choroid plexus carcinoma (CPC) (2%; median age= 18 years). Among adult patients who were diagnosed with ACC as the first primary tumor, all presented with aggressive disease as per histologic and clinical criteria at diagnosis, and 75% of patients died (median follow-up time of 19 months, range= 1-69 months). Five adult patients (22%) had a second primary tumor, including bronchoalveolar lung cancer (2 cases), ACC, uterine cervical carcinoma and fibrosarcoma. The diagnosis of these tumors was established from 8 to 36 months after the first primary tumor. Three families presented more than one case of ACT. Nine malignant neoplasms were diagnosed in asymptomatic carriers using Toronto protocol. Conclusions: This study confirms a high frequency of TP53 p.R337H mutation in pediatric group with ACT. In addition, we observed the occurrence of other tumors of LFS/LFL spectrum and a difference in the aggressiveness of ACTs depending on the age group in which they were diagnosed. The predominance of maternal mutated allele inheritance was first demonstrated in the affected Brazilian's families.
- High Prevalence of Alterations in DNA Mismatch Repair Genes of Lynch Syndrome in Pediatric Patients with Adrenocortical Tumors Carrying a Germline Mutation on TP53(2020) BRONDANI, Vania Balderrama; MONTENEGRO, Luciana; LACOMBE, Amanda Meneses Ferreira; MAGALHAES, Breno Marchiori; NISHI, Mirian Yumie; FUNARI, Mariana Ferreira de Assis; NARCIZO, Amanda de Moraes; CARDOSO, Lais Cavalca; SIQUEIRA, Sheila Aparecida Coelho; ZERBINI, Maria Claudia Nogueira; DENES, Francisco Tibor; LATRONICO, Ana Claudia; MENDONCA, Berenice Bilharinho; ALMEIDA, Madson Queiroz; LERARIO, Antonio Marcondes; SOARES, Ibere Cauduro; FRAGOSO, Maria Candida Barisson VillaresAdrenocortical cancer is a rare malignant neoplasm associated with a dismal prognosis. Identification of the molecular pathways involved in adrenal tumorigenesis is essential for a better understanding of the disease mechanism and improvement of its treatment. The aim of this study is to define the prevalence of alterations in DNA mismatch repair (MMR) genes in Lynch syndrome among pediatric patients with adrenocortical neoplasia from southern Brazil, where the prevalence of a specific TP53 germline mutation (p.Arg337His) is quite high. Thirty-six pediatric patients were retrospectively evaluated. Immunohistochemistry (IHC) for theMMR enzymes MLH1, MSH2, MSH6, and PMS2, as well as next-generation sequencing (NGS) were performed. For IHC, 36 pediatric tumors were tested. In all of them, the expression of all evaluated MMR proteins was well-preserved. For NGS, 35 patients with pediatric tumor were tested. Three patients (8.57%) with the TP53 p.Arg337His germline mutation presented pathogenic and likely pathogenic variants in the MMR genes (two in MLH1 and one in MSH6). The prevalence of alteredMMR genes among pediatric patients was elevated (8.57%) and higher than in colorectal and endometrial cancer cohorts. Pediatric patients with adrenocortical tumors should, thus, be strongly considered as at genetic risk for Lynch syndrome.
- 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.