MARIA ADELAIDE ALBERGARIA PEREIRA
Projetos de Pesquisa
Unidades Organizacionais
Instituto Central, Hospital das Clínicas, Faculdade de Medicina - Médico
5 resultados
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- Penetrance of Functioning and Nonfunctioning Pancreatic Neuroendocrine Tumors in Multiple Endocrine Neoplasia Type 1 in the Second Decade of Life(2014) GONCALVES, Tatiana D.; TOLEDO, Rodrigo A.; SEKIYA, Tomoko; MATUGUMA, Sergio E.; MALUF FILHO, Fauze; ROCHA, Manoel S.; SIQUEIRA, Sheila A. C.; GLEZER, Andrea; BRONSTEIN, Marcelo D.; PEREIRA, Maria A. A.; JUREIDINI, Ricardo; BACCHELLA, Telesforo; MACHADO, Marcel C. C.; TOLEDO, Sergio P. A.; LOURENCO JR., Delmar M.Context: Data are scarce on the penetrance of multiple endocrine neoplasia type 1 (MEN1)-related nonfunctioning pancreatic neuroendocrine tumors (NF-PETs) and insulinomas in young MEN1 patients. Apotential positive correlation between tumor size and malignancy (2-3 cm, 18%; >3 cm, 43%) has greatly influenced the management of MEN1 adults with NF-PETs. Objective: The aim of the study was to estimate the penetrance of NF-PETs, insulinomas, and gastrinomas in young MEN1 carriers. Design: The data were obtained from a screening program (1996-2012) involving 113 MEN1 patients in a tertiary academic reference center. Patients: Nineteen MEN1 patients (aged 12-20 y; 16 patients aged 15-20 y and 3 patients aged 12-14 y) were screened for NF-PETs, insulinomas, and gastrinomas. Methods: Magnetic resonance imaging/computed tomography and endoscopic ultrasound (EUS) were performed on 10 MEN1 carriers, magnetic resonance imaging/computed tomography was performed on five patients, and four other patients underwent an EUS. Results: The overall penetrance of PETs during the second decade of life was42%(8 of 19). All eight PET patients had NF-PETs, and half of those tumors were multicentric. One-fifth of the screened patients (21%; 4 of 19) harbored at least one large tumor (>2.0 cm). Insulinoma was detected in two NF-PET patients (11%) at the initial screening; gastrinoma was not present in any cases. Six of the 11 (54%) screened patients aged 15-20 years who underwent an EUS had NF-PETs. Potential false-positive EUS results were excluded based on EUS-guided biopsy results, the reproducibility of the NF-PET findings, or the observation of increased tumor size during follow-up. Distal pancreatectomy and the nodule enucleation of pancreatic head tumors were conducted on three patients with large tumors (>2.0 cm; T2N0M0) that were classified as grade 1 neuroendocrine tumors (Ki-67 < 2%). Conclusions: Our data demonstrated high penetrance of NF-PETs in 15- to 20-year-old MEN1 patients. The high percentage of the patients presenting consensus criteria for surgery for NF-PET alone or NF-PET/insulinoma suggests a potential benefit for the periodic surveillance of these tumors in this age group.
- Association between the p27 rs2066827 variant and tumor multiplicity in patients harboring MEN1 germline mutations(2014) LONGUINI, Viviane C.; LOURENCO JR., Delmar M.; SEKIYA, Tomoko; MEIRELLES, Osorio; GONCALVES, Tatiana D.; COUTINHO, Flavia L.; FRANCISCO, Guilherme; OSAKI, Luciana H.; CHAMMAS, Roger; ALVES, Venancio A. F.; SIQUEIRA, Sheila A. C.; SCHLESINGER, David; NASLAVSKY, Michel S.; ZATZ, Mayana; DUARTE, Yeda A. O.; LEBRAO, Maria Lucia; GAMA, Patricia; LEE, Misu; MOLATORE, Sara; PEREIRA, Maria Adelaide A.; JALLAD, Raquel S.; BRONSTEIN, Marcello D.; CUNHA-NETO, Malebranche B.; LIBERMAN, Bernardo; FRAGOSO, Maria Candida B. V.; TOLEDO, Sergio P. A.; PELLEGATA, Natalia S.; TOLEDO, Rodrigo A.Objective: To date, no evidence of robust genotype-phenotype correlation or disease modifiers for multiple endocrine neoplasia type 1 (MEN1) syndrome has been described, leaving the highly variable clinical presentation of patients unaccounted for. Design: As the CDKN1B (p27) gene causes MEN4 syndrome and it is transcriptionally regulated by the product of the MEN1 gene (menin), we sought to analyze whether p27 influences the phenotype of MEN1-mutated patients. The cohort consisted of 100 patients carrying germline MEN1 gene mutations and 855 population-matched control individuals. Methods: Genotyping of the coding p27 c.326T>G (V109G) variant was performed by sequencing and restriction site digestion, and the genotypes were associated with clinical parameters by calculating odds ratios (ORs) and their 95% CIs using logistic regression. Results: There were significant differences in p27 V109G allele frequencies between controls and MEN1-mutated patients (OR=2.55, P=0.019, CI=1.013-5.76). Among patients who are >= 30 years old carrying truncating MEN1 mutations, the T allele was strongly associated with susceptibility to tumors in multiple glands (three to four glands affected vs one to two glands affected; OR=18.33; P=0.002, CI=2.88-16.41). This finding remained significant after the Bonferroni's multiple testing correction, indicating a robust association. No correlations were observed with the development of MEN1-related tumors such as hyperparathyroidism, pituitary adenomas, and enteropancreatic and adrenocortical tumors. Conclusions: Our study suggests that the p27 tumor suppressor gene acts as a disease modifier for the MEN1 syndrome associated with MEN1 germline mutations. If confirmed in independent patient cohorts, this finding could facilitate the management of this clinically complex disease.
conferenceObject High Frequency of Subclinical Cushing's Syndrome in the Inherited Autosomal Dominant Primary Macronodular Adrenal Hyperplasia Due to ARMC5 Mutations(2014) ALENCAR, Guilherme Asmar; ALMEIDA, Madson Q.; LERARIO, Antonio Marcondes; RESENDE, Gabriela; NISHI, Mirian Yumie; PEREIRA, Maria Adelaide Albergaria; MENDONCA, Berenice B.; FRAGOSO, Maria Candida B. V.- ARMC5 Mutations Are a Frequent Cause of Primary Macronodular Adrenal Hyperplasia(2014) ALENCAR, Guilherme Asmar; LERARIO, Antonio Marcondes; NISHI, Mirian Yumie; MARIANI, Beatriz Marinho de Paula; ALMEIDA, Madson Queiroz; TREMBLAY, Johanne; HAMET, Pavel; BOURDEAU, Isabelle; ZERBINI, Maria Claudia Nogueira; PEREIRA, Maria Adelaide Albergaria; GOMES, Gilberto Carlos; ROCHA, Manoel de Souza; CHAMBO, Jose Luis; LACROIX, Andre; MENDONCA, Berenice Bilharinho; FRAGOSO, Maria Candida Barisson VillaresContext: Primary macronodular adrenal hyperplasia (PMAH) is a rare cause of Cushing's syndrome, usually characterized by functioning adrenal macronodules and increased cortisol production. Familial clustering of PMAH has been described, suggesting an inherited genetic cause for this condition. Objective: The aim of the present study was to identify the gene responsible for familial PMAH. Patients and Methods: Forty-seven individuals of a Brazilian family with PMAH were evaluated. A single-nucleotide polymorphism-based genome-wide linkage analysis followed by whole-exome sequencing were then performed in selected family members. Additionally, 29 other patients with PMAH and 125 randomly selected healthy individuals were studied to validate the genetic findings. Moreover, PMAH tissue was also analyzed through whole-exome sequencing, conventional sequencing, and microsatellite analysis. Results: A heterozygous germline variant in the ARMC5 gene (p.Leu365Pro) was identified by whole-exome sequencing in a candidate genomic region (16p11.2). Subsequently, the same variant was confirmed by conventional sequencing in all 16 affected family members. The variant was predicted to be damaging by in silico methods and was not found in available online databases or in the 125 selected healthy individuals. Seven additional ARMC5 variants were subsequently identified in 5 of 21 patients with apparently sporadic PMAH and in 2 of 3 families with the disease. Further molecular analysis identified a somatic mutational event in 4 patients whose adrenal tissue was available. Conclusions: Inherited autosomal dominant mutations in the ARMC5 gene are a frequent cause of PMAH. Biallelic inactivation of ARMC5 is consistent with its role as a potential tumor suppressor gene.
conferenceObject Inherited Autosomal Dominant Mutations in ARMC5 Gene a Frequent Cause of Primary Macronodular Adrenal Hyperplasia(2014) ALENCAR, Guilherme Asmar; LERARIO, Antonio M.; NISHI, Mirian Yumie; MARIANI, Beatriz M. P.; ALMEIDA, Madson Q.; TREMBLAY, Johanne; HAMET, Pavel; BOURDEAU, Isabelle; ZERBINI, Maria Claudia N.; PEREIRA, Maria Adelaide Albergaria; GOMES, Gilberto Carlos; ROCHA, Manoel Souza; CHAMBO, Jose Luiz; LACROIX, Andre; MENDONCA, Berenice B.; FRAGOSO, Maria Candida Barisson Villares