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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- Evidence for a Founder Effect of SDHB Exon 1 Deletion in Brazilian Patients With Paraganglioma(2023) FAGUNDES, Gustavo F. C.; FREITAS-CASTRO, Felipe; SANTANA, Lucas S.; AFONSO, Ana Caroline F.; PETENUCI, Janaina; FUNARI, Mariana F. A.; GUIMARAES, Augusto G.; LEDESMA, Felipe L.; PEREIRA, Maria Adelaide A.; VICTOR, Carolina R.; FERRARI, Marcela S. M.; COELHO, Fernando M. A.; SROUGI, Victor; TANNO, Fabio Y.; CHAMBO, Jose L.; LATRONICO, Ana Claudia; MENDONCA, Berenice B.; V, Maria Candida B. Fragoso; HOFF, Ana O.; ALMEIDA, Madson Q.Context Limited information is available concerning the genetic spectrum of pheochromocytoma and paraganglioma (PPGL) patients in South America. Germline SDHB large deletions are very rare worldwide, but most of the individuals harboring the SDHB exon 1 deletion originated from the Iberian Peninsula. Objective Our aim was to investigate the spectrum of SDHB genetic defects in a large cohort of Brazilian patients with PPGLs. Methods Genetic investigation of 155 index PPGL patients was performed by Sanger DNA sequencing, multiplex ligation-dependent probe amplification, and/or target next-generation sequencing panel. Common ancestrality was investigated by microsatellite genotyping with haplotype reconstruction, and analysis of deletion breakpoint. Results Among 155 index patients, heterozygous germline SDHB pathogenic or likely pathogenic variants were identified in 22 cases (14.2%). The heterozygous SDHB exon 1 complete deletion was the most frequent genetic defect in SDHB, identified in 8 out of 22 (36%) of patients. Haplotype analysis of 5 SDHB flanking microsatellite markers demonstrated a significant difference in haplotype frequencies in a case-control permutation test (P = 0.03). More precisely, 3 closer/informative microsatellites were shared by 6 out of 8 apparently unrelated cases (75%) (SDHB-GATA29A05-D1S2826-D1S2644 | SDHB-186-130-213), which was observed in only 1 chromosome (1/42) without SDHB exon 1 deletion (X-2 = 29.43; P < 0.001). Moreover, all cases with SDHB exon 1 deletion had the same gene breakpoint pattern of a 15 678 bp deletion previously described in the Iberian Peninsula, indicating a common origin. Conclusion The germline heterozygous SDHB exon 1 deletion was the most frequent genetic defect in the Brazilian PPGL cohort. Our findings demonstrated a founder effect for the SDHB exon 1 deletion in Brazilian patients with paragangliomas.
- A matched case-control study of the prognosis of early breast cancer in patients with Li-Fraumeni syndrome (BREAST TP53)(2023) PETRY, Vanessa; BONADIO, Renata Colombo; TESTA, Laura; COHN, Daniela JBH.; CAGNACCI, Allyne; CAMPOS, Roberta G.; FRAGOSO, Maria Candida Bv; ESTEVEZ-DIZ, Maria del PilarIntroduction: Breast cancer (BC) is the most common type of cancer in premenopausal women with germline TP53 pathogenic variants (mTP53) (Li Fraumeni syndrome -LFS). However, little is known about the BC prognosis in these patients. This study analyzed the BC-related oncologic outcomes of patients with LFS.Methods: We evaluated a cohort of LFS patients with BC in comparison with a control cohort of BC patients with no pathogenic variant in a hereditary cancer panel. The primary endpoint was recurrence-free survival (RFS). Due to the risk of second malignancies in LFS, only locoregional and distant recurrences were considered events for RFS. Secondary endpoints included rates of contralateral BC, overall survival (OS), and breast cancer-specific survival (BCSS).Results: Forty-one patients were evaluated in the mTP53 group and 82 in the control group. Median age at BC diagnosis was 40 and 41 years, respectively. The mTP53 group received less adjuvant radiotherapy than the control group (63.4% vs 93.9%, P < 0.001). Other relevant baseline characteristics and treatment received were similar between groups. 5y-RFS rates were 79.4% in the mTP53 versus 93.6% in the control group (HR 2.43, 95% CI 0.74-8.01, P = 0.143); and were not impacted by the use of adjuvant radiotherapy. 5y-BCSS rates were 92.2% and 98.6%, respectively (HR 1.87, IC95% 0.25-13.48, P = 0.534).Conclusions: Our results showed no statistically significant difference in BC-related RFS and BCSS between pa-tients with mTP53 and a control group with no pathogenic variant. Larger multicentric studies are warranted to confirm these results.
- Frequency of radiotherapy-induced malignancies in Li-Fraumeni syndrome patients with early breast cancer and influence of the radiotherapy technique(2023) PETRY, V.; BONADIO, R. Colombo; MOUTINHO, K.; SENNA, L.; TESTA, L.; FRAGOSO, M. C.; DIZ, M. D. P. Estevez
- Intra-individual Variability of Serum Aldosterone and Implications for Primary Aldosteronism Screening(2023) MACIEL, Ana Alice W.; FREITAS, Thais C.; FAGUNDES, Gustavo F. C.; PETENUCI, Janaina; VILELA, Leticia A. P.; BRITO, Luciana P.; GOLDBAUM, Tatiana S.; ZERBINI, Maria Claudia N.; LEDESMA, Felipe L.; TANNO, Fabio Y.; SROUGI, Victor; CHAMBO, Jose L.; PEREIRA, Maria Adelaide A.; COELHO, Fernando M. A.; CAVALCANTE, Aline C. B. S.; CARNEVALE, Francisco C.; PILAN, Bruna; PIO-ABREU, Andrea; V, Joao Silveira; CONSOLIM-COLOMBO, Fernanda M.; BORTOLOTTO, Luiz A.; LATRONICO, Ana Claudia; V, Maria Candida B. Fragoso; DRAGER, Luciano F.; MENDONCA, Berenice B.; ALMEIDA, Madson Q.Context Primary aldosteronism (PA) screening relies on an elevated aldosterone to renin ratio with a minimum aldosterone level, which varies from 10 to 15 ng/dL (277-415.5 pmol/L) using immunoassay. Objective To evaluate intra-individual coefficient of variation (CV) of aldosterone and aldosterone to direct renin concentration ratio (A/DRC) and its impact on PA screening. Methods A total of 671 aldosterone and DRC measurements were performed by the same chemiluminescence assays in a large cohort of 216 patients with confirmed PA and at least 2 screenings. Results The median intra-individual CV of aldosterone and A/DRC was 26.8% and 26.7%. Almost 40% of the patients had at least one aldosterone level <15 ng/dL, 19.9% had at least 2 aldosterone levels <15 ng/dL, and 16.2% had mean aldosterone levels <15 ng/dL. A lower cutoff of 10 ng/dL was associated with false negative rates for PA screening of 14.3% for a single aldosterone measurement, 4.6% for 2 aldosterone measurements, and only 2.3% for mean aldosterone levels. Considering the minimum aldosterone, true positive rate of aldosterone thresholds was 85.7% for 10 ng/dL and 61.6% for 15 ng/dL. An A/DRC >2 ng/dL/mu IU/mL had a true positive rate for PA diagnosis of 94.4% and 98.4% when based on 1 or 2 assessments, respectively. CV of aldosterone and A/DRC were not affected by sex, use of interfering antihypertensive medications, PA lateralization, hypokalemia, age, and number of hormone measurements. Conclusion Aldosterone concentrations had a high CV in PA patients, which results in an elevated rate of false negatives in a single screening for PA. Therefore, PA screening should be based on at least 2 screenings with concomitant aldosterone and renin measurements.
- Intra-individual Variability of Serum Aldosterone and Implications for Primary Aldosteronism Screening (Nov, dgac679, 2022)(2023) MACHEI, A. A. W.; FREITAS, T. C.; FAGUNDES, G. F. C.; PETENUCI, J.; VILELA, L. A. P.; BRITO, L. P.; GOLDBAUM, T. S.; ZERBINI, M. C. N.; LEDESMA, F. L.; YANNO, F. Y.; SROUGI, V; CHAMBO, J. L.; PEREIRA, M. A. A.; COELHO, F. M. A.; CAVALCANTE, A. C. B. S.; CARNEVALE, F. C.; PILAN, B.; PIO-ABREU, A.; V, J. Silveira; CONSOLIM-COLOMBO, F. M.; BORTOLOTTO, L. A.; LATRONICO, A. C.; V, M. C. B. Fragoso; DRAGER, L. F.; MENDONCA, B. B.; ALMEIDA, M. Q.
- Epigenetic dedifferentiation as a therapeutic strategy in adrenal cancer(2023) MOHAN, Dipika R.; BORGES, Kleiton S.; FINCO, Isabella; LAPENSEE, Christopher R.; REGE, Juilee; LITTLE, Donald W.; ELSE, Tobias; ALMEIDA, Madson Q.; DANG, Derek; HAGGERTY-SKEANS, James; LATRONICO, Ana Claudia; MENDONCA, Berenice B.; AUCHUS, Richard J.; RAINEY, William E.; MARIE, Suely K.; GIORDANO, Thomas J.; VENNETI, Sriram; FRAGOSO, Maria Candida B.; BREAULT, David T.; LERARIO, Antonio M.; HAMMER, Gary D.
- & beta;-Catenin-Driven Differentiation Is a Tissue-Specific Epigenetic Vulnerability in Adrenal Cancer(2023) MOHAN, Dipika R.; BORGES, Kleiton S.; FINCO, Isabella; LAPENSEE, Christopher R.; REGE, Juilee; SOLON, April L.; III, Donald W. Little; ELSE, Tobias; ALMEIDA, Madson Q.; DANG, Derek; HAGGERTY-SKEANS, James; APFELBAUM, April A.; VINCO, Michelle; WAKAMATSU, Alda; MARIANI, Beatriz M. P.; AMORIM, Larissa Costa; LATRONICO, Ana Claudia; MENDONCA, Berenice B.; ZERBINI, Maria Claudia N.; LAWLOR, Elizabeth R.; OHI, Ryoma; AUCHUS, Richard J.; RAINEY, William E.; MARIE, Suely K. N.; GIORDANO, Thomas J.; VENNETI, Sriram; FRAGOSO, Maria Candida Barisson Villares; BREAULT, David T.; LERARIO, Antonio Marcondes; HAMMER, Gary D.Adrenocortical carcinoma (ACC) is a rare cancer in which tissue-specific differentiation is paradoxically associated with dismal out-comes. The differentiated ACC subtype CIMP-high is prevalent, incurable, and routinely fatal. CIMP-high ACC possess abnormal DNA methylation and frequent 3-catenin-activating mutations. Here, we demonstrated that ACC differentiation is maintained by a balance between nuclear, tissue-specific 3-catenin-containing com-plexes, and the epigenome. On chromatin, 3-catenin bound master adrenal transcription factor SF1 and hijacked the adrenocortical super-enhancer landscape to maintain differentiation in CIMP-high ACC; off chromatin, 3-catenin bound histone methyltransfer-ase EZH2. SF1/3-catenin and EZH2/3-catenin complexes present in normal adrenals persisted through all phases of ACC evolution. Pharmacologic EZH2 inhibition in CIMP-high ACC expelled SF1/ 3-catenin from chromatin and favored EZH2/3-catenin assembly, erasing differentiation and restraining cancer growth in vitro and in vivo. These studies illustrate how tissue-specific programs shape oncogene selection, surreptitiously encoding targetable therapeutic vulnerabilities. Significance: Oncogenic 3-catenin can use tissue-specific part-ners to regulate cellular differentiation programs that can be reversed by epigenetic therapies, identifying epigenetic control of differentiation as a viable target for 3-catenin-driven cancers.
conferenceObject Retrospective Analysis of Prognostic Factors in Pediatric Patients with Adrenocortical Tumor from Unique Tertiary Center with Long-Term Follow-up(2023) BACHEGA, Fernanda; SUARTZ, Caio; ALMEIDA, Madson; BRONDANI, Vania; CHARCHAR, Helaine; LACOMBE, Amanda; MARTINS-FILHO, Sebastiao; SOARES, Ibere; ZERBINI, Maria Claudia; DENES, Francisco; MENDONCA, Berenice; LOPES, Roberto; LATRONICO, Ana Claudia; FRAGOSO, Maria Candida- Adjuvant mitotane versus surveillance in low-grade, localised adrenocortical carcinoma (ADIUVO): an international, multicentre, open-label, randomised, phase 3 trial and observational study(2023) TERZOLO, Massimo; FASSNACHT, Martin; PEROTTI, Paola; LIBE, Rossella; KASTELAN, Darko; LACROIX, Andre; ARLT, Wiebke; HAAK, Harm Reinout; LOLI, Paola; DECOUDIER, Benedicte; LASOLLE, Helene; QUINKLER, Marcus; HAISSAGUERRE, Magalie; CHABRE, Olivier; CARON, Philippe; STIGLIANO, Antonio; GIORDANO, Roberta; ZATELLI, Maria Chiara; BANCOS, Irina; FRAGOSO, Maria Candida Barisson Villares; CANU, Letizia; LUCONI, Michaela; PUGLISI, Soraya; BASILE, Vittoria; REIMONDO, Giuseppe; KROISS, Matthias; MEGERLE, Felix; HAHNER, Stefanie; KIMPEL, Otilia; DUSEK, Tina; NOELTING, Svenja; BOURDEAU, Isabelle; CHORTIS, Vasileios; ETTAIEB, Madeleine Hester; COSENTINI, Deborah; GRISANTI, Salvatore; BAUDIN, Eric; BERCHIALLA, Paola; BOVIS, Francesca; SORMANI, Maria Pia; BRUZZI, Paolo; BEUSCHLEIN, Felix; BERTHERAT, Jerome; BERRUTI, AlfredoBackground Adjuvant treatment with mitotane is commonly used after resection of adrenocortical carcinoma; however, treatment remains controversial, particularly if risk of recurrence is not high. We aimed to assess the efficacy and safety of adjuvant mitotane compared with surveillance alone following complete tumour resection in patients with adrenocortical carcinoma considered to be at low to intermediate risk of recurrence. Methods ADIUVO was a multicentre, open-label, parallel, randomised, phase 3 trial done in 23 centres across seven countries. Patients aged 18 years or older with adrenocortical carcinoma and low to intermediate risk of recurrence (R0, stage I-III, and Ki67 <= 10%) were randomly assigned to adjuvant oral mitotane two or three times daily (the dose was adjusted by the local investigator with the target of reaching and maintaining plasma mitotane concentrations of 14-20 mg/L) for 2 years or surveillance alone. All consecutive patients at 14 study centres fulfilling the eligibility criteria of the ADIUVO trial who refused randomisation and agreed on data collection via the European Network for the Study of Adrenal Tumors adrenocortical carcinoma registry were included prospectively in the ADIUVO Observational study. The primary endpoint was recurrence-free survival, defined as the time from randomisation to the first radiological evidence of recurrence or death from any cause (whichever occurred first), assessed in all randomly assigned patients by intention to treat. Overall survival, defined as time from the date of randomisation to the date of death from any cause, was a secondary endpoint analysed by intention to treat in all randomly assigned patients. Safety was assessed in all patients who adhered to the assigned regimen, which was defined by taking at least one tablet of mitotane in the mitotane group and no mitotane at all in the surveillance group. The ADIUVO trial is registered with ClinicalTrials.gov, NCT00777244, and is now complete. Findings Between Oct 23, 2008, and Dec 27, 2018, 45 patients were randomly assigned to mitotane and 46 to surveillance alone. Because the study was discontinued prematurely, 5-year recurrence-free and overall survival are reported instead of recurrence-free and overall survival as defined in the protocol. 5-year recurrence-free survival was 79% (95% CI 67-94) in the mitotane group and 75% (63-90) in the surveillance group (hazard ratio 0.74 [95% CI 0.30-1.85]). Two people in the mitotane group and five people in the surveillance group died, and 5-year overall survival was not significantly different (95% [95% CI 89-100] in the mitotane group and 86% [74-100] in the surveillance group). All 42 patients who received mitotane had adverse events, and eight (19%) discontinued treatment. There were no grade 4 adverse events or treatment-related deaths. Interpretation Adjuvant mitotane might not be indicated in patients with low-grade, localised adrenocortical carcinoma considering the relatively good prognosis of these patients, and no significant improvement in recurrence-free survival and treatment-associated toxicity in the mitotane group. However, the study was discontinued prematurely due to slow recruitment and cannot rule out an efficacy of treatment.
- Efficacy of Oral Furosemide Test for Primary Aldosteronism Diagnosis(2023) FREITAS, Thais C.; MACIEL, Ana Alice W.; FAGUNDES, Gustavo F. C.; PETENUCI, Janaina; SANTANA, Lucas S.; GUIMARAES, Augusto G.; FREITAS-CASTRO, Felipe; SROUGI, Victor; TANNO, Fabio Y.; CHAMBO, Jose L.; PEREIRA, Maria Adelaide A.; BRITO, Luciana P.; PIO-ABREU, Andrea; BORTOLOTTO, Luiz A.; LATRONICO, Ana Claudia; V, Maria Candida B. Fragoso; DRAGER, Luciano F.; MENDONCA, Berenice B.; ALMEIDA, Madson Q.Context: Confirmatory tests represent a fundamental step in primary aldosteronism (PA) diagnosis, but they are laborious and often require a hospital environment due to the risks involved.Objective: To evaluate the efficacy of oral furosemide as a new confirmatory test for PA diagnosis.Methods: We prospectively evaluated the diagnostic performance of 80 mg of oral furosemide in 64 patients with PA and 22 with primary hypertension (controls). Direct renin concentration (DRC) was measured before, and 2 hours and 3 hours after the oral furosemide. In addition, the oral furosemide test was compared with 2 other confirmatory tests: the furosemide upright test (FUT) and saline infusion test (SIT) or captopril challenge test (CCT) in all patients with PA.Results: The cut-off of 7.6 mu U/mL for DRC at 2 hours after oral furosemide had a sensitivity of 92%, specificity of 82%, and accuracy of 90% for PA diagnosis. In 5 out of 6 controls with low-renin hypertension, which might represent a PA spectrum, renin remained suppressed. Excluding these 6 controls with low-renin hypertension, the DRC cut-off of 10 mu U/mL at 2 hours after oral furosemide had a sensitivity of 95.3%, specificity of 93.7% and accuracy of 95% for PA diagnosis. DRC after 3 hours of oral furosemide did not improve diagnostic performance. Using the cut-off of 10 mu U/mL, the oral furosemide test and the FUT were concordant in 62 out of 64 (97%) patients with PA. Only 4 out of 64 cases with PA (6.4%) ended the oral furosemide test with potassium <3.5 mEq/L. Hypotension was not evidenced in any patient with PA during the test.Conclusion: The oral furosemide test was safe, well-tolerated and represents an effective strategy for PA investigation.