Wang X.,Mayo Medical School |
Pankratz V.S.,Health science Research |
Fredericksen Z.,Health science Research |
Tarrell R.,Health science Research |
And 40 more authors.
Human Molecular Genetics | Year: 2010
Recent studies have identified single nucleotide polymorphisms (SNPs) that significantly modify breast cancer risk in BRCA1 and BRCA2 mutation carriers. Since these risk modifiers were originally identified as genetic risk factors for breast cancer in genome-wide association studies (GWASs), additional risk modifiers for BRCA1 and BRCA2 may be identified from promising signals discovered in breast cancer GWAS. A total of 350 SNPs identified as candidate breast cancer risk factors (P < 1 × 3 10-3) in two breast cancer GWAS studies were genotyped in 3451 BRCA1 and 2006 BRCA2 mutationcarriersfromninecenters. Associations with breast cancer risk were assessed using Cox models weighted for penetrance. Eight SNPs in BRCA1 carriers and 12 SNPs in BRCA2 carriers, representing an enrichment over the number expected, were significantly associated with breast cancer risk (Ptrend < 0.01). The minor alleles of rs6138178 in SNRPB and rs6602595 in CAMK1D displayed the strongest associations in BRCA1 carriers (HR 5 0.78, 95% CI: 0.69-0.90, Ptrend = 3.6 × 10-4 and HR 5 1.25, 95% CI: 1.10-1.41, Ptrend = 4.2 × 10-4), whereas rs9393597 in LOC134997 and rs12652447 in FBXL7 showed the strongest associations in BRCA2 carriers (HR 5 1.55, 95% CI: 1.25-1.92, Ptrend 5 6 × 10-5 and HR 5 1.37, 95% CI: 1.16-1.62, Ptrend 5 1.7 × 10-4). The magnitude and direction of the associations were consistent with the original GWAS. In sub-sequent risk assessment studies, the loci appeared to interact multiplicatively for breast cancer risk in BRCA1 and BRCA2 carriers. Promising candidate SNPs from GWAS were identified as modifiers of breast cancer risk in BRCA1 and BRCA2 carriers. Upon further validation, these SNPs together with other genetic and environmental factors may improve breast cancer risk assessment in these populations. © The Author 2010. Published by Oxford University Press. All rights reserved. For Permissions, please email: firstname.lastname@example.org.
Caputo S.,French Institute of Health and Medical Research |
Benboudjema L.,French Institute of Health and Medical Research |
Sinilnikova O.,Hospices Civils Of Lyon Center Leon Berard |
Sinilnikova O.,University of Lyon |
And 40 more authors.
Nucleic Acids Research | Year: 2012
BRCA1 and BRCA2 are the two main genes responsible for predisposition to breast and ovarian cancers, as a result of protein-inactivating mono-allelic mutations. It remains to be established whether many of the variants identified in these two genes, so-called unclassified/unknown variants (UVs), contribute to the disease phenotype or are simply neutral variants (or polymorphisms). Given the clinical importance of establishing their status, a nationwide effort to annotate these UVs was launched by laboratories belonging to the French GGC consortium (Groupe Génétique et Cancer), leading to the creation of the UMD-BRCA1/BRCA2 databases (http://www.umd .be/BRCA1/ and http://www.umd.be/BRCA2/). These databases have been endorsed by the French National Cancer Institute (INCa) and are designed to collect all variants detected in France, whether causal, neutral or UV. They differ from other BRCA databases in that they contain co-occurrence data for all variants. Using these data, the GGC French consortium has been able to classify certain UVs also contained in other databases. In this article, we report some novel UVs not contained in the BIC database and explore their impact in cancer predisposition based on a structural approach. © The Author(s) 2011. Published by Oxford University Press.
Tessereau C.,University of Lyon |
Tessereau C.,Genomic Vision |
Lesecque Y.,University of Lyon |
Monnet N.,University of Lyon |
And 10 more authors.
Nucleic Acids Research | Year: 2014
Large tandem repeat sequences have been poorly investigated as severe technical limitations and their frequent absence from the genome reference hinder their analysis. Extensive allelotyping of this class of variation has not been possible until now and their mutational dynamics are still poorly known. In order to estimate the mutation rate of a macrosatellite, we analysed in detail the RNU2 locus, which displays at least 50 different alleles containing 5-82 copies of a 6.1 kb repeat unit. Mining data from the 1000 Genomes Project allowed us to precisely estimate copy numbers of the RNU2 repeat unit using read depth of coverage. This further revealed significantly different mean values in various recent modern human populations, favoring a scenario of fast evolution of this locus. Its proximity to a disease gene with numerous founder mutations, BRCA1, within the same linkage disequilibrium block, offered the unique opportunity to trace RNU2 arrays over a large timescale. Analysis of the transmission of RNU2 arrays associated with one 'private' mutation in an extended kindred and four founder mutations in multiple kindreds gave an estimation by maximum likelihood of 5 × 10-3 mutations per generation, which is close to that of microsatellites. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.
Bolton K.L.,U.S. National Cancer Institute |
Bolton K.L.,University of California at Los Angeles |
Chenevix-Trench G.,Queensland Institute of Medical Research |
Goh C.,Addenbrookes Hospital |
And 81 more authors.
JAMA - Journal of the American Medical Association | Year: 2012
Context: Approximately 10% of women with invasive epithelial ovarian cancer (EOC) carry deleterious germline mutations in BRCA1 or BRCA2. A recent article suggested that BRCA2-related EOC was associated with an improved prognosis, but the effect of BRCA1 remains unclear. Objective: To characterize the survival of BRCA carriers with EOC compared with noncarriers and to determine whether BRCA1 and BRCA2 carriers show similar survival patterns. Design, Setting, and Participants: A pooled analysis of 26 observational studies on the survival of women with ovarian cancer, which included data from 1213 EOC cases with pathogenic germline mutations in BRCA1 (n=909) or BRCA2 (n=304) and from 2666 noncarriers recruited and followed up at variable times between 1987 and 2010 (the median year of diagnosis was 1998). Main Outcome Measure: Five-year overall mortality. Results: The 5-year overall survival was 36% (95% CI, 34%-38%) for noncarriers, 44% (95% CI, 40%-48%) for BRCA1 carriers, and 52% (95% CI, 46%-58%) for BRCA2 carriers. After adjusting for study and year of diagnosis, BRCA1 and BRCA2 mutation carriers showed amore favorable survival than noncarriers (for BRCA1: hazard ratio [HR], 0.78; 95% CI, 0.68-0.89; P<.001; and for BRCA2: HR, 0.61; 95% CI, 0.50-0.76; P<.001). These survival differences remained after additional adjustment for stage, grade, histology, and age at diagnosis (for BRCA1: HR, 0.73; 95% CI, 0.64-0.84; P<.001; and for BRCA2: HR, 0.49; 95% CI, 0.39-0.61; P<.001). The BRCA1 HR estimate was significantly different from the HR estimated in the adjusted model (P for heterogeneity=.003). Conclusion: Among patients with invasive EOC, having a germline mutation in BRCA1 or BRCA2 was associated with improved 5-year overall survival. BRCA2 carriers had the best prognosis. ©2012 American Medical Association. All rights reserved.
Tessereau C.,University of Lyon |
Leone M.,Hospices Civils Of Lyon Center Leon Berard |
Buisson M.,University of Lyon |
Duret L.,University of Lyon |
And 3 more authors.
Genes Chromosomes and Cancer | Year: 2015
The duplication in the primate lineage of a portion of the breast and ovarian cancer susceptibility gene BRCA1 has created a BRCA1 pseudogene 45 kb away. Non-allelic homologous recombination (NAHR) between BRCA1 and BRCA1P1 has generated recurrent deleterious germ-line 37-kb deletions encompassing the first two exons of BRCA1, accounting for several breast and ovarian cancer families in various populations. In principle, NAHR intermediates resolution could also lead through a non-crossover configuration to interlocus gene conversion (IGC), but none had been described as yet. Here, we report for the first time an IGC event identified in a breast and ovarian cancer family involving exactly the same segment as that involved in the 37-kb deletions. Close examination of the consequences of this IGC event showed that it does not impact BRCA1 expression. Detailed analysis of the regions of homology between BRCA1 and its pseudogene revealed the specificity of the segment where recombination systematically occurs. © 2015 Wiley Periodicals, Inc.