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Arch. endocrinol. metab. (Online) ; 63(4): 369-375, July-Aug. 2019. tab, graf
Article in English | LILACS | ID: biblio-1019359


ABSTRACT Objective Paraganglioma (PGL) and pheochromocytoma (PCC) are rare neuroendocrine tumors that were considered to be predominantly sporadic. However, with the identification of novel susceptibility genes over the last decade, it is currently estimated that up to 40% of cases can occur in the context of a hereditary syndrome. We aimed to characterize PGL/PCC families to exemplify the different scenarios in which hereditary syndromes can be suspected and to emphasize the importance for patients and their families of making an opportune genetic diagnosis. Materials and methods Retrospective analysis of patients diagnosed with PGL/PCC. Germline mutations were studied using next-generation sequencing panels including SDHA, SDHB, SDHC and SDHD. Clinical data were collected from clinical records, and all patients received genetic counseling. Results We describe 4 families with PGL/PCC and germline mutations in SDH complex genes. 2 families have SDHB mutations and 2 SDHD mutations. The clinical presentation of the patients and their families was heterogeneous, with some being atypical according to the literature. Conclusions PGL/PCC are more commonly associated with a germline mutation than any other cancer type, therefore, all individuals with these types of tumors should undergo genetic risk evaluation. NGS multigene panel testing is a cost-effective approach given the overlapping phenotypes. Individuals with germline mutations associated with PGL/PCC should undergo lifelong clinical, biochemical and imaging surveillance and their families should undergo genetic counseling. For all these reasons, it is critical that all medical staff can suspect and diagnose these inherited cancer predisposition syndromes.

Humans , Male , Female , Paraganglioma/genetics , Pheochromocytoma/genetics , Adrenal Gland Neoplasms/genetics , Germ-Line Mutation/genetics , Pedigree , Genetic Testing/methods , Retrospective Studies , Sentinel Surveillance , Genetic Predisposition to Disease
Arch. endocrinol. metab. (Online) ; 62(6): 623-635, Dec. 2018. tab, graf
Article in English | LILACS | ID: biblio-983814


ABSTRACT Objective: Initial diagnosis of medullary thyroid carcinoma (MTC) is frequently associated with advanced stages and a poor prognosis. Thus, the need for earlier diagnoses and detection in relatives at risk for the disease has led to increased use of RET genetic screening. Subjects and methods: We performed RET screening in 247 subjects who were referred to the Brazilian Research Consortium for Multiple Endocrine Neoplasia (BRASMEN) Center in the State of Ceará. Direct genetic sequencing was used to analyze exons 8, 10, 11, and 13-16 in MTC index cases and specific exons in at risk relatives. Afterward, clinical follow-up was offered to all the patients with MTC and their affected relatives. Results: RET screening was performed in 60 MTC index patients and 187 at-risk family members. At the initial clinical assessment of the index patients, 54 (90%) were diagnosed with apparently sporadic disease and 6 (10%) diagnosed with hereditary disease. After RET screening, we found that 31 (52%) index patients had sporadic disease, and 29 (48%) had hereditary disease. Regarding at-risk relatives, 73/187 were mutation carriers. Mutations in RET codon 804 and the rare p.M918V mutation were the most prevalent. Conclusions: Performing RET screening in Ceará allowed us to identify a different mutation profile in this region compared with other areas. RET screening also enabled the diagnosis of a significant number of hereditary MTC patients who were initially classified as sporadic disease patients and benefited their relatives, who were unaware of the risks and the consequences of bearing a RET mutation.

Humans , Male , Female , Adolescent , Adult , Middle Aged , Aged , Aged, 80 and over , Young Adult , Thyroid Neoplasms/diagnosis , Thyroid Neoplasms/genetics , Germ-Line Mutation/genetics , Carcinoma, Neuroendocrine/diagnosis , Carcinoma, Neuroendocrine/genetics , Proto-Oncogene Proteins c-ret/genetics , Genetic Carrier Screening/methods , Time Factors , Brazil , Thyroid Neoplasms/pathology , Immunohistochemistry , Transfection/methods , Gene Rearrangement/genetics , Reproducibility of Results , Risk Factors , Age Factors , Carcinoma, Neuroendocrine/pathology , Risk Assessment , Early Detection of Cancer , Genetic Association Studies
J. pediatr. (Rio J.) ; 94(4): 432-439, July-Aug. 2018. tab, graf
Article in English | LILACS | ID: biblio-954624


Abstract Objective: To evaluate the clinical features associated with adrenocortical hormone overexpression and familial cancer profiling as potential markers for early detection of adrenocortical tumors in children from South and Southeast Brazil. Methods: The clinical manifestations and anthropometric measurements of 103 children diagnosed with adrenocortical tumors were analyzed. Results: Between 1982 and 2011, 69 girls and 34 boys diagnosed with adrenocortical tumors were followed-up for a median time of 9.0 years (0-34 years). Signs of androgen overproduction alone (n = 75) or associated with cortisol (n = 18) were present in 90.3%. TP53 p.R337H mutation was found in 90.5% of patients. Stages I, II, III, and IV were observed in 45.6%, 27.2%, 19.4%, and 7.8% of patients, respectively. At diagnosis, there were no significant differences in height (p = 0.92) and weight (p = 0.22) among children with adrenocortical tumors, but children with virilization alone had significantly higher height-for-age Z-scores (0.92 ± 1.4) than children with hypercortisolism alone or combined (−0.32 ± 1,8; p = 0.03). The five-year overall survival was 76.7% (SD ± 4.2). Patients with advanced-stage disease had a significantly worse prognosis than those with limited disease (p < 0.001). During follow-up, ten of 55 p.R337H carrier parents developed cancer, whereas none of the 55 non-carriers did. Conclusions: Signs of adrenocortical hormone overproduction appear early, even in cases with early-stage. These signs can be identified at the physical examination and anthropometric measurements. In southern Brazil, pediatric adrenocortical tumor is a sentinel cancer for detecting families with germline p.R337H mutation in TP53 gene.

Resumo Objetivo: Avaliar as manifestações clínicas da hiperexpressão de hormônios do córtex da adrenal e câncer familiar como marcadores para a detecção precoce de tumores adrenocorticais em crianças do Sul e Sudeste do Brasil. Pacientes e métodos: Foram analisadas as manifestações clínicas e antropométricas de 103 crianças diagnosticadas com tumores adrenocorticais. Resultados: Entre 1982 e 2011, 69 meninas e 34 meninos diagnosticados com tumores adrenocorticais foram acompanhados por um tempo mediano de nove anos (0-34). Ao diagnóstico, sinais de virilização isolada (n = 75) ou associada ao cortisol (n = 18) estavam presentes em 90,3% dos pacientes; a mutação do gene TP53 p.R337H foi identificada em 90,5% dos pacientes. Os pacientes foram classificados em estádio I (45,6%), II (27,2%), III (19,4%) e IV (7,8%). Ao diagnóstico, não houve diferença significativa para as medidas de altura (p = 0,92) e de peso (p = 0,22) entre as crianças com tumores adrenocorticais, mas crianças com virilização tiveram escore-Z mais elevado para a idade (0,92 ± 1,4) do que aquelas com hipercortisolismo isolado ou combinado (−0,32 ± 1,8; p = 0,03). A sobrevida global de cinco anos foi de 76,7% (DP ± 4,2). Pacientes com estádios avançados tiveram pior prognóstico (p < 0,001). Durante o seguimento, 10 dos 55 genitores portadores da p.R337H desenvolveram câncer, enquanto que nenhum caso ocorreu entre os 55 não portadores. Conclusões: Os sinais de hiperprodução de hormônios adrenocorticais aparecem precocemente no desenvolvimento do tumor e podem ser identificados pelo exame físico e pelas medidas antropométricas na consulta pediátrica de rotina. O tumor adrenocortical pediátrico é sentinela para a detecção de câncer em famílias que segregam a mutação germinativa p.R337H do gene TP53.

Humans , Male , Female , Infant , Child, Preschool , Child , Genes, p53/genetics , Tumor Suppressor Protein p53/genetics , Adrenal Cortex Neoplasms/diagnosis , Adrenal Cortex Neoplasms/genetics , Germ-Line Mutation/genetics , Genetic Predisposition to Disease/genetics , Pedigree , Longitudinal Studies , Neoplasm Staging
Rev. cuba. hematol. inmunol. hemoter ; 34(2): 116-124, abr.-jun. 2018.
Article in Spanish | LILACS, CUMED | ID: biblio-978417


La predisposición de algunas familias a padecer hemopatías mieloides malignas ha sido descrita desde hace varias décadas; sin embargo, solo recientemente ha sido posible conocer las bases moleculares de estos síndromes. La importancia de reconocer y diagnosticar la presencia de mutaciones predisponentes de la línea germinal en pacientes con hemopatías malignas y en sus familiares determinó que la Organización Mundial de la Salud (OMS) introdujera esta nueva categoría en su última revisión de la clasificación de las neoplasias malignas y leucemias agudas. Mediante el uso de las modernas técnicas de biología molecular se ha logrado el descubrimiento de mutaciones en diferentes genes que aportan nuevos elementos en el proceso de leucemogénesis, permiten ofrecer consejo genético, una mejor selección del donante de médula ósea y se erigen en la fuente de futuras dianas terapéuticas. En este trabajo se revisan algunos de los síndromes de hemopatías mieloides malignas hereditarias (HMMH) y se enfatiza en la necesidad de realizar una exhaustiva historia clínica personal y familiar que permita un elevado índice de sospecha para el diagnóstico de estas entidades(AU)

The familial predisposition to inherited myeloid malignancies has been described since several decades ago; however, only recently have been possible to known the molecular basis of these syndromes. The importance to recognize and diagnosed predisposing germ line mutations in patients and relatives contributed to the introduction of this new category in the latest update of myeloid neoplasm and acute leukemia by World Health Organization (WHO). The use of modern molecular biology techniques has achieved the discovery of genetic mutations that shed light inside leukemogenesis process, allow offering a genetic counseling, a better donor selection and are the basis of future therapeutics targets. The main hereditary myeloid malignancy syndromes (IMMS) are reviewed, emphasizing the need of exhaustive personal and family clinical history and to have a high suspicion index to diagnose these entities(AU)

Humans , Hematopoietic Stem Cell Transplantation/methods , Hematologic Neoplasms/diagnosis , Hematologic Neoplasms/genetics , Medical Records/standards , Germ-Line Mutation/genetics
Braz. j. med. biol. res ; 51(9): e7427, 2018. tab, graf
Article in English | LILACS | ID: biblio-951761


Genetic and functional aberrations of guanine nucleotide-binding protein, alpha stimulating (GNAS), aryl hydrocarbon receptor interacting protein (AIP), and pituitary tumor transforming gene (PTTG) are among the most prominent events in pituitary tumorigenesis. A cohort of Brazilian patients with somatotropinomas (n=41) and non-functioning pituitary adenomas (NFPA, n=21) from a single tertiary-referral center were evaluated for GNAS and AIP mutations and gene expression of AIP and PTTG. Results were compared to the clinical and biological (Ki67 and p53 expression) characteristics of tumors and their response to therapy, if applicable. Genetic analysis revealed that 27% of somatotropinomas and 4.8% of NFPA harbored GNAS mutations (P=0.05). However, no differences were observed in clinical characteristics, tumor extension, response to somatostatin analog therapy, hormonal/surgical remission rates, Ki67 index, and p53 expression between mutated and non-mutated somatotropinomas patients. PTTG overexpression (RQ mean=10.6, min=4.39, max=11.9) and AIP underexpression (RQ mean=0.56, min=0.46-max=0.92) were found in virtually all cases without a statistically significant relationship with clinical and biological tumor features. No patients exhibited somatic or germline pathogenic AIP mutations. In conclusion, mutations in GNAS and abnormal PTTG and AIP expression had no impact on tumor features and treatment outcomes in this cohort. Our data support some previous studies and point to the need for further investigations, probably involving epigenetic and transcriptome analysis, to improve our understanding of pituitary tumor behavior.

Humans , Male , Female , Adult , Middle Aged , Pituitary Neoplasms/genetics , Adenoma/genetics , Germ-Line Mutation/genetics , Growth Hormone-Secreting Pituitary Adenoma/genetics , Pituitary Gland/pathology , Pituitary Neoplasms/pathology , Brazil , DNA, Neoplasm , Genetic Markers , Adenoma/pathology , Cell Transformation, Neoplastic , Cohort Studies , Intracellular Signaling Peptides and Proteins , Growth Hormone-Secreting Pituitary Adenoma/pathology , Carcinogenesis
Rev. saúde pública (Online) ; 52: 94, 2018. tab, graf
Article in English | LILACS | ID: biblio-979019


ABSTRACT OBJECTIVE: To analyze the cost effectiveness of the diagnostic program for the germline mutation in BRCA1/2 genes and of preventative strategies for the relatives of patients diagnosed with ovarian cancer associated with this mutation. METHODS: The study analyzed the cost effectiveness by developing an analysis of the Markov decision process from the perspective of the National Health System. The strategies compared reflect upon the adoption of genetic testing and preventative strategies for relatives or the usual care currently proposed. The incremental cost-effectiveness ratio was expressed in terms of cost per case avoided. The sensitivity analysis was performed in a univariate and deterministic manner. RESULTS: The study showed increments for effectiveness and for costs when performing genetic testing and adopting prophylactic measures for family members. The incremental cost-effectiveness ratio was estimated at R$908.58 per case of cancer avoided, a figure considered lower than the study's cost-effectiveness threshold (R$7,543.50). CONCLUSIONS: The program analyzed should be considered a cost-effective strategy for the national situation. Studies in various other countries have reached similar conclusions. One possible ramification of this research might the need to perform a budgetary-impact analysis of making the program one of the country's health policies.

Humans , Female , Adolescent , Adult , Ovarian Neoplasms/genetics , Ovarian Neoplasms/prevention & control , Program Evaluation/economics , Germ-Line Mutation/genetics , Genes, BRCA1 , Genes, BRCA2 , Ovarian Neoplasms/economics , Reference Values , Brazil , Breast Neoplasms/genetics , Genetic Testing/economics , Reproducibility of Results , Risk Factors , Markov Chains , Cost-Benefit Analysis , Middle Aged
Arch. endocrinol. metab. (Online) ; 61(5): 490-500, Sept.-Oct. 2017. tab, graf
Article in English | LILACS | ID: biblio-887599


ABSTRACT Phaeochromocytoma and paraganglioma are rare catecholamine-producing tumours, recognised to have one of the richest hereditary backgrounds of all neoplasms, with germline mutations seen in approximately 30% of patients. They can be a part of genetic syndromes such as MEN 2 or Neurofibromatosis type 1, or can be found as apparently sporadic tumours. Germline mutations are almost always found in syndromic patients. Nonetheless, apparently sporadic phaeochromocytoma too show high germline mutation rates. Early detection of a genetic mutation can lead to early diagnosis of further tumours via surveillance, early treatment and better prognosis. Apart from this, the genetic profile has important relevance for tumour location and biochemical profile, and can be a useful predictor of future tumour behaviour. It also enables family screening and surveillance. Moreover, recent studies have demonstrated significant driver somatic mutations in up to 75% of all tumours. Arch Endocrinol Metab. 2017;61(5):490-500

Humans , Paraganglioma/genetics , Pheochromocytoma/genetics , Adrenal Gland Neoplasms/genetics , Germ-Line Mutation/genetics
J. coloproctol. (Rio J., Impr.) ; 37(3): 174-178, July-Sept. 2017.
Article in English | LILACS | ID: biblio-893994


Abstract Background Risk assessment for Lynch Syndrome may be a complex and challenging task. Demonstration of germline mutations has the benefits of confirming Lynch Syndrome diagnosis and may also provide screening and surgical orientation for affected members and relief for non-affected relatives. Objective The present paper aimed to critically review the criteria to diagnose Lynch Syndrome, focusing the attention on the new perspective of adopting universal screening for patients diagnosed with colorectal cancer. Methods We performed a literature review about the rationale and preliminary results of universal testing for Lynch Syndrome. Results The use of selective eligibility criteria to determine who should undergo Lynch Syndrome testing may fail in a substantial proportion of cases. Moreover, universal strategy is feasible, cost-effective and more sensitive than previous methods. However, there still exist problems regarding clinical practice implementation and compliance either by medical doctors and patients. Conclusions Standard guidelines for colorectal cancer screening are not ideal to provide early detection of Lynch Syndrome patients. And although universal screening has been associated with an increased identification of Lynch Syndrome patients, a successful implementation of this approach is still limited by the lack of clinical expertise among physicians, and also requires standardization of the existing protocols for routine genetic screening.

Resumo Introdução A avaliação de risco para síndrome de Lynch (SL) pode ser tarefa complexa e desafiadora. A demonstração de mutações na linha germinal resulta em benefícios, como a confirmação do diagnóstico de SL e também pode proporcionar orientações para a triagem e procedimentos cirúrgicos para os membros afetados, além de trazer alívio para os parentes não afetados. Objetivo Este artigo teve por objetivo oferecer uma revisão crítica dos critérios para o diagnóstico de SL, com enfoque na atenção sobre a nova perspectiva de adoção da triagem universal para pacientes diagnosticados com câncer colorretal (CCR). Métodos Procedemos a uma revisão da literatura com ênfase nas justificativas e resultados preliminares de testes universais para SL. Resultados O uso de critérios seletivos de qualificação, com vistas a determinar quem deveria passar por um teste para SL, pode ser malsucedido em substancial percentual de casos. Foi também constatado que a estratégia universal é exequível, com bom custo-benefício e com maior sensibilidade, em comparação com os métodos previamente utilizados. Contudo, ainda existem problemas concernentes à sua implementação na prática clínica e também na cooperação de médicos e de pacientes. Conclusões As orientações padronizadas para a triagem de CCR não são ideais, em termos de se obter a imediata detecção de pacientes com SL. Por outro lado, embora a triagem universal tenha sido associada a um aumento na identificação de pacientes com SL, a bem-sucedida implementação dessa abordagem fica ainda limitada pela pouca experiência clínica entre os médicos e, além disso, também há a necessidade de padronização dos protocolos existentes para a triagem genética de rotina.

Humans , Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis , Germ-Line Mutation/genetics , Colorectal Neoplasms/diagnosis , Mass Screening , Risk Assessment
Rev. latinoam. enferm ; 23(2): 259-266, Feb-Apr/2015. tab, graf
Article in English | LILACS, BDENF | ID: lil-747163


OBJECTIVE: to assess the clinical effect of topical treatment using Ulmo honey associated with oral ascorbic acid in patients with venous ulcers. METHOD: longitudinal and descriptive quantitative study. During one year, 18 patients were assessed who were clinically diagnosed with venous ulcer in different stages, male and female, adult, with a mean injury time of 13 months. Ulmo honey was topically applied daily. The dressing was applied in accordance with the technical standard for advanced dressings, combined with the daily oral consumptions of 500 mg of ascorbic acid. The monitoring instrument is the assessment table of venous ulcers. RESULTS: full healing was achieved in 100% of the venous ulcers. No signs of complications were observed, such as allergies or infection. CONCLUSION: the proposed treatment showed excellent clinical results for the healing of venous ulcers. The honey demonstrated debriding and non-adherent properties, was easy to apply and remove and was well accepted by the users. The described results generated a research line on chronic wound treatment. .

OBJETIVO: avaliar o efeito clínico de tratamento tópico com mel de Ulmo associado à administração oral de ácido ascórbico em pacientes portadores de úlceras venosas. MÉTODO: estudo quantitativo descritivo longitudinal. Um total de 18 pacientes adultos, ambos os sexos, clinicamente diagnosticados com úlcera venosa em diferentes estágios e com duração de 13 meses em média, foram avaliados pelo período de um ano. A aplicação tópica diária de mel de Ulmo foi realizada de acordo com a norma técnica de tratamento avançado combinada com o consumo diário de 500 mg de ácido ascórbico. O instrumento usado para monitoramento foi a tabela de avaliação de úlceras venosas. RESULTADOS: cicatrização completa foi observada em 100% das úlceras venosas. Não foram observados sinais de complicação tais como alergias ou infecção. CONCLUSÃO: o tratamento proposto apresentou resultados clínicos excelentes na cicatrização das úlceras venosas. Além de favorecer o debridamento, o mel não é aderente, é fácil de aplicar e remover, e é de fácil aceitação por parte dos usuários. Os resultados descritos geraram uma linha investigativa no tratamento de feridas crônicas. .

OBJETIVO: evaluar el efecto clínico del tratamiento con miel de Ulmo tópico asociado a ácido ascórbico oral en pacientes portadores de úlceras venosas. MÉTODO: estudio cuantitativo descriptivo longitudinal. Durante el período de un año se evaluaron 18 pacientes diagnosticados clínicamente de úlcera venosa en sus diferentes estadios, de ambos sexos, adultos, con 13 meses promedio de antigüedad de la lesión. Se realizó la aplicación tópica diaria de miel de Ulmo con curación según la norma técnica de curaciones avanzadas, combinada con el consumo oral diario de 500 mg de ácido ascórbico. El instrumento de seguimiento es la tabla de valoración de úlceras venosas. RESULTADOS: se logró la cicatrización total en el 100% de las úlceras venosas. No se observaron signos de complicación, tales como alergias o infección. CONCLUSIÓN: el tratamiento propuesto mostró excelentes resultados clínicos en la cicatrización de úlceras venosas, presentando la miel propiedades debridantes, no adherentes, fácil de aplicar, remover y aceptación del usuario. Los resultados descritos generaron una línea investigativa en el tratamiento de heridas crónicas. .

Humans , Female , Adult , Middle Aged , Aged , Young Adult , Antineoplastic Agents/pharmacology , Breast Neoplasms/etiology , Genetic Predisposition to Disease , Germ-Line Mutation/genetics , Pharmacogenetics , Polymorphism, Single Nucleotide/genetics , Biomarkers, Tumor/genetics , Breast Neoplasms/drug therapy , Breast Neoplasms/epidemiology , Case-Control Studies , /genetics , DNA, Neoplasm/genetics , Follow-Up Studies , Genome-Wide Association Study , Genotype , Membrane Transport Proteins/genetics , Methyltransferases/genetics , Polymerase Chain Reaction , Prognosis , Registries , Risk Factors , United States/epidemiology
Acta gastroenterol. latinoam ; 44(1): 9-15, 2014 Mar.
Article in Spanish | LILACS, BINACIS | ID: biblio-1157430


Gastrointestinal stromal tumors (GIST) are the most common mesenchymatous neoplasms of the human digestive tract. They locate preferentially in stomach, duodenum or small bowel. Usually sporadic, familial cases unrelated to neurofibromatosis may be due to germline mutations in KIT or PDGFRA. We describe the first Argentine family with GIST in which we found, diffuse cutaneous melanosis, lentiginosis, and dysphagia. Dysphagia was not observed in the four families previously described with the same mutation. Histopathology resulted consistent with GIST, and tumor immunohistochemistry was likewise positive for DOG-1, CD117 (KIT) and CD34. The search for germline mutations identified the KIT c.1697T > C (p.559V > A) substitution in exon 11. Treatment with imatinib is furnishing positive results.

Melanosis/genetics , Germ-Line Mutation/genetics , Proto-Oncogene Proteins c-kit/genetics , Deglutition Disorders/genetics , Gastrointestinal Stromal Tumors/genetics , Adolescent , Adult , Child , Female , Humans , Immunohistochemistry , Pedigree , Male , Melanosis/diagnosis , Middle Aged , Deglutition Disorders/diagnosis , Gastrointestinal Stromal Tumors/diagnosis
Arq. gastroenterol ; 49(4): 273-278, Oct.-Dec. 2012. graf, tab
Article in English | LILACS | ID: lil-660306


CONTEXT: CHEK2 encodes a cell cycle checkpoint kinase that plays an important role in the DNA damage repair pathway, activated mainly by ATM (Ataxia Telangiectasia Mutated) in response to double-stranded DNA breaks. A germline mutation in CHEK2, 1100delC, has been described as a low penetrance allele in a significant number of families with breast and colorectal cancer in certain countries and is also associated with increased risk of contralateral breast cancer in women previously affected by the disease. About 5%-10% of all breast and colorectal cancers are associated with hereditary predisposition and its recognition is of great importance for genetic counseling and cancer risk management. OBJECTIVES: Here, we have assessed the frequency of the CHEK2 1100delC mutation in the germline of 59 unrelated Brazilian individuals with clinical criteria for the hereditary breast and colorectal cancer syndrome. METHODS: A long-range PCR strategy followed by gene sequencing was used. RESULTS: The 1100delC mutation was encountered in the germline of one (1.7%) individual in this high risk cohort. This indicates that the CHEK2 1100delC is not commonly encountered in Brazilian families with multiple diagnoses of breast and colorectal cancer. CONCLUSION: These results should be confirmed in a larger series of families and further testing should be undertaken to investigate the molecular mechanisms underlying the hereditary breast and colorectal cancer phenotype.

INTRODUÇÃO: CHEK2 codifica uma proteína quinase envolvida em um ponto de checagem do ciclo celular que desempenha um papel importante na via de reparação do DNA, danos ativados principalmente por ATM (Ataxia Telangiectasia Mutado) em resposta a danos na dupla hélice do DNA. A mutação germinativa 1100delC no gene CHEK2 tem sido descrita como um alelo de baixa penetrância em um número significativo de famílias com câncer de mama e cólon em certos países e também está associada com risco aumentado de câncer de mama contralateral em mulheres previamente afetadas pela doença. Cerca de 5%-10% de todos os cânceres de mama e colorretais estão associados a predisposição hereditária e o seu reconhecimento é de grande importância para o aconselhamento genético e gestão do risco de câncer. OBJETIVOS: Neste estudo foi avaliada a frequência da mutação germinativa 1100delC no gene CHEK2 em 59 diferentes indivíduos brasileiros com critérios clínicos para a síndrome de câncer de mama e cólon hereditários. MÉTODO: Utilizamos como estratégia a realização do PCR de longo alcance seguido de sequenciamento. RESULTADOS: A mutação 1100delC foi encontrada em um indivíduo (1,7%), indicando que esta mutação germinativa não é comumente encontrada em famílias brasileiras com múltiplos diagnósticos de câncer de mama e câncer colorretal. CONCLUSÃO: Estes resultados devem ser confirmados em uma série maior de famílias, e estudos adicionais devem ser realizados para investigar a patologia molecular do fenótipo HBCC.

Female , Humans , Male , Middle Aged , Breast Neoplasms/genetics , Colonic Neoplasms/genetics , Germ-Line Mutation/genetics , Protein-Serine-Threonine Kinases/genetics , Brazil , Genetic Predisposition to Disease , Genotype , Pedigree , Phenotype , Polymerase Chain Reaction
Rev. méd. Chile ; 140(11): 1457-1463, nov. 2012. ilus
Article in Spanish | LILACS | ID: lil-674014


Recently, MUTYH mutations have been reported to predispose to the development of polyposis. However, polyposis caused by mutations in MUTYH has been characterized as an autosomal recessive hereditary disease, different from the autosomal dominant pattern observed in polyposis caused by APC mutations. We report a 41-year-old female consulting for anemia. Colonoscopy detected multiple sessile polyps and a cecal carcinoma. The patient was operated and in the surgical piece, the tumor invaded serosa and there was lymph node involvement. Approximately 100 polyps were found. The patient received 5-fluorouracil, as adjuvant therapy. The patient had a sister (of a total of 12 brothers) with a colorectal carcinoma. The genetic study identified a homozygous mutation of the MUTYH gene, called c.340T > C, that produces an amino acid change of tyrosine for histidine called p.Y114H. The sister with colorectal cancer was a heterozygous carrier of this mutation.

Adult , Female , Humans , Adenomatous Polyposis Coli/genetics , DNA Glycosylases/genetics , Germ-Line Mutation/genetics , Genetic Predisposition to Disease/etiology , Homozygote , Pedigree , Polymerase Chain Reaction
Arq. bras. endocrinol. metab ; 56(3): 184-189, Apr. 2012. ilus, tab
Article in English | LILACS | ID: lil-626270


OBJECTIVE: This study aimed at identifing mutations in two Chinese genealogies with MEN1. SUBJECTS AND METHODS: Three members of two Chinese families with MEN1 were enrolled in this study, and all of the coding regions and adjacent sequences of the MEN1 gene were amplified and sequenced. RESULTS: A recurrent mutation of heterozygous change T>A at IVS 4+1 was found in family I, and a novel insGAGGTGG mutation (c.703-709dup7bp) resulted in a frameshift (p.A237Gfsx13) in family II. CONCLUSION: We are able to add a new mutation of MEN1 gene in Chinese patients with MEN1 that will be useful for the diagnosis and treatment of the disease.

OBJETIVO: O objetivo deste estudo foi identificar as mutações em duas famílias chinesas com NEM1. SUJEITOS E MÉTODOS: Três membros das duas famílias chinesas foram estudados. Em todos eles, as regiões codificadoras e sequências adjacentes do gene MEN1 foram amplificadas e sequenciadas. RESULTADOS: Uma alteração heterozigota recorrente de T>A em IVS 4+1 foi encontrada na família I, e uma nova mutação insGAGGTGG (c.703-709dup7bp) levou a um frameshift (p.A237Gfsx13) na família II. CONCLUSÃO: Adicionou-se uma nova mutação ao gene MEN1 em pacientes chineses com diagnóstico de NEM1 que vai ser útil no diagnóstico e tratamento da doença.

Female , Humans , Germ-Line Mutation/genetics , Multiple Endocrine Neoplasia Type 1/genetics , Parathyroid Neoplasms/genetics , Point Mutation/genetics , Base Sequence , China , Pedigree
Biol. Res ; 45(2): 117-130, 2012. ilus, tab
Article in English | LILACS | ID: lil-648570


A sample of 58 familial breast cancer patients from Venezuela were screened for germline mutations in the coding sequences and exon-intron boundaries of BRCA1 (MIM no. 113705) and BRCA2 (MIM no. 600185) genes by using conformation-sensitive gel electrophoresis. Ashkenazi Jewish founder mutations were not found in any of the samples. We identified 6 (10.3%) and 4 (6.9%) patients carrying germline mutations in BRCA1 and BRCA2, respectively. Four pathogenic mutations were found in BRCA1, one is a novel mutation (c.951_952insA), while the other three had been previously reported (c.1129_1135insA, c.4603G>T and IVS20+1G>A). We also found 4 pathogenic mutations in BRCA2, two novel mutations (c.2732_2733insA and c.3870_3873delG) and two that have been already reported (c.3036_3039delACAA and c.6024_6025_delTA). In addition, 17 variants of unknown significance (6 BRCA1 variants and 11 BRCA2 variants), 5 BRCA2 variants with no clinical importance and 22 polymorphisms (12 in BRCA1 and10 in BRCA2) were also identified. This is the first genetic study on BRCA gene mutations conducted in breast cancer patients from Venezuela. The ethnicity of our population, as well as the heterogeneous and broad spectrum of BRCA genes mutations, must be considered to optimize genetic counseling and disease prevention in affected families.

Adult , Aged , Female , Humans , Middle Aged , Breast Neoplasms/genetics , Genes, BRCA1 , Genetic Predisposition to Disease/genetics , Germ-Line Mutation/genetics , Polymorphism, Genetic/genetics , Base Sequence , DNA Mutational Analysis , Molecular Sequence Data , Venezuela
Clinics ; 67(supl.1): 13-18, 2012. ilus, tab
Article in English | LILACS | ID: lil-623125


Multiple endocrine neoplasias are autosomal dominant disorders characterized by the occurrence of tumors in at least two endocrine glands. Two MEN syndromes have long been known and are well characterized: the MEN type 1 (MEN1) and type 2 (MEN2). These syndromes are caused by germline mutations in the MEN1 and RET genes, respectively, and have a different tumor spectrum. Recently, a variant of the MEN syndromes arose spontaneously in a rat colony and was named MENX. Affected animals consistently develop multiple endocrine tumors, with a spectrum that shares features with both MEN1 and MEN2 human syndromes. Genetic studies identified a germline mutation in the Cdkn1b gene, encoding the p27 cell cycle inhibitor, as the causative mutation for MENX. Capitalizing on these findings, heterozygous germline mutations in the human homologue, CDKN1B, were searched for and identified in patients with multiple endocrine tumors. As a consequence of this discovery, a novel human MEN syndrome, named MEN4, was recognized, which is caused by mutations in p27. Altogether, these studies identified Cdkn1b/CDKN1B as a novel tumor susceptibility gene for multiple endocrine tumors in both rats and humans. Here we review the characteristics of the MENX and MEN4 syndromes and we briefly address the main function of p27 and how they are affected by MENX/4-associated mutations.

Animals , Humans , Rats , Adrenal Gland Neoplasms/genetics , /genetics , Germ-Line Mutation/genetics , Mutation , Multiple Endocrine Neoplasia/genetics , Adrenal Gland Neoplasms/pathology , Adrenal Glands/pathology , Hyperplasia , Multiple Endocrine Neoplasia/classification , Multiple Endocrine Neoplasia/pathology
Clinics ; 67(supl.1): 33-36, 2012. ilus
Article in English | LILACS | ID: lil-623128


Medullary thyroid carcinoma currently accounts for 5-8% of all thyroid cancers. The clinical course of this disease varies from extremely indolent tumors that can go unchanged for years to an extremely aggressive variant that is associated with a high mortality rate. As many as 75% of all medullary thyroid carcinomas are sporadic, with an average age at presentation reported as 60 years, and the remaining 25% are hereditary with an earlier age of presentation, ranging from 20 to 40 years. Germline RET proto-oncogene mutations are the genetic causes of multiple endocrine neoplasia type 2 and a strong genotype-phenotype correlation exists, particularly between a specific RET codon mutation and the (a) age-related onset and (b) thyroid tumor progression, from C-cell hyperplasia to medullary thyroid carcinoma and, ultimately, to nodal metastases. RET mutations predispose an individual to the development of medullary thyroid carcinomas and can also influence the individual response to RET protein receptor-targeted therapies. RET codon 609point mutations are rare genetic events belonging to the intermediate risk category for the onset of medullary thyroid carcinoma. A large genealogy resulting in a less aggressive form of medullary thyroid carcinoma is associated with the high penetrance of pheochromocytoma and has been reported in the literature. In this short review article, we comment on our previous report of a large multiple endocrine neoplasia type 2A kindred with the same Cys609Ser germline RET mutation in which, conversely, the syndrome was characterized by a slightly aggressive, highly penetrant form of medullary thyroid carcinoma that was associated with low penetrance of pheochromocytoma and primary hyperparathyroidism.

Humans , Carcinoma, Medullary/genetics , Codon/genetics , Germ-Line Mutation/genetics , /genetics , Proto-Oncogene Proteins c-ret/genetics , Thyroid Neoplasms/genetics , Cysteine/genetics , Genetic Association Studies , Hyperparathyroidism/genetics , Italy , Pedigree , Serine/genetics
Clinics ; 67(supl.1): 43-48, 2012.
Article in English | LILACS | ID: lil-623130


We briefly review the characteristics of pituitary tumors associated with multiple endocrine neoplasia type 1. Multiple endocrine neoplasia type 1 is an autosomal-dominant disorder most commonly characterized by tumors of the pituitary, parathyroid, endocrine-gastrointestinal tract, and pancreas. A MEDLINE search for all available publications regarding multiple endocrine neoplasia type 1 and pituitary adenomas was undertaken. The prevalence of pituitary tumors in multiple endocrine neoplasia type 1 may vary from 10% to 60% depending on the studied series, and such tumors may occur as the first clinical manifestation of multiple endocrine neoplasia type 1 in 25% of sporadic and 10% of familial cases. Patients were younger and the time between initial and subsequent multiple endocrine neoplasia type 1 endocrine lesions was significantly longer when pituitary disease was the initial manifestation of multiple endocrine neoplasia type 1. Tumors were larger and more invasive and clinical manifestations related to the size of the pituitary adenoma were significantly more frequent in patients with multiple endocrine neoplasia type 1 than in subjects with non-multiple endocrine neoplasia type 1. Normalization of pituitary hypersecretion was much less frequent in patients with multiple endocrine neoplasia type 1 than in subjects with non-multiple endocrine neoplasia type 1. Pituitary tumors in patients with multiple endocrine neoplasia type 1 syndrome tend to be larger, invasive and more symptomatic, and they tend to occur in younger patients when they are the initial presentation of multiple endocrine neoplasia type 1.

Humans , Adenoma/genetics , Mutation , Multiple Endocrine Neoplasia Type 1/genetics , Pituitary Neoplasms/genetics , Adenoma/pathology , Genes, Neoplasm/genetics , Germ-Line Mutation/genetics , Multiple Endocrine Neoplasia Type 1/pathology , Pituitary Neoplasms/pathology , Syndrome
Clinics ; 67(supl.1): 49-56, 2012. ilus, tab
Article in English | LILACS | ID: lil-623131


Multiple endocrine neoplasia type 1 is an inherited endocrine tumor syndrome, predominantly characterized by tumors of the parathyroid glands, gastroenteropancreatic tumors, pituitary adenomas, adrenal adenomas, and neuroendocrine tumors of the thymus, lungs or stomach. Multiple endocrine neoplasia type 1 is caused by germline mutations of the multiple endocrine neoplasia type 1 tumor suppressor gene. The initial germline mutation, loss of the wild-type allele, and modifying genetic and possibly epigenetic and environmental events eventually result in multiple endocrine neoplasia type 1 tumors. Our understanding of the function of the multiple endocrine neoplasia type 1 gene product, menin, has increased significantly over the years. However, to date, no clear genotype-phenotype correlation has been established. In this review we discuss reports on exceptional clinical presentations of multiple endocrine neoplasia type 1, which may provide more insight into the pathogenesis of this disorder and offer clues for a possible genotype-phenotype correlation.

Humans , Adenoma/genetics , Genetic Association Studies , Germ-Line Mutation/genetics , Multiple Endocrine Neoplasia Type 1/genetics , Pituitary Neoplasms/genetics , Proto-Oncogene Proteins/metabolism , Adenoma/metabolism , Genetic Predisposition to Disease , Multiple Endocrine Neoplasia Type 1/metabolism , Pituitary Neoplasms/metabolism
Clinics ; 67(supl.1): 57-61, 2012. ilus, tab
Article in English | LILACS | ID: lil-623132


Hirschsprung disease is a congenital form of aganglionic megacolon that results from cristopathy. Hirschsprung disease usually occurs as a sporadic disease, although it may be associated with several inherited conditions, such as multiple endocrine neoplasia type 2. The rearranged during transfection (RET) proto-oncogene is the major susceptibility gene for Hirschsprung disease, and germline mutations in RET have been reported in up to 50% of the inherited forms of Hirschsprung disease and in 15-20% of sporadic cases of Hirschsprung disease. The prevalence of Hirschsprung disease in multiple endocrine neoplasia type 2 cases was recently determined to be 7.5% and the cooccurrence of Hirschsprung disease and multiple endocrine neoplasia type 2 has been reported in at least 22 families so far. It was initially thought that Hirschsprung disease could be due to disturbances in apoptosis or due to a tendency of the mutated RET receptor to be retained in the Golgi apparatus. Presently, there is strong evidence favoring the hypothesis that specific inactivating haplotypes play a key role in the fetal development of congenital megacolon/Hirschsprung disease. In the present study, we report the genetic findings in a novel family with multiple endocrine neoplasia type 2: a specific RET haplotype was documented in patients with Hirschsprung disease associated with medullary thyroid carcinoma, but it was absent in patients with only medullary thyroid carcinoma. Despite the limited number of cases, the present data favor the hypothesis that specific haplotypes not linked to RET germline mutations are the genetic causes of Hirschsprung disease.

Humans , Carcinoma, Medullary/genetics , Germ-Line Mutation/genetics , Haplotypes/genetics , Hirschsprung Disease/genetics , /genetics , Proto-Oncogene Proteins c-ret/genetics , Thyroid Neoplasms/genetics , Genotype , Mutation