RESUMO
PURPOSE: BRCA1 and BRCA2 genotyping results have clinical implications for cancer risk assessment and targeted therapy. Current practice in Israel is to genotype for the predominant BRCA1/2 mutations first, followed by full gene analysis in eligible mutation-negative individuals. This work assessed the rate of non-predominant mutations in BRCA1/2 in ethnically diverse high-risk cases. METHODS: Breast and/or ovarian cancer patients who tested negative for the predominant BRCA1/2 mutations were referred for comprehensive BRCA1/2 genotyping if calculated risk for carrying a BRCA mutation was ≥ 10%. RESULTS: Of 1258 eligible patients, 41 (3.3%) carried one of 38 mutations: 3% of Ashkenazi Jews and 3.4% of mixed ethnicities. Detection rate was < 5% among patients diagnosed with cancer younger than 40 or with bilateral breast cancer, and was 5.5% of ovarian cancer patients. Three of the carriers (7.3%) carried gene rearrangements. Three mutations were reported in more than one case. CONCLUSIONS: The overall yield of comprehensive BRCA1/2 testing in ethnically diverse high-risk Israeli individuals is 3.3%. This is lower than expected by probability models. A slightly higher rate of BRCA1/2 carriers was seen among ovarian cancer cases. These data should guide BRCA1/2 optimal testing strategy in Israel.
Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Predisposição Genética para Doença , Neoplasias Ovarianas/genética , Adulto , Idoso , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Feminino , Genótipo , Mutação em Linhagem Germinativa , Humanos , Israel/epidemiologia , Judeus/genética , Pessoa de Meia-Idade , Mutação , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/patologiaRESUMO
mRNA trafficking, which enables the localization of mRNAs to particular intracellular targets, occurs in a wide variety of cells. The importance of the resulting RNA distribution for cellular functions, however, has been difficult to assess. We have found that cofilin-1 mRNA is rapidly localized to the leading edge of human lung carcinoma cells and that VICKZ family RNA-binding proteins help mediate this localization through specific interactions with the 3'UTR of cofilin mRNA. Using a phagokinetic assay for cell motility, we have been able to quantify the effect of mRNA localization on the rescue of lung carcinoma cells in which cofilin was knocked down by using short hairpin RNA (shRNA). Although restoring cofilin protein to normal endogenous levels rescues general lamellipodia formation around the periphery of the cell, only when the rescuing cofilin mRNA can localize to the leading edge is it capable of also fully rescuing directed cell movement. These results demonstrate that localization of an mRNA can provide an additional level of regulation for the function of its protein product.