Sainte-Foy-lès-Lyon, France
Sainte-Foy-lès-Lyon, France

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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.


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: journals.permissions@oxfordjournals.org.


PubMed | University of Cologne, University Of Clermont Ferrand, Vilnius University, Fondazione Instituto Of Oncologia Molecolare Ifom and 103 more.
Type: Journal Article | Journal: PloS one | Year: 2015

While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04-1.15, p = 1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03-1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted pinteraction values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.


PubMed | University of Cologne, St George's, University of London, Vilnius University, Institute of Human Genetics and 119 more.
Type: Journal Article | Journal: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology | Year: 2015

BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes.Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach.The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments.There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers.Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies.


PubMed | University of Cologne, University of Turin, Vilnius University, Erasmus Medical Center and 133 more.
Type: Journal Article | Journal: JAMA | Year: 2015

Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists.To identify mutation-specific cancer risks for carriers of BRCA1/2.Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk.Mutations of BRCA1 or BRCA2.Breast and ovarian cancer risks.Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR=1.46; 95% CI, 1.22-1.74; P=210(-6)), c.4328 to c.4945 (BCCR2; RHR=1.34; 95% CI, 1.01-1.78; P=.04), and c. 5261 to c.5563 (BCCR2, RHR=1.38; 95% CI, 1.22-1.55; P=610(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR=0.62 (95% CI, 0.56-0.70; P=910(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR=1.71; 95% CI, 1.06-2.78; P=.03), c.772 to c.1806 (BCCR1; RHR=1.63; 95% CI, 1.10-2.40; P=.01), and c.7394 to c.8904 (BCCR2; RHR=2.31; 95% CI, 1.69-3.16; P=.00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR=0.51; 95% CI, 0.44-0.60; P=610(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR=0.57; 95% CI, 0.41-0.80; P=.001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers.Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.


PubMed | Karolinska Institutet, University of Cologne, Instituto Oncologico Veneto Iov Irccs Instituto Of Ricovero E Cura A Carattere Scientifico, Rutgers Cancer Institute of New Jersey and 126 more.
Type: | Journal: Nature communications | Year: 2016

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 10(-20)), ER-negative BC (P=1.1 10(-13)), BRCA1-associated BC (P=7.7 10(-16)) and triple negative BC (P-diff=2 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 10(-3)) and ABHD8 (P<2 10(-3)). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.


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.


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.


PubMed | University of Utah, Genomic Vision, University of Lyon and Hospices Civils Of Lyon Center Leon Berard
Type: Journal Article | Journal: 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.


Bolton K.L.,U.S. National Cancer Institute | Bolton K.L.,University of California at Los Angeles | Chenevix-Trench G.,Royal Brisbane Hospital | Goh C.,Addenbrookes Hospital | And 80 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.

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