ABSTRACT
ANTECEDENTES: En los últimos 15 años, el carcinoma familiar de ovario, ha sido atribuido en su mayoría a mutaciones en BRCA 1 y 2. Sin embargo, aproximadamente el 25% de los nuevos casos se asocian a mutaciones aisladas de genes implicados en el mecanismo de reparación del ADN por recombinación homóloga. Mutaciones monoalélicas de RAD51 han sido identificadas en pacientes con historia de carcinoma mama y ovario, tamizaje negativo para BRCA 1 y 2, y por lo menos con un caso de carcinoma de ovario en el linaje. OBJETIVO: Describir las mutaciones en el complejo RAD51 con el fin de identificar su papel en el cáncer de ovario familiar. MÉTODO: Se realizó una búsqueda de la literatura en bases de datos de los últimos 10 años con los siguientes términos MeSH: "RAD51", "ovarian cancer" "ovarian neoplasm", "family ovarian cancer". RESULTADOS: Se encontró una prevalencia de la mutación en genes del complejo RAD51 que varía entre 0,2% y 2,5%, según la etnia estudiada, siendo una de las causas de tumores serosos de ovario de alto grado en mujeres entre los 57 y 60 años. CONCLUSIÓN: Mutaciones de RAD51 en pacientes negativas para mutaciones de BRCA 1 y 2, se asocian al síndrome familiar mama-ovario, con un aumento del riesgo para carcinoma de ovario, pero sin modificaciones para el carcinoma de mama.
BACKGROUND: In the last fifteen years, familiar ovarian carcinoma has been related to BRCA 1 and 2 mutations. However, 25% of new cases of ovarian neoplasm are explained by isolated genes involved in the mechanism of homologous recombination. Patients with family history of ovarian and breast carcinoma, negative for BRCA mutations and at least with one case of invasive ovarian carcinoma have been identify with monoallelic mutations in RAD51. OBJECTIVE: To describe mutations on RAD51 complex, in order to identify its role in familiar ovarian cancer. METHODOLOGY: A systematic review of the literature of the last ten years involving the main data bases and using the following MeSH terms: "RAD51", "ovarian cancer", "ovarian neoplasm", "family ovarian cancer". RESULTS: Prevalence reported for RAD51 mutation is between 0.2 and 2.5%, associated with the ethnicity of the population involved. Also is considered a cause for high grade serous ovarian carcinoma in women between 57 and 60 years old. RAD51C and RAD51D germ line mutations are related to ovarian-breast hereditary syndrome, in negative population for BRCA 1 and 2 mutations. CONCLUSION: Patients with RAD51 mutations, negative for BRCA mutation are associated with ovarian-breast cancer syndrome increasing the risk just for ovarian cancer.
Subject(s)
Humans , Female , Ovarian Neoplasms/genetics , Rad51 Recombinase/genetics , Family , Genetic Predisposition to Disease , MutationABSTRACT
GABA(A) receptor α5-selective inverse agonists enhance cognitive performance in pre-clinical species. However, a key aspect of the clinical development of such compounds is the demonstration that in man such compounds are devoid of the anxiogenic-like activity associated with non-selective inverse agonists such as FG 7142. The triazolophthalazine α5IA (3-(5-methylisoxazol-3-yl)-6-[(1-methyl-1,2,3-triazol-4-yl)methyloxy]-1,2,4-triazolo[3,4-a]phthalazine) is an α5-selective inverse agonist which enhances cognitive performance in rodents and encouragingly in human Phase I Safety and Tolerability studies it was devoid of the anxiogenic-like activity associated with FG 7142. However, in order to appropriately interpret this latter observation, it was considered important to demonstrate that the absence of anxiogenic-like activity occurs at significant levels of receptor occupancy. Consequently, the occupancy of human brain GABA(A) receptors was measured using [¹¹C]flumazenil positron emission tomography in three healthy normal young male volunteers following a single oral dose of 2 mg α5IA. One hour after dosing, mean occupancy levels were 53% and this fell to 16% by 8 h post-dose, with the plasma α5IA concentration corresponding to 50% occupancy being 10 ng/mL. These data clearly show that an α5-selective inverse agonist is not associated with anxiogenic-like side effects at doses that give ~50% occupancy.
