title: Two novel variants in the 3'UTR of the BRCA1 gene in familial breast and/or ovarian cancer.
abstract: For the majority of breast and/or ovarian cancer patients tested for BRCA1/2 genes, mutation screening of the coding regions remains negative. MicroRNAs which negatively regulate mRNA translation by binding to 3' untranslated region (3'UTR) are implicated in cancer. Genetic changes in the 3'UTR of several genes were reported to be associated with higher susceptibility to particular tumor types. The aim of this study was to analyze the BRCA1 3'UTR in patients tested negative for BRCA1/2 deleterious mutations, in order to find variants implicated in the decrease of BRCA1 expression through modification of miRNA binding. Genotyping analyses were performed on genomic DNA of 70 BRCA negatives index cases, selected among patients with breast or ovarian cancer, less than 50 years old, with a strong family history. The co-occurrence of the identified variants with deleterious BRCA1 mutations was then determined in a control population of 210 patients. A luciferase gene reporter assay was used to investigate the impact of the variants on the BRCA1 gene expression. Two novel variants, c.*750A>G and c.*1286C>A, were identified in the 3'UTR of BRCA1 gene, in two patients. The former was found three times in the control population, whereas the latter was absent. The used functional assay did not reveal any effect on the luciferase expression. This study reveals a weak genomic variability in the 3'UTR of the BRCA1 gene. All together, the results led us to classify the variant c.*750A>G as probably neutral, the variant c.*1286C>A remaining unclassified.
authors.affiliation: Département de recherche clinique, Centre de lutte contre le Cancer François Baclesse, Avenue du Général Harris, 14000, Caen, France. s.lheureux@baclesse.fr
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Lheureux
authors.forename: Bernard
authors.initials: B
authors.lastname: Lambert
authors.forename: Sophie
authors.initials: S
authors.lastname: Krieger
authors.forename: Angelina
authors.initials: A
authors.lastname: Legros
authors.forename: Dominique
authors.initials: D
authors.lastname: Vaur
authors.forename: Christophe
authors.initials: C
authors.lastname: Denoyelle
authors.forename: Pascaline
authors.initials: P
authors.lastname: Berthet
authors.forename: Laurent
authors.initials: L
authors.lastname: Poulain
authors.forename: Agnès
authors.initials: A
authors.lastname: Hardouin
mesh_terms: D020413:3' Untranslated Regions; D000328:Adult; D001943:Breast Neoplasms / Q000235:genetics*; D005192:Family Health; D005260:Female; D017353:Gene Deletion; D019398:Genes, BRCA1; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics*; D016133:Polymerase Chain Reaction; D017422:Sequence Analysis, DNA
chemical_list: D020413:3' Untranslated Regions; D035683:MicroRNAs; D008156:Luciferases