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
12 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 12
- The effect of hormonal secretion on survival in adrenocortical carcinoma: A multi-center study(2024) SADA, Alaa; FOSTER, Trenton R.; AL-WARD, Ruaa; SAWANI, Sahar; CHARCHAR, Helaine; PISHDAD, Reza; BEN-SHLOMO, Anat; DY, Benzon M.; LYDEN, Melanie L.; BERGSLAND, Emily; JASIM, Sina; RAJ, Nitya; SHANK, Jessica B.; HAMIDI, Oksana; HAMRAHIAN, Amir H.; CHAMBO, Jose L.; SROUGI, Victor; FRAGOSO, Maria C. B. V.; GRAHAM, Paul H.; HABRA, Mouhammed Amir; BANCOS, Irina; MCKENZIE, Travis J.Background: Current evidence suggests that cortisol secreting adrenocortical carcinoma has worse prognosis compared to non-secreting adrenocortical carcinoma. However, the effect of other secretory subtypes is unknown.Methods: This multicenter study within the American-Australian-Asian Adrenal Alliance included adults with adrenocortical carcinoma (1997-2020). We compared overall survival and disease-free survival among cortisol secreting, mixed cortisol/androgen secreting, androgen secreting, and non-secreting adrenocortical carcinoma.Results: Of the 807 patients (mean age 50), 719 included in the secretory subtype analysis: 24.5% were cortisol secreting, 13% androgen secreting, 28% mixed cortisol/androgen, 32.5% non-secreting, and 2% were mineralocorticoid secreting. Median overall survival and disease-free survival for the entire cohort were 60 and 9 months, respectively.Median overall survival was 36 months for cortisol, 30 for mixed, 60 for androgen secreting, and 115 for non-secreting adrenocortical carcinoma, P < .01. Median disease-free survival was 7 months for cortisol, 8 for mixed, 10 for androgen, and 12 for non-secreting adrenocortical carcinoma, P 1/4 .06. On multivariable analysis of age, sex, Ki67%, secretory subtype, stage, resection, and adjuvant therapy, predictors of worse overall survival were older age, higher Ki67%, stage IV, mixed secreting, R1, and no adjuvant therapy, P < .05. On subgroup analysis of R0 resection, predictors of worse overall survival included older age and higher Ki67%. Ki67% >= 40, stage III and cortisol secretion were associated with worse disease-free survival.Conclusion: Mixed cortisol/androgen secreting adrenocortical carcinoma was associated with worse overall survival, while cortisol or androgen secreting alone were not. Notably, among patients after R0 resection, secretory subtype did not affect overall survival. Cortisol secreting adrenocortical carcinoma demonstrated worse disease-free survival. Ki67% remained a strong predictor of worse overall survival and disease-free survival independent of stage.(c) 2023 Elsevier Inc. All rights reserved.
- Response to Letter to the Editor from de Ponthaud et al: ""Cytoreductive Surgery of the Primary Tumor in Metastatic Adrenocortical Carcinoma: Impact on Patients' Survival"" (Feb, 10.1210/clinem/dgac097, 2022)(2022) SROUGI, V; HABRA, M. A.; V, M. C. B. Fragoso
- 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.
- Rectal leiomyosarcoma as the initial phenotypic manifestation of Li–Fraumeni-like syndrome: a case report and review of the literature(2022) SEVERINO, N. P.; WAISBERG, J.; FRAGOSO, M. C. B. V.; LIMA, L. G. C. A. de; BALSAMO, F.; HENRIQUES, A. C.; BIANCO, B.; GEHRKE, F. de SousaBackground: Leiomyosarcoma is a rare malignant tumor of smooth muscle origin and represents 10–20% of all soft tissue sarcomas. Primary colon and rectal sarcomas constitute < 0.1% of all large bowel malignancies. In Li–Fraumeni syndrome, sarcomas are the second most frequent cancer (25%). Li–Fraumeni syndrome is a genetic disease with a familial predisposition to multiple malignant neoplasms. This syndrome has an autosomal dominant pattern of inheritance and high penetrance characterized by germline TP53 mutations. Patients with a history of cancer who do not meet all the “classic” criteria for Li–Fraumeni syndrome are considered to have Li–Fraumeni-like syndrome. To the best of our knowledge, this article is the first report of a patient with rectal leiomyosarcoma as the initial phenotypic manifestation of Li–Fraumeni-like syndrome. The authors also present a literature review. Case presentation: A 67-year-old Brazilian woman underwent anterior rectosigmoidectomy and panhysterectomy secondary to rectal leiomyosarcoma. She subsequently developed carcinomatosis and died 2 years after the operation. Her family medical history consisted of a daughter who died at 32 years of age from breast cancer, a granddaughter diagnosed with adrenocortical carcinoma at 6 years of age and two siblings who died from prostate cancer. A genetic study was carried out to identify a pathogenic variant of Li–Fraumeni syndrome. In the DNA extracted from the peripheral blood leukocyte, restriction fragment length polymorphism was analyzed to search for mutations in the TP53 gene. The DNA sequencing identified the germline pathogenic variant p. R337H heterozygous in exon 10 of TP53. The patient was classified as having Li–Fraumeni-like syndrome. Conclusion: In patients with rectal leiomyosarcoma, it is advisable to investigate the family history of cancer and perform genetic studies to screen for Li–Fraumeni syndrome. © 2022, The Author(s).
- 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.
- ARMC5 controls the degradation of most Pol II subunits, and ARMC5 mutation increases neural tube defect risks in mice and humans(2024) LUO, Hongyu; LAO, Linjiang; AU, Kit Sing; NORTHRUP, Hope; HE, Xiao; FORGET, Diane; GAUTHIER, Marie-Soleil; COULOMBE, Benoit; BOURDEAU, Isabelle; SHI, Wei; GAGLIARDI, Lucia; FRAGOSO, Maria Candida Barisson Villares; PENG, Junzheng; WU, JiangpingBackgroundNeural tube defects (NTDs) are caused by genetic and environmental factors. ARMC5 is part of a novel ubiquitin ligase specific for POLR2A, the largest subunit of RNA polymerase II (Pol II).ResultsWe find that ARMC5 knockout mice have increased incidence of NTDs, such as spina bifida and exencephaly. Surprisingly, the absence of ARMC5 causes the accumulation of not only POLR2A but also most of the other 11 Pol II subunits, indicating that the degradation of the whole Pol II complex is compromised. The enlarged Pol II pool does not lead to generalized Pol II stalling or a generalized decrease in mRNA transcription. In neural progenitor cells, ARMC5 knockout only dysregulates 106 genes, some of which are known to be involved in neural tube development. FOLH1, critical in folate uptake and hence neural tube development, is downregulated in the knockout intestine. We also identify nine deleterious mutations in the ARMC5 gene in 511 patients with myelomeningocele, a severe form of spina bifida. These mutations impair the interaction between ARMC5 and Pol II and reduce Pol II ubiquitination.ConclusionsMutations in ARMC5 increase the risk of NTDs in mice and humans. ARMC5 is part of an E3 controlling the degradation of all 12 subunits of Pol II under physiological conditions. The Pol II pool size might have effects on NTD pathogenesis, and some of the effects might be via the downregulation of FOLH1. Additional mechanistic work is needed to establish the causal effect of the findings on NTD pathogenesis.
- N-type calcium channel v2.2 is a target of TCF21 in adrenocortical carcinomas(2022) PASSAIA, Barbara Dos Santos; KREMER, Jean Lucas; FRAGOSO, Maria Candida Villares; LOTFI, Claudimara Ferini PaciccoTranscription factor 21 (TCF21) directly binds and regulates SF1 mRNA expression in tumor and normal adrenocortical cells, and both are involved in the development and steroidogenesis of the adrenal cortex. TCF21 is a tumor suppressor gene and its expression is reduced in malignant tumors. In adrenocortical tumors, it is less expressed in adrenocortical carcinomas (ACC) than in adrenocortical adenomas (ACA) and normal tissues. However, a comprehensive analysis to identify TCF21 targets has not yet been conducted in any type of cancer. In this study, we performed Chromatin Immunoprecipitation and Sequencing (ChIP-Seq) in an adrenocortical carcinoma cell line (NCI-H295R) overexpressing TCF21, with the aim of identifying TCF21 new targets. The five most frequently identified sequences corresponded to the PRDM7, CNTNAP2, CACNA1B, PTPRN2, and KCNE1B genes. Validation experiments showed that, in NCI-H295R cells, TCF21 negatively regulates the expression of the CACNA1B gene. Recently, it was observed that the N-type calcium channel v2.2 (Cav2.2) encoded by the CACNA1B gene is important in Angiotensin II signal transduction for corticosteroid biosynthesis in NCI-H295R adrenocortical carcinoma cells. Indeed, TCF21 inhibits CACNA1B and Cav2.2 expression in NCI-H295R. In addition, in a cohort of 55 adult patients with adrenocortical tumors, CACNA1B expression was higher in ACC than ACA and was related to poor disease-free survival in ACC patients. These results suggest a mechanism of steroidogenesis control by TCF21 in adrenocortical tumor cells, in addition to the control observed through SF1 inhibition. Importantly, steroid production could impair tumor immunogenicity, contributing to the immune resistance described in adrenal cancer.
- & 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.
- Clinical and Pathological Predictors of Death for Adrenocortical Carcinoma(2024) PATO, Eduardo; SROUGI, Victor; ZERBINI, Claudia; LEDESMA, Felipe L.; TANNO, Fabio; ALMEIDA, Madson Q.; NAHAS, William; LATRONICO, Ana Claudia; MENDONCA, Berenice B.; CHAMBO, Jose L.; V, Maria Candida B. FragosoAdrenocortical carcinoma (ACC) is a rare and lethal disease with a poor prognosis. This study aims to share our 41-year experience as a referral center, focusing on identifying risk factors associated with ACC mortality. Our retrospective analysis included a cohort of 150 adult patients with ACC in all stage categories, treated between 1981 and 2022. Tumor hormonal hypersecretion was observed in 78.6% of the patients, and the median age of diagnosis was 40 years. The majority presented as European Network for the Study of Adrenal Tumors (ENSAT) III or IV (22.9% and 31.2%, respectively), and the overall mortality rate was 54.6%. Independent predictors of death were elevated secretion of cortisol (HR = 2.0), androstenedione (HR = 2.2), estradiol (HR = 2.8), 17-OH progesterone (HR = 2.0), and 11-deoxycortisol (HR = 5.1), higher Weiss (HR = 4.3), modified Weiss (HR = 4.4), and Helsinki scores (HR = 12.0), advanced ENSAT stage (HR = 27.1), larger tumor size (HR = 2.7), higher Ki-67 percentage (HR = 2.3), and incomplete surgical resection (HR = 2.5). Mitosis greater than 5/50 high-power field (HR = 5.6), atypical mitosis (HR = 2.3), confluent necrosis (HR = 15.4), venous invasion (HR = 2.8), and capsular invasion (HR = 2.4) were also identified as independent predictors of death. Knowing the risk factors for ACC's mortality may help determine the best treatment option.