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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- 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.
- 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.
- Penetrance and Clinical Features of Pheochromocytoma in a Six-Generation Family Carrying a Germline TMEM127 Mutation(2015) TOLEDO, Sergio P. A.; LOURENCO JR., Delmar M.; SEKIYA, Tomoko; LUCON, Antonio M.; BAENA, Marcos E. S.; CASTRO, Claudio C.; BORTOLOTTO, Luiz A.; ZERBINI, Maria C. N.; SIQUEIRA, Sheila A. C.; TOLEDO, Rodrigo A.; DAHIA, Patricia L. M.Context: The phenotype of familial pheochromocytoma (PHEO) associated with germline TMEM127 mutations (TMEM127-related PHEO) has not been clearly defined. Objective: This study aimed to investigate the penetrance, full phenotypic spectrum and effectiveness of clinical/genetic screening in TMEM127-related PHEO. Design, Setting, and Participants: Clinical and genetic screening, and genetic counseling were offered to 151 individuals from a six-generation family carrying a TMEM127 germline mutation in a referral center. Intervention and Main Outcome Measures: TMEM127 genetic testing was offered to at-risk relatives and clinical surveillance for pheochromocytoma was performed in mutation-positive carriers. Results: Forty seven individuals carried the c.410-2A>C TMEM127 mutation. Clinical data were obtained from 34 TMEM127-mutation carriers followed up for 8.7 +/- 8.1 years (range, 1-20 y). Pheochromocytoma was diagnosed in 11 carriers (32%) at a median age of 43 years. In nine patients, symptoms started at 29 years (range, 10-55 y) and two cases were asymptomatic. Tumors were multicentric in five (45%) and bilateral in five (45%) patients. Six patients (54%) had at least one adrenomedullary nodule less than 10 mm. No paragangliomas, distant metastases, or other manifestations were detected. Cumulative penetrance of pheochromocytoma was 0% at 0-20 years, 3% at 21-30 years, 15% at 31-40 years, 24% at 41-50 years, and 32% at 51-65 years. The youngest case was diagnosed at 22 years and the earliest symptoms were reported at age 10. Conclusions: Tumor multicentricity, nodular adrenomedullary hyperplasia, and the occurrence of symptoms more than a decade earlier than the age at diagnosis are novel findings in TMEM127-related PHEO. The high penetrance of pheochromocytoma in this condition validates the benefits of genetic testing of at-risk relatives. We thus recommend that TMEM127 genetic testing should be offered to at-risk individuals at age 22 years and mutation carriers should undergo clinical surveillance annually.
- RET Y791F: alone or accompanied?(2015) TOLEDO, Rodrigo A.; LOURECO JR., Delmar M.; CAMACHO, Cleber; LINDSEY, Susan; CERUTTI, Janete; MACIEL, Rui M. B.; TOLEDO, Sergio P. A.