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
6 resultados
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- ARMC5 mutations in a large French-Canadian family with cortisol-secreting beta-adrenergic/vasopressin responsive bilateral macronodular adrenal hyperplasia(2016) BOURDEAU, Isabelle; OBLE, Sylvie; MAGNE, Fabien; LEVESQUE, Isabelle; CACERES-GORRITI, Katia Y.; NOLET, Serge; AWADALLA, Philip; TREMBLAY, Johanne; HAMET, Pavel; FRAGOSO, Maria Candida Barisson Villares; LACROIX, AndreBackground: Bilateral macronodular adrenal hyperplasia (BMAH) is a rare cause of Cushing's syndrome (CS) and its familial clustering has been described previously. Recent studies identified that ARMC5 mutations occur frequently in BMAH, but the relation between ARMC5 mutation and the expression of aberrant G-protein-coupled receptor has not been examined in detail yet. Methods: We studied a large French-Canadian family with BMAH and sub-clinical or overt CS. Screening was performed using the 1-mg dexamethasone suppression test (DST) in 28 family members. Screening for aberrant regulation of cortisol by various hormone receptors were examined in vivo in nine individuals. Sequencing of the coding regions of ARMC5 gene was carried out. Results: Morning ambulating cortisol post 1 mg DST were >50 nmol/l in 5/8 members in generation II (57-68 years old), 9/22 in generation III (26-46 years old). Adrenal size was enlarged at different degrees. All affected patients increased cortisol following upright posture, insulin-induced hypoglycemia and/or isoproterenol infusion. beta-blockers led to the reduction of cortisol secretion in all patients with the exception of two who had adrenalectomies because of beta-blockers intolerance. We identified a heterozygous germline variant in the ARMC5 gene c.327_328insC, (p.Ala110Argfs*9) in nine individuals with clinical or subclinical CS, in four out of six individuals with abnormal suppression to dexamethasone at initial investigation and one out of six individuals with current normal clinical screening tests. Conclusions: Systematic screening of members of the same family with hereditary BMAH allows the diagnosis of unsuspected subclinical CS associated with early BMAH. The relation between the causative ARMC5 mutation and the reproducible pattern of aberrant beta-adrenergic and V1-vasopressin receptors identified in this family remains to be elucidated.
- MANAGEMENT OF ENDOCRINE DISEASE Management of pregnant patients with Cushing's syndrome(2015) BRONSTEIN, M. D.; MACHADO, M. C.; FRAGOSO, M. C. B. V.Progress in the diagnosis and treatment of endocrine diseases has turned pregnancy into a possibility for women with such medical disorders, including Cushing's syndrome (CS). Nevertheless, despite its rarity, pregnancy in patients with CS can be troublesome because of the risk of maternal-fetal complications. Therefore, hypercortisolism, if present, should be surgically or medically controlled in most cases. Moreover, changes in the hypothalamic-pituitary-adrenal axis during normal pregnancy may mislead the diagnosis of CS during this period, because many laboratory assessments suggestive of CS may be present in normal pregnancy, with clinical features mimicking those seen in patients with CS. The aim of the present review is to update the diagnostic approach to this medical condition, mainly for pregnant women without previous diagnosis of CS, and to describe the therapeutic strategies for CS during pregnancy in order to minimize complications for both mother and fetus.
- S-GRAS score for prognostic classification of adrenocortical carcinoma: an international, multicenter ENSAT study(2022) ELHASSAN, Y. S.; ALTIERI, B.; BERHANE, S.; COSENTINI, D.; CALABRESE, A.; HAISSAGUERRE, M.; KASTELAN, D.; V, M. C. B. Fragoso; BERTHERAT, J.; GHUZLAN, A. Al; HAAK, H.; BOUDINA, M.; CANU, L.; LOLI, P.; SHERLOCK, M.; KIMPEL, O.; LAGANA, M.; SITCH, A. J.; KROISS, M.; ARLT, W.; TERZOLO, M.; BERRUTI, A.; DEEKS, J. J.; LIBE, R.; FASSNACHT, M.; RONCHI, C. L.Objective Adrenocortical carcinoma (ACC) has an aggressive but variable clinical course. Prognostic stratification based on the European Network for the Study of Adrenal Tumours stage and Ki67 index is limited. We aimed to demonstrate the prognostic role of a points-based score (S-GRAS) in a large cohort of patients with ACC. Design This is a multicentre, retrospective study on ACC patients who underwent adrenalectomy. Methods The S-GRAS score was calculated as a sum of the following points: tumour stage (1-2 = 0; 3 = 1; 4 = 2), grade (Ki67 index 0-9% = 0; 10-19% = 1; >= 20% = 2 points), resection status (R0 = 0; RX = 1; R1 = 2; R2 = 3), age (<50 years = 0; >= 50 years = 1), symptoms (no = 0; yes = 1), and categorised, generating four groups (0-1, 2-3, 4-5, and 6-9). Endpoints were progression-free survival (PFS) and disease-specific survival (DSS). The discriminative performance of S-GRAS and its components was tested by Harrell's Concordance index (C-index) and Royston-Sauerbrei's R-D(2) statistic. Results We included 942 ACC patients. The S-GRAS score showed superior prognostic performance for both PFS and DSS, with best discrimination obtained using the individual scores (0-9) (C-index = 0.73, R-D(2) = 0.30, and C-index = 0.79, R-D(2) = 0.45, respectively, all P < 0.01vs each component). The superiority of S-GRAS score remained when comparing patients treated or not with adjuvant mitotane (n = 481 vs 314). In particular, the risk of recurrence was significantly reduced as a result of adjuvant mitotane only in patients with S-GRAS 4-5. Conclusion The prognostic performance of S-GRAS is superior to tumour stage and Ki67 in operated ACC patients, independently from adjuvant mitotane. S-GRAS score provides a new important guide for personalised management of ACC (i.e. radiological surveillance and adjuvant treatment).
- Association between the p27 rs2066827 variant and tumor multiplicity in patients harboring MEN1 germline mutations(2014) LONGUINI, Viviane C.; LOURENCO JR., Delmar M.; SEKIYA, Tomoko; MEIRELLES, Osorio; GONCALVES, Tatiana D.; COUTINHO, Flavia L.; FRANCISCO, Guilherme; OSAKI, Luciana H.; CHAMMAS, Roger; ALVES, Venancio A. F.; SIQUEIRA, Sheila A. C.; SCHLESINGER, David; NASLAVSKY, Michel S.; ZATZ, Mayana; DUARTE, Yeda A. O.; LEBRAO, Maria Lucia; GAMA, Patricia; LEE, Misu; MOLATORE, Sara; PEREIRA, Maria Adelaide A.; JALLAD, Raquel S.; BRONSTEIN, Marcello D.; CUNHA-NETO, Malebranche B.; LIBERMAN, Bernardo; FRAGOSO, Maria Candida B. V.; TOLEDO, Sergio P. A.; PELLEGATA, Natalia S.; TOLEDO, Rodrigo A.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.
- Somatic USP8 mutations are frequent events in corticotroph tumor progression causing Nelson's tumor(2018) PEREZ-RIVAS, Luis G.; THEODOROPOULOU, Marily; PUAR, Troy H.; FAZEL, Julia; STIEG, Mareike R.; FERRAU, Francesco; ASSIE, Guillaume; GADELHA, Monica R.; DEUTSCHBEIN, Timo; FRAGOSO, Maria C.; KUSTERS, Benno; SAEGER, Wolfgang; HONEGGER, Juergen; BUCHFELDER, Michael; KORBONITS, Marta; BERTHERAT, Jerome; STALLA, Guenter K.; HERMUS, Ad R.; BEUSCHLEIN, Felix; REINCKE, MartinObjective: Somatic mutations in the ubiquitin-specific protease 8 (USP8) gene are frequent in corticotroph tumors causing Cushing's disease (CD). Corticotroph tumor progression, the so-called Nelson's syndrome (NS), is a potentially life-threatening complication of bilateral adrenalectomy in patients with refractory CD that is caused by the development of an ACTH-secreting tumor of the pituitary gland. Whether USP8 alterations are also present in progressive Nelson's tumors has not been studied in detail so far. Design and Methods: Retrospective, multicenter study involving tumors from 33 patients with progressive corticotroph tumors (29 females) and screening for somatic mutations on the mutational hotspot of the USP8 gene in the exon 14 with Sanger sequencing. Results: Fifteen out of 33 tumors (45%) presented with a mutation in the exon 14 of USP8, with c.2159C>A (p. Pro720Gln) being the most frequent (9/33), followed by c.2155_2157delTCC (p.Ser718del, 4/33) and c.2152T>C (p.Ser718Pro, 2/33). This prevalence is similar to that previously reported for CD. Mutations were found exclusively in females. Other variables, such as age at diagnosis with NS, body mass index, hyperpigmentation, visual field defects, adenoma size or mortality, did not significantly differ between patients with wild-type and mutant tumors. Patients with USP8 mutant tumors exhibited higher levels of plasma ACTH after surgery (median: 640 vs 112 pg/mL, P = 0.03). No differences were observed in ACTH normalization (<50 pg/mL) and tumor control after surgery for Nelson's tumor. Conclusion: Somatic mutations in USP8 are common in Nelson's tumors, indicating that they do not drive the corticotroph tumor progression that leads to NS, and may be associated with a less favorable biochemical outcome after surgery for Nelson's tumor.
- Combined expression of BUB1B, DLGAP5, and PINK1 as predictors of poor outcome in adrenocortical tumors: validation in a Brazilian cohort of adult and pediatric patients(2012) FRAGOSO, Maria Candida B. V.; ALMEIDA, Madson Queiroz; MAZZUCO, Tania L.; MARIANI, Beatriz M. P.; BRITO, Luciana P.; GONCALVES, Talita Cardoso; ALENCAR, Guilherme A.; LIMA, Lorena de O.; FARIA, Andre M.; BOURDEAU, Isabelle; LUCON, Antonio M.; FREIRE, Daniel S.; LATRONICO, Ana Claudia; MENDONCA, Berenice B.; LACROIX, Andre; LERARIO, Antonio M.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.