DELMAR MUNIZ LOURENCO JUNIOR
Projetos de Pesquisa
Unidades Organizacionais
Instituto Central, Hospital das Clínicas, Faculdade de Medicina - Médico
Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas, Faculdade de Medicina - Médico
LIM/25 - Laboratório de Endocrinologia Celular e Molecular, Hospital das Clínicas, Faculdade de Medicina
Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas, Faculdade de Medicina - Médico
LIM/25 - Laboratório de Endocrinologia Celular e Molecular, Hospital das Clínicas, Faculdade de Medicina
13 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 13
- Assessing the emerging oncogene protein kinase C epsilon as a candidate gene in families with Carney complex-2(2012) TOLEDO, Rodrigo A.; SEKIYA, Tomoko; HORVATH, Anelia; FAUCZ, Fabio; FRAGOSO, Maria C. B. V.; LONGUINI, Viviane C.; LOURENCO JR., Delmar M.; TOLEDO, Sergio P. A.; STRATAKIS, Constantine A.
- EPAS1 Mutations and Paragangliomas in Cyanotic Congenital Heart Disease(2018) VAIDYA, Anand; FLORES, Shahida K.; CHENG, Zi-Ming; NICOLAS, Marlo; DENG, Yilun; OPOTOWSKY, Alexander R.; LOURENCO JR., Delmar M.; BARLETTA, Justine A.; RANA, Huma Q.; PEREIRA, M. Adelaide; TOLEDO, Rodrigo A.; DAHIA, Patricia L. M.
- Germline mutation landscape of multiple endocrine neoplasia type 1 using full gene next-generation sequencing(2018) CARVALHO, Rafael A.; URTREMARI, Betsaida; JORGE, Alexander A. L.; SANTANA, Lucas S.; QUEDAS, Elisangela P. S.; SEKIYA, Tomoko; LONGUINI, Viviane C.; MONTENEGRO, Fabio L. M.; LERARIO, Antonio M.; TOLEDO, Sergio P. A.; MARX, Stephen J.; TOLEDO, Rodrigo A.; JR, Delmar M. LourencoBackground: Loss-of-function germline MEN1 gene mutations account for 75-95% of patients with multiple endocrine neoplasia type 1 (MEN1). It has been postulated that mutations in non-coding regions of MEN1 might occur in some of the remaining patients; however, this hypothesis has not yet been fully investigated. Objective: To sequence for the entire MEN1 including promoter, exons and introns in a large MEN1 cohort and determine the mutation profile. Methods and patients: A target next-generation sequencing (tNGS) assay comprising 7.2 kb of the full MEN1 was developed to investigate germline mutations in 76 unrelated MEN1 probands (49 familial, 27 sporadic). tNGS results were validated by Sanger sequencing (SS), and multiplex ligation-dependent probe amplification (MLPA) assay was applied when no mutations were identifiable by both tNGS and SS. Results: Germline MEN1 variants were verified in coding region and splicing sites of 57/76 patients (74%) by both tNGS and SS (100% reproducibility). Thirty-eight different pathogenic or likely pathogenic variants were identified, including 13 new and six recurrent variants. Three large deletions were detected by MLPA only. No mutation was detected in 16 patients. In untranslated, regulatory or in deep intronic MEN1 regions of the 76 MEN1 cases, no point or short indel pathogenic variants were found in untranslated, although 33 benign/likely benign and three new VUS variants were detected. Conclusions: Our study documents that point or short indel mutations in non-coding regions of MEN1 are very rare events. Also, tNGS proved to be a highly effective technology for routine genetic MEN1 testing.
conferenceObject Clinical Features and Penetrance of Pheochromocytoma in a Large Family with a Germline TMEM127 Mutation(2014) LOURENCO, Delmar Muniz; TOLEDO, Rodrigo A.; SEKIYA, Tomoko; LUCON, Marmo; CASTRO, C. C.; BORTOLOTTO, L. A.; TOLEDO, Sergio P. A.; DAHIA, Patricia L.- Natural history, treatment, and long-term follow up of patients with multiple endocrine neoplasia type 2B: an international, multicentre, retrospective study(2019) CASTINETTI, Frederic; WAGUESPACK, Steven G.; MACHENS, Andreas; UCHINO, Shinya; HASSE-LAZAR, Kornelia; SANSO, Gabriella; ELSE, Tobias; DVORAKOVA, Sarka; QI, Xiao Ping; ELISEI, Rossella; MAIA, Ana Luisa; GLOD, John; LOURENCO JR., Delmar Muniz; VALDES, Nuria; MATHIESEN, Jes; WOHLLK, Nelson; BANDGAR, Tushar R.; DRUI, Delphine; KORBONITS, Marta; DRUCE, Maralyn R.; BRAIN, Caroline; KURZAWINSKI, Tom; PATOCS, Atila; BUGALHO, Maria Joao; LACROIX, Andre; CARON, Philippe; FAINSTEIN-DAY, Patricia; CHAZOT, Francoise Borson; KLEIN, Marc; LINKS, Thera P.; LETIZIA, Claudio; FUGAZZOLA, Laura; CHABRE, Olivier; CANU, Letizia; COHEN, Regis; TABARIN, Antoine; UROIC, Anita Spehar; MAITER, Dominique; LABOUREAU, Sandrine; MIAN, Caterina; PECZKOWSKA, Mariola; SEBAG, Frederic; BRUE, Thierry; MIREBEAU-PRUNIER, Delphine; LECLERC, Laurence; BAUSCH, Birke; BERDELOU, Amandine; SUKURAI, Akihiro; VLCEK, Petr; KRAJEWSKA, Jolanta; BARONTINI, Marta; VARGAS, Carla Vaz Ferreira; VALERIO, Laura; CEOLIN, Lucieli; AKSHINTALA, Srivandana; HOFF, Ana; GODBALLE, Christian; JARZAB, Barbara; JIMENEZ, Camilo; ENG, Charis; IMAI, Tsuneo; SCHLUMBERGER, Martin; GRUBBS, Elizabeth; DRALLE, Henning; NEUMANN, Hartmut P.; BAUDIN, EricBackground Multiple endocrine neoplasia type 2B is a rare syndrome caused mainly by Met918Thr germline RET mutation, and characterised by medullary thyroid carcinoma, phaeochromocytoma, and extra-endocrine features. Data are scarce on the natural history of multiple endocrine neoplasia type 2B. We aimed to advance understanding of the phenotype and natural history of multiple endocrine neoplasia type 2B, to increase awareness and improve detection. Methods This study was a retrospective, multicentre, international study in patients carrying the Met918Thr RET variant with no age restrictions. The study was done with registry data from 48 centres globally. Data from patients followed-up from 1970 to 2016 were retrieved from May 1, 2016, to May 31, 2018. Our primary objectives were to determine overall survival, and medullary thyroid carcinoma-specific survival based on whether the patient had undergone early thyroidectomy before the age of 1 year. We also assessed remission of medullary thyroid carcinoma, incidence and treatment of phaeochromocytoma, and the penetrance of extra-endocrine features. Findings 345 patients were included, of whom 338 (98%) had a thyroidectomy. 71 patients (21%) of the total cohort died at a median age of 25 years (range <1-59). Thyroidectomy was done before the age of 1 year in 20 patients, which led to long-term remission (ie, undetectable calcitonin level) in 15 (83%) of 18 individuals (2 patients died of causes unrelated to medullary thyroid carcinoma). Medullary thyroid carcinoma-specific survival curves did not show any significant difference between patients who had thyroidectomy before or after 1 year (comparison of survival curves by log-rank test: p=0.2; hazard ratio 0.35; 95% CI 0.07-1.74). However, there was a significant difference in remission status between patients who underwent thyroidectomy before and after the age of 1 year (p<0.0001). There was a significant difference in remission status between patients who underwent thyroidectomy before and after the age of 1 year (p<0.0001). In the other 318 patients who underwent thyroidectomy after 1 year of age, biochemical and structural remission was obtained in 47 (15%) of 318 individuals. Bilateral phaeochromocytoma was diagnosed in 156 (50%) of 313 patients by 28 years of age. Adrenal-sparing surgery was done in 31 patients: three (10%) of 31 patients had long-term recurrence, while normal adrenal function was obtained in 16 (62%) patients. All patients with available data (n=287) had at least one extra-endocrine feature, including 106 (56%) of 190 patients showing marfanoid body habitus, mucosal neuromas, and gastrointestinal signs. Interpretation Thyroidectomy done at no later than 1 year of age is associated with a high probability of cure. The reality is that the majority of children with the syndrome will be diagnosed after this recommended age. Adrenal-sparing surgery is feasible in multiple endocrine neoplasia type 2B and affords a good chance for normal adrenal function. To improve the prognosis of such patients, it is imperative that every health-care provider be aware of the extra-endocrine signs and the natural history of this rare syndrome. The implications of this research include increasing awareness of the extra-endocrine symptoms and also recommendations for thyroidectomy before the age of 1 year.
conferenceObject Penetrance of TMEM127-related pheochromocytoma in a six-generation family(2014) TOLEDO, S. P. A.; LOURENCO JR., D. M.; SEKIYA, T.; LUCON, A. M.; BAENA, R. C.; CASTRO, C. C.; BORTOLOTTO, L. A.; ZERBINI, M. C. N.; SIQUEIRA, S. A. C.; TOLEDO, R. A.; DAHIA, P. L. M.- RET Y791F Variant Does Not Increase the Risk for Medullary Thyroid Carcinoma(2015) TOLEDO, Rodrigo A.; MACIEL, Rui M. B.; ERLIC, Zoran; LOURENCO JR., Delmar M.; CERUTTI, Janete M.; ENG, Charis; NEUMANN, Hartmut P.; TOLEDO, Sergio P.
- A differential diagnosis of inherited endocrine tumors and their tumor counterparts(2013) TOLEDO, Sergio P. A.; LOURENCO JR., Delmar M.; TOLEDO, Rodrigo A.Inherited endocrine tumors have been increasingly recognized in clinical practice, although some difficulties still exist in differentiating these conditions from their sporadic endocrine tumor counterparts. Here, we list the 12 main topics that could add helpful information and clues for performing an early differential diagnosis to distinguish between these conditions. The early diagnosis of patients with inherited endocrine tumors may be performed either clinically or by mutation analysis in at-risk individuals. Early detection usually has a large impact in tumor management, allowing preventive clinical or surgical therapy in most cases. Advice for the clinical and surgical management of inherited endocrine tumors is also discussed. In addition, recent clinical and genetic advances for 17 different forms of inherited endocrine tumors are briefly reviewed.
- Comprehensive assessment of the disputed RET Y791F variant shows no association with medullary thyroid carcinoma susceptibility(2015) TOLEDO, Rodrigo A.; HATAKANA, Roxanne; LOURENCO JR., Delmar M.; LINDSEY, Susan C.; CAMACHO, Cleber P.; ALMEIDA, Marcio; LIMA JR., Jose V.; SEKIYA, Tomoko; GARRALDA, Elena; NASLAVSKY, Michel S.; YAMAMOTO, Guilherme L.; LAZAR, Monize; MEIRELLES, Osorio; SOBREIRA, Tiago J. P.; LEBRAO, Maria Lucia; DUARTE, Yeda A. O.; BLANGERO, John; ZATZ, Mayana; CERUTTI, Janete M.; MACIEL, Rui M. B.; TOLEDO, Sergio P. A.Accurate interpretation of germline mutations of the rearranged during transfection (RET) proto-oncogene is vital for the proper recommendation of preventive thyroidectomy in medullary thyroid carcinoma (MTC)-prone carriers. To gain information regarding the most disputed variant of RET, ATA-A Y791F, we sequenced blood DNA samples from a cohort of 2904 cancer-free elderly individuals (1261 via Sanger sequencing and 1643 via whole-exome/genome sequencing). We also accessed the exome sequences of an additional 8069 individuals from non-cancer-related laboratories and public databanks as well as genetic results from the Catalogue of Somatic Mutations in Cancer (COSMIC) project. The mean allelic frequency observed in the controls was 0.0031, with higher occurrences in Central European populations (0.006/0.008). The prevalence of RET Y791F in the control databases was extremely high compared with the 40 known RET pathogenic mutations (P=0.00003), while no somatic occurrence has been reported in tumours. In this study, we report new, unrelated Brazilian individuals with germline RET Y791F-only: two tumour-free elderly controls; two individuals with sporadic MTC whose Y791F-carrying relatives did not show any evidence of tumours; and a 74-year-old phaeochromocytoma patient without MTC. Furthermore, we showed that the co-occurrence of Y791F with the strong RET C634Y mutation explains the aggressive MTC phenotypes observed in a large affected family that was initially reported as Y791F-only. Our literature review revealed that limited analyses have led to the misclassification of RET Y791F as a probable pathogenic variant and, consequently, to the occurrence of unnecessary thyroidectomies. The current study will have a substantial clinical influence, as it reveals, in a comprehensive manner, that RET Y791F only shows no association with MTC susceptibility.
- 65 YEARS OF THE DOUBLE HELIX Genetics informs precision practice in the diagnosis and management of pheochromocytoma(2018) NEUMANN, Hartmut P.; YOUNG JR., William F.; KRAUSS, Tobias; BAYLEY, Jean-Pierre; SCHIAVI, Francesca; OPOCHER, Giuseppe; BOEDEKER, Carsten C.; TIROSH, Amit; CASTINETTI, Frederic; RUF, Juri; BELTSEVICH, Dmitry; WALZ, Martin; GROEBEN, Harald-Thomas; DOBSCHUETZ, Ernst von; GIMM, Oliver; WOHLLK, Nelson; PFEIFER, Marija; LOURENCO JR., Delmar M.; PECZKOWSKA, Mariola; PATOCS, Attila; NGEOW, Joanne; MAKAY, Ozer; SHAH, Nalini S.; TISCHLER, Arthur; LEIJON, Helena; PENNELLI, Gianmaria; HERAS, Karina Villar Gomez de las; LINKS, Thera P.; BAUSCH, Birke; ENG, CharisAlthough the authors of the present review have contributed to genetic discoveries in the field of pheochromocytoma research, we can legitimately ask whether these advances have led to improvements in the diagnosis and management of patients with pheochromocytoma. The answer to this question is an emphatic Yes! In the field of molecular genetics, the well-established axiom that familial (genetic) pheochromocytoma represents 10% of all cases has been overturned, with >35% of cases now attributable to germline disease-causing mutations. Furthermore, genetic pheochromocytoma can now be grouped into five different clinical presentation types in the context of the ten known susceptibility genes for pheochromocytoma-associated syndromes. We now have the tools to diagnose patients with genetic pheochromocytoma, identify germline mutation carriers and to offer gene-informed medical management including enhanced surveillance and prevention. Clinically, we now treat an entire family of tumors of the paraganglia, with the exact phenotype varying by specific gene. In terms of detection and classification, simultaneous advances in biochemical detection and imaging localization have taken place, and the histopathology of the paraganglioma tumor family has been revised by immunohistochemical-genetic classification by gene-specific antibody immunohistochemistry. Treatment options have also been substantially enriched by the application of minimally invasive and adrenal-sparing surgery. Finally and most importantly, it is now widely recognized that patients with genetic pheochromocytoma/paraganglioma syndromes should be treated in specialized centers dedicated to the diagnosis, treatment and surveillance of this rare neoplasm.