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
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- 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.
- Preventive medicine of von Hippel-Lindau disease-associated pancreatic neuroendocrine tumors(2018) KRAUSS, Tobias; FERRARA, Alfonso Massimiliano; LINKS, Thera P.; WELLNER, Ulrich; BANCOSS, Irina; KVACHENYUK, Andrey; HERAS, Karim Villar Gomez de las; YUKINA, Marina Y.; PETROV, Roman; BULLIVANT, Garrett; DUECKER, Laura von; JADHAV, Swati; PLOECKINGER, Ursula; WELIN, Staffan; SCHALIN-JANTTI, Camilla; GIMM, Oliver; PFEIFER, Marija; NGEOW, Joanne; HASSE-LAZAR, Kornelia; SANSO, Gabriela; QI, Xiaoping; UGURLU, M. Umit; DIAZ, Rene E.; WOHLLK, Nelson; PECZKOWSKA, Mariola; ABERLE, Jens; JR, Delmar M. Lourenco; PEREIRA, Maria A. A.; V, Maria C. B. Fragoso; HOFF, Ana O.; ALMEIDA, Madson Q.; VIOLANTE, Alice H. D.; OUIDUTE, Ana R. P.; ZHANG, Zhewei; RECASENS, Monica; DIAZ, Luis Robles; KUNAVISARUT, Tada; WANNACHALEE, Taweesak; SIRINVARAVONG, Sirinart; JONASCH, Eric; GROZINSKY-GLASBERG, Simona; FRAENKEL, Merav; BELTSEVICH, Dmitry; I, Viacheslav Egorov; BAUSCH, Dirk; SCHOTT, Matthias; TILING, Nikolaus; PENNELLI, Gianmaria; ZSCHIEDRICH, Stefan; DAERR, Roland; RUF, Juri; DENECKE, Timm; LINK, Karl-Heinrich; ZOVATO, Stefania; DOBSCHUETZ, Ernst von; YAREMCHUK, Svetlana; AMTHAUER, Holger; MAKAY, Ozer; PATOCS, Attila; WALZ, Martin K.; HUBER, Tobias B.; SEUFERT, Jochen; HELLMAN, Per; EKATERINA, Raymond H.; KUCHINSKAYA, Ekaterina; SCHIAVI, Francesca; MALINOC, Angelica; REISCH, Nicole; JARZAB, Barbara; BARONTINI, Marta; JANUSZEWICZ, Andrzej; SHAH, Nalini; YOUNG JR., William F.; OPOCHER, Giuseppe; ENG, Charis; NEUMANN, Hartmut P. H.; BAUSCH, BirkePancreatic neuroendocrine tumors (PanNETs) are rare in von Hippel-Lindau disease (VHL) but cause serious morbidity and mortality. Management guidelines for VHL-PanNETs continue to be based on limited evidence, and survival data to guide surgical management are lacking. We established the European-American-Asian-VHL-PanNET-Registry to assess data for risks for metastases, survival and long-term outcomes to provide best management recommendations. Of 2330 VHL patients, 273 had a total of 484 PanNETs. Median age at diagnosis of PanNET was 35 years (range 10-75). Fifty-five (20%) patients had metastatic PanNETs. Metastatic PanNETs were significantly larger (median size 5 vs 2 cm; P < 0.001) and tumor volume doubling time (TVDT) was faster (22 vs 126 months; P = 0.001). All metastatic tumors were >= 2.8 cm. Codons 161 and 167 were hotspots for VHL germline mutations with enhanced risk for metastatic PanNETs. Multivariate prediction modeling disclosed maximum tumor diameter and TVDT as significant predictors for metastatic disease (positive and negative predictive values of 51% and 100% for diameter cut-off >= 2.8 cm, 44% and 91% for TVDT cut-off of <= 24 months). In 117 of 273 patients, PanNETs > 1.5 cm in diameter were operated. Ten-year survival was significantly longer in operated vs non-operated patients, in particular for PanNETs < 2.8 cm vs >= 2.8 cm (94% vs 85% by 10 years; P = 0.020; 80% vs 50% at 10 years; P = 0.030). This study demonstrates that patients with PanNET approaching the cut-off diameter of 2.8 cm should be operated. Mutations in exon 3, especially of codons 161/167 are at enhanced risk for metastatic PanNETs. Survival is significantly longer in operated non-metastatic VHL-PanNETs.