Effects of BRCA2 cis-regulation in normal breast and cancer risk amongst BRCA2 mutation carriers
Introduction: Cis-acting regulatory single nucleotide polymorphisms (SNPs) at specific loci may modulate penetrance of germline mutations at the same loci by introducing different levels of expression of the wild-type allele. We have previously reported that BRCA2 shows differential allelic expression and we hypothesize that the known variable penetrance of BRCA2 mutations might be associated with this mechanism. Methods: We combined haplotype analysis and differential allelic expression of BRCA2 in breast tissue to identify expression haplotypes and candidate cis-regulatory variants. These candidate variants underwent selection based on in silico predictions for regulatory potential and di…
The GATA3 X308_Splice breast cancer mutation is a hormone context-dependent oncogenic driver
AbstractAs the catalogue of oncogenic driver mutations is expanding, it is becoming clear that alterations in a given gene should not be lumped into one single class, since they might have different functions. The transcription factorGATA3is a paradigm of this. Here, we address the functions of the most commonGATA3mutation (X308_Splice) which generates a neoprotein that we designate as neoGATA3, associated with good patient prognosis. Based on extensive analyses of molecular and clinical data from approximately 3000 breast cancer patients, supported by mechanistic studiesin vitro, we show that neoGATA3 interferes with the transcriptional programs controlled by estrogen and progesterone rece…