Publications (2)13.44 Total impact
-
Article: BRCA2 Deep Intronic Mutation Causing Activation of a Cryptic Exon: Opening toward a New Preventive Therapeutic Strategy.
[show abstract] [hide abstract]
ABSTRACT: Diagnostic screening of the BRCA1/2 genes in breast cancer families is mostly done on genomic DNA. For families with a very strong family history and no mutation identified in the coding sequences or the exon-intron boundaries, BRCA1/2 transcripts' analysis is an efficient approach to uncover gene inversion and pre-mRNA splicing defaults missed by conventional DNA-based protocols. We analyzed RNA from patients of negative BRCA families by reverse transcriptase PCR and identified an insertion in one family that we characterized by sequencing and by using a minigene splicing assay. More than 2,000 additional BRCA1/2 negative families were subsequently screened for this mutation using a dedicated PCR approach. Nine families were found to harbor a BRCA2 mutant transcript containing a 95-nucleotide cryptic exon between exons 12 and 13. This cryptic exon results from a new mutation located deep into intron 12, c.6937+594T > G, which reinforces the strength of a preexisting 5' splice site, turning it into a perfect consensus sequence. It is systematically included in transcripts produced by the mutant allele in cells from mutation carriers or produced by a mutant splicing reporter minigene. The inclusion of the cryptic exon was prevented when we cotransfected the minigene with antisense oligonucleotides complementary to the 3' or mutated 5' splice sites. This first deep intronic BRCA mutation emphasizes the importance of analyzing RNA to provide comprehensive BRCA1/2 diagnostic tests and opens the possibility of using antisense therapy in the future as an alternative strategy for cancer prevention. Clin Cancer Res; 18(18); 4903-9. ©2012 AACR.Clinical Cancer Research 07/2012; 18(18):4903-9. · 7.74 Impact Factor -
Article: Acetyl-CoA carboxylase alpha gene and breast cancer susceptibility.
[show abstract] [hide abstract]
ABSTRACT: The identification of an interaction between BRCA1 and acetyl-CoA carboxylase alpha (ACCalpha), a key enzyme in lipid synthesis, led us to investigate the role of ACCalpha in breast cancer development, where it might contribute to the energy-sensing mechanisms of malignant transformation. In order to investigate if certain ACCalpha alleles may be high-risk breast cancer susceptibility alleles, 37 extended breast and breast/ovarian cancer families negative for BRCA1 and BRCA2 mutations were exhaustively screened for sequence variations in the entire coding sequence, intron-exon junctions, 5'UTR, 3'UTR (untranslated regions) and the promoter regions of the ACCalpha gene. Two possibly disease-associated ACCalpha variants were each identified in a single family and were not present in 137 controls. Multiple polymorphisms were detected in breast cancer families, including 12 single nucleotide polymorphisms where the frequency of the rare allele estimated in controls was >0.10. The observed lack of variation in the ACCalpha coding region along with the presence of extended areas of linkage disequilibrium and low haplotype diversity indicates an overall high preservation of this gene. The prevalence of the ACCalpha haplotypes composed of common polymorphisms was determined in 453 breast cancer cases and 469 female controls. One haplotype was found to be associated with a substantial and highly significant increase in breast cancer risk (odds ratio = 3.10, 95% confidence interval 1.87-5.14, P < 0.0001), whereas three other haplotypes were found to have a protective effect. Our results indicate that mutations in the ACCalpha gene are unlikely to be a major cause of high-risk breast cancer susceptibility; however, certain common ACCalpha alleles may influence breast cancer risk. This study provides the first insight into the involvement of the ACCalpha gene in breast cancer predisposition and calls for further, large-scale studies that will be needed to understand the role of ACCalpha in tumour susceptibility and development.Carcinogenesis 12/2004; 25(12):2417-24. · 5.70 Impact Factor
