Showing papers by "Dominique Stoppa-Lyonnet published in 2012"
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University of Cambridge1, University of Toronto2, University of Pennsylvania3, University of Southampton4, University of Helsinki5, University of Southern California6, QIMR Berghofer Medical Research Institute7, Columbia University8, National Institutes of Health9, Mayo Clinic10, Leipzig University11, Claude Bernard University Lyon 112, University of Melbourne13, University of Utah14, Cancer Prevention Institute of California15, Vilnius University16, University of Latvia17, University of Copenhagen18, Complutense University of Madrid19, University of Turin20, University of Florence21, Sapienza University of Rome22, German Cancer Research Center23, Memorial Hospital of South Bend24, Erasmus University Rotterdam25, Utrecht University26, Royal Devon and Exeter Hospital27, Churchill Hospital28, University Hospital of Wales29, University College London30, Fox Chase Cancer Center31, University of Kansas32, University of Cologne33, Technische Universität München34, Dresden University of Technology35, University of Kiel36, University of Düsseldorf37, Heidelberg University38, University of Ulm39, Hannover Medical School40, University of Münster41, Charité42, University of Würzburg43, University of Paris44, Georgetown University45, Laval University46, University of Padua47, Peter MacCallum Cancer Centre48, University of Chicago49, Harvard University50, University of Delaware51, American Cancer Society52, Medical University of Vienna53, Ohio State University54, University of Southern Denmark55, University of Pisa56, Karolinska Institutet57, Lund University58, City of Hope National Medical Center59, University of California, San Francisco60, Roswell Park Cancer Institute61, Cedars-Sinai Medical Center62
TL;DR: Pathologic characteristics of BRCA1 and BRCa2 tumors may be useful for improving risk-prediction algorithms and informing clinical strategies for screening and prophylaxis.
Abstract: BACKGROUND: Previously, small studies have found that BRCA1 and BRCA2 breast tumors differ in their pathology. Analysis of larger datasets of mutation carriers should allow further tumor characterization.METHODS: We used data from 4,325 BRCA1 and 2,568 BRCA2 mutation carriers to analyze the pathology of invasive breast, ovarian, and contralateral breast cancers.RESULTS: There was strong evidence that the proportion of estrogen receptor (ER)-negative breast tumors decreased with age at diagnosis among BRCA1 (P-trend = 1.2 × 10(-5)), but increased with age at diagnosis among BRCA2, carriers (P-trend = 6.8 × 10(-6)). The proportion of triple-negative tumors decreased with age at diagnosis in BRCA1 carriers but increased with age at diagnosis of BRCA2 carriers. In both BRCA1 and BRCA2 carriers, ER-negative tumors were of higher histologic grade than ER-positive tumors (grade 3 vs. grade 1; P = 1.2 × 10(-13) for BRCA1 and P = 0.001 for BRCA2). ER and progesterone receptor (PR) expression were independently associated with mutation carrier status [ER-positive odds ratio (OR) for BRCA2 = 9.4, 95% CI: 7.0-12.6 and PR-positive OR = 1.7, 95% CI: 1.3-2.3, under joint analysis]. Lobular tumors were more likely to be BRCA2-related (OR for BRCA2 = 3.3, 95% CI: 2.4-4.4; P = 4.4 × 10(-14)), and medullary tumors BRCA1-related (OR for BRCA2 = 0.25, 95% CI: 0.18-0.35; P = 2.3 × 10(-15)). ER-status of the first breast cancer was predictive of ER-status of asynchronous contralateral breast cancer (P = 0.0004 for BRCA1; P = 0.002 for BRCA2). There were no significant differences in ovarian cancer morphology between BRCA1 and BRCA2 carriers (serous: 67%; mucinous: 1%; endometrioid: 12%; clear-cell: 2%).Conclusions/Impact: Pathologic characteristics of BRCA1 and BRCA2 tumors may be useful for improving risk-prediction algorithms and informing clinical strategies for screening and prophylaxis. Cancer Epidemiol Biomarkers Prev; 1-14. ©2011 AACR.
514 citations
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TL;DR: The genomic signature defined predicted BRCA1/2 inactivation in BLCs with 100% sensitivity and 90% specificity (97% accuracy) may ease the challenge of selecting patients for genetic testing or recruitment to clinical trials of novel emerging therapies that target DNA repair deficiencies in cancer.
Abstract: BRCA1 inactivation is a frequent event in basal-like breast carcinomas (BLC). However, BRCA1 can be inactivated by multiple mechanisms and determining its status is not a trivial issue. As an alternate approach, we profiled 65 BLC cases using single-nucleotide polymorphism arrays to define a signature of BRCA1-associated genomic instability. Large-scale state transitions (LST), defined as chromosomal break between adjacent regions of at least 10 Mb, were found to be a robust indicator of BRCA1 status in this setting. Two major ploidy-specific cutoffs in LST distributions were sufficient to distinguish highly rearranged BLCs with 85% of proven BRCA1-inactivated cases from less rearranged BLCs devoid of proven BRCA1-inactivated cases. The genomic signature we defined was validated in a second independent series of 55 primary BLC cases and 17 BLC-derived tumor cell lines. High numbers of LSTs resembling BRCA1-inactivated BLC were observed in 4 primary BLC cases and 2 BLC cell lines that harbored BRCA2 mutations. Overall, the genomic signature we defined predicted BRCA1/2 inactivation in BLCs with 100% sensitivity and 90% specificity (97% accuracy). This assay may ease the challenge of selecting patients for genetic testing or recruitment to clinical trials of novel emerging therapies that target DNA repair deficiencies in cancer.
496 citations
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TL;DR: It is envisaged that the research and clinical application of models developed by ENIGMA will be relevant to the interpretation of sequence variants in other disease genes.
Abstract: As genetic testing for predisposition to human diseases has become an increasingly common practice in medicine, the need for clear interpretation of the test results is apparent. However, for many disease genes, including the breast cancer susceptibility genes BRCA1 and BRCA2, a significant fraction of tests results in the detection of a genetic variant for which disease association is not known. The finding of an "unclassified" variant (UV)/variant of uncertain significance (VUS) complicates genetic test reporting and counseling. As these variants are individually rare, a large collaboration of researchers and clinicians will facilitate studies to assess their association with cancer predisposition. It was with this in mind that the ENIGMA consortium (www.enigmaconsortium.org) was initiated in 2009. The membership is both international and interdisciplinary, and currently includes more than 100 research scientists and clinicians from 19 countries. Within ENIGMA, there are presently six working groups focused on the following topics: analysis, clinical, database, functional, tumor histopathology, and mRNA splicing. ENIGMA provides a mechanism to pool resources, exchange methods and data, and coordinately develop and apply algorithms for classification of variants in BRCA1 and BRCA2. It is envisaged that the research and clinical application of models developed by ENIGMA will be relevant to the interpretation of sequence variants in other disease genes.
269 citations
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TL;DR: This study embarked upon the largest BRCA1 and BRCa2 splice study to date by testing 272 VUSs within the BRC a splice network of Unicancer, and defined guidelines for transcript analysis along with a tentative classification of splice variants.
Abstract: Assessing the impact of variants of unknown significance (VUS) on splicing is a key issue in molecular diagnosis. This impact can be predicted by in silico tools, but proper evaluation and user guidelines are lacking. To fill this gap, we embarked upon the largest BRCA1 and BRCA2 splice study to date by testing 272 VUSs (327 analyses) within the BRCA splice network of Unicancer. All these VUSs were analyzed by using six tools (splice site prediction by neural network, splice site finder (SSF), MaxEntScan (MES), ESE finder, relative enhancer and silencer classification by unanimous enrichment, and human splicing finder) and the predictions obtained were compared with transcript analysis results. Combining MES and SSF gave 96% sensitivity and 83% specificity for VUSs occurring in the vicinity of consensus splice sites, that is, the surrounding 11 and 14 bases for the 5' and 3' sites, respectively. This study was also an opportunity to define guidelines for transcript analysis along with a tentative classification of splice variants. The guidelines drawn from this large series should be useful for the whole community, particularly in the context of growing sequencing capacities that require robust pipelines for variant interpretation.
228 citations
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Antonis C. Antoniou1, Karoline Kuchenbaecker1, Penny Soucy, Jonathan Beesley2 +177 more•Institutions (85)
TL;DR: The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCa1 and BRCA2 mutation carriers.
Abstract: Introduction: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2). Methods: To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework. Results: Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95% CI: 0.81 to 0.94, P-trend = 3 x 10(-4)). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95% CI: 0.74 to 0.90, P-trend = 3.1 x 10(-5), P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df P = 0.007; rs1292011 2df P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95% CI: 0.74 to 0.90, P-trend = 4 x 10(-5)) and there was marginal evidence of association with ER- negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95% CI: 0.62 to 1.00, P-trend = 0.049). Conclusions: The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers.
92 citations
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TL;DR: This study demonstrates that BRCA1 pathogenic germline mutations coupled with somatic loss of the wild‐type allele are not sufficient for hereditary breast cancers to display an ER‐negative phenotype, and has led to the identification of three potential novel breast cancer genes.
Abstract: BRCA1 encodes a tumour suppressor protein that plays pivotal roles in homologous recombination (HR) DNA repair, cell-cycle checkpoints, and transcriptional regulation. BRCA1 germline mutations confer a high risk of early-onset breast and ovarian cancer. In more than 80% of cases, tumours arising in BRCA1 germline mutation carriers are oestrogen receptor (ER)-negative; however, up to 15% are ER-positive. It has been suggested that BRCA1 ER-positive breast cancers constitute sporadic cancers arising in the context of a BRCA1 germline mutation rather than being causally related to BRCA1 loss-of-function. Whole-genome massively parallel sequencing of ER-positive and ER-negative BRCA1 breast cancers, and their respective germline DNAs, was used to characterize the genetic landscape of BRCA1 cancers at base-pair resolution. Only BRCA1 germline mutations, somatic loss of the wild-type allele, and TP53 somatic mutations were recurrently found in the index cases. BRCA1 breast cancers displayed a mutational signature consistent with that caused by lack of HR DNA repair in both ER-positive and ER-negative cases. Sequencing analysis of independent cohorts of hereditary BRCA1 and sporadic non-BRCA1 breast cancers for the presence of recurrent pathogenic mutations and/or homozygous deletions found in the index cases revealed that DAPK3, TMEM135, KIAA1797, PDE4D, and GATA4 are potential additional drivers of breast cancers. This study demonstrates that BRCA1 pathogenic germline mutations coupled with somatic loss of the wild-type allele are not sufficient for hereditary breast cancers to display an ER-negative phenotype, and has led to the identification of three potential novel breast cancer genes (ie DAPK3, TMEM135, and GATA4).
64 citations
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TL;DR: Findings from genome-wide association studies can lead to an improved understanding of tumor development and may prove useful for breast and ovarian cancer risk prediction for BRCA1 and B RCA2 mutation carriers.
Abstract: Background: Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Methods: Genotyping data for 12,599 BRCA1 and 7,132 BRCA2 mutation carriers from 40 studies were combined. Results: We confirmed associations between rs8170 at 19p13.1 and breast cancer risk for BRCA1 mutation carriers [HR, 1.17; 95% confidence interval (CI), 1.07-1.27; P = 7.42 x 10(-4)] and between rs16917302 at ZNF365 (HR, 0.84; 95% CI, 0.73-0.97; P = 0.017) but not rs311499 at 20q13.3 (HR, 1.11; 95% CI, 0.94-1.31; P = 0.22) and breast cancer risk for BRCA2 mutation carriers. Analyses based on tumor histopathology showed that 19p13 variants were predominantly associated with estrogen receptor (ER)-negative breast cancer for both BRCA1 and BRCA2 mutation carriers, whereas rs16917302 at ZNF365 was mainly associated with ER-positive breast cancer for both BRCA1 and BRCA2 mutation carriers. We also found for the first time that rs67397200 at 19p13.1 was associated with an increased risk of ovarian cancer for BRCA1 (HR, 1.16; 95% CI, 1.05-1.29; P = 3.8 x 10(-4)) and BRCA2 mutation carriers (HR, 1.30; 95% CI, 1.10-1.52; P = 1.8 x 10(-3)). Conclusions: 19p13.1 and ZNF365 are susceptibility loci for ovarian cancer and ER subtypes of breast cancer among BRCA1 and BRCA2 mutation carriers. Impact: These findings can lead to an improved understanding of tumor development and may prove useful for breast and ovarian cancer risk prediction for BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev; 21(4); 645-57. (C) 2012 AACR.
53 citations
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TL;DR: This study represents the first evaluation of the deleterious and unclassified genetic variants in the BRCA1/2 genes found in a Lebanese population with a relatively high risk of breast cancer.
Abstract: Breast cancer is the most prevalent malignancy in women in Western countries, currently accounting for one third of all female cancers. Familial aggregation is thought to account for 5–10 % of all BC cases, and germline mutations in BRCA1 and BRCA2 account for less of the half of these inherited cases. In Lebanon, breast cancer represents the principal death-causing malignancy among women, with 50 % of the cases diagnosed before the age of 50 years. In order to study BRCA1/2 mutation spectra in the Lebanese population, 72 unrelated patients with a reported family history of breast and/or ovarian cancers or with an early onset breast cancer were tested. Fluorescent direct sequencing of the entire coding region and intronic sequences flanking each exon was performed. A total of 38 BRCA1 and 40 BRCA2 sequence variants were found. Seventeen of them were novel. Seven confirmed deleterious mutations were identified in 9 subjects providing a frequency of mutations of 12.5 %. Fifteen variants were considered of unknown clinical significance according to BIC and UMD-BRCA1/BRCA2 databases. In conclusion, this study represents the first evaluation of the deleterious and unclassified genetic variants in the BRCA1/2 genes found in a Lebanese population with a relatively high risk of breast cancer.
45 citations
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Susan J. Ramus1, Antonis C. Antoniou2, Karoline Kuchenbaecker2, Penny Soucy3 +189 more•Institutions (84)
TL;DR: The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCa2 mutations regarding their risk of ovarian cancer.
Abstract: Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four single-nucleotide polymorphisms (SNPs), rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31), and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in BRCA2 carriers; rs10088218 per-allele hazard ratio (HR) = 0.81 (95% CI: 0.67-0.98) P-trend = 0.033, rs2665390 HR = 1.48 (95% CI: 1.21-1.83) P-trend = 1.8 × 10(-4), rs717852 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.6 × 10(-4), rs9303542 HR = 1.16 (95% CI: 1.02-1.33) P-trend = 0.026. Two loci were associated with ovarian cancer risk in BRCA1 carriers; rs10088218 per-allele HR = 0.89 (95% CI: 0.81-0.99) P-trend = 0.029, rs2665390 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.1 × 10(-4). The HR estimates for the remaining loci were consistent with odds ratio estimates for the general population. The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer.
40 citations
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TL;DR: It is demonstrated that most missense mutations associated with A-T lead to an abnormal cytoplasmic localization of ATM, correlated with its decreased expression, which highlights ATM mislocalization as a new mechanism of ATM dysfunction, which may lead to therapeutic strategies for missense mutation associated A- T.
Abstract: Ataxia telangiectasia (A-T) is a rare autosomal recessive disorder characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, immune defects and predisposition to malignancies. A-T is caused by biallelic inactivation of the ATM gene, in most cases by frameshift or nonsense mutations. More rarely, ATM missense mutations with unknown consequences on ATM function are found, making definitive diagnosis more challenging. In this study, a series of 15 missense mutations, including 11 not previously reported, were identified in 16 patients with clinical diagnosis of A-T belonging to 14 families and 1 patient with atypical clinical features. ATM function was evaluated in patient lymphoblastoid cell lines by measuring H2AX and KAP1 phosphorylation in response to ionizing radiation, confirming the A-T diagnosis for 16 cases. In accordance with previous studies, we showed that missense mutations associated with A-T often lead to ATM protein underexpression (15 out of 16 cases). In addition, we demonstrated that most missense mutations lead to an abnormal cytoplasmic localization of ATM, correlated with its decreased expression. This new finding highlights ATM mislocalization as a new mechanism of ATM dysfunction, which may lead to therapeutic strategies for missense mutation associated A-T.
38 citations
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TL;DR: The closer to reproductive decision-making BRCA1/2 carriers are, i.e., when they are more likely to be making future reproductive plans, the less frequently they intend to have PGD.
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TL;DR: The findings show that, taking into account environmental and lifestyle modifiers, mutation position might be important for the clinical management of BRCA1 and B RCA2 mutation carriers and could also be helpful in understanding how BRCa1 andBRCA2 genes are involved in BC.
Abstract: Introduction
Mutations in BRCA1 and BRCA2 confer a high risk of breast cancer (BC), but the magnitude of this risk seems to vary according to the study and various factors. Although controversial, there are data to support the hypothesis of allelic risk heterogeneity.
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Pomeranian Medical University1, University of Szczecin2, University of Cambridge3, University of Newcastle4, QIMR Berghofer Medical Research Institute5, University of Lyon6, Rappaport Faculty of Medicine7, University of Toronto8, Mount Sinai Hospital, Toronto9, Odense University Hospital10, University of Pisa11, Karolinska Institutet12, Lund University13, Uppsala University14, University of Gothenburg15, Linköping University16, Umeå University17, University of Pennsylvania18, Carlos III Health Institute19, Netherlands Cancer Institute20, University of Amsterdam21, University of Groningen22, Leiden University23, Maastricht University24, Radboud University Nijmegen25, Erasmus University Rotterdam26, Utrecht University27, Central Manchester University Hospitals NHS Foundation Trust28, The Royal Marsden NHS Foundation Trust29, Guy's and St Thomas' NHS Foundation Trust30, University of Southampton31, Boston Children's Hospital32, University of Kansas33, Fox Chase Cancer Center34, Curie Institute35, Paris Descartes University36, Claude Bernard University Lyon 137, French Institute of Health and Medical Research38, University of Iceland39, Georgetown University40, University of Cologne41, Ludwig Maximilian University of Munich42, University of Kiel43, Charité44, University of Düsseldorf45, University Hospital Heidelberg46, University of Ulm47, University of Münster48, Laval University49, Mayo Clinic50, National Institutes of Health51
TL;DR: The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers, and this association need to be evaluated in larger series of BRCC mutation carriers.
Abstract: BACKGROUND: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity. METHODS: To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 C>T (rs6917) polymorphism and the MTHFR 677 C>T (rs1801133) polymorphism, respectively. RESULTS: There was no evidence of association between the PHB 1630 C>T and MTHFR 677 C>T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 C>T polymorphism were at increased risk of both breast and ovarian cancer (HR 1.50, 95% CI 1.10-2.04 and HR 2.16, 95% CI 1.24-3.76, respectively). However, there was no evidence of association under a multiplicative model for the effect of each minor allele. CONCLUSION: The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers. British Journal of Cancer (2012) 106, 2016-2024. doi:10.1038/bjc.2012.160 www.bjcancer.com Published online 15 May 2012 (C) 2012 Cancer Research UK
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TL;DR: This work identified small-effect genetic variants associated with allelic expression differences in BRCA2 which could possibly affect the risk in mutation carriers through altering expression levels of the wild-type allele.
Abstract: 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 disruption of transcription factor binding, and were functionally analyzed in vitro and in vivo in normal and breast cancer cell lines. SNPs tagging the expression haplotypes were correlated with the total expression of several genes in breast tissue measured by Taqman and microarray technologies. The effect of the expression haplotypes on breast cancer risk in BRCA2 mutation carriers was investigated in 2,754 carriers. Results: We identified common haplotypes associated with differences in the levels of BRCA2 expression in human breast cells. We characterized three cis-regulatory SNPs located at the promoter and two intronic regulatory elements which affect the binding of the transcription factors C/EBPa, HMGA1, D-binding protein (DBP) and ZF5. We showed that the expression haplotypes also correlated with changes in the expression of other genes in normal breast. Furthermore, there was suggestive evidence that the minor allele of SNP rs4942440, which is associated with higher BRCA2 expression, is also associated with a reduced risk of breast cancer (per-allele hazard ratio (HR) = 0.85, 95% confidence interval (CI) = 0.72 to 1.00, P-trend = 0.048). Conclusions: Our work provides further insights into the role of cis-regulatory variation in the penetrance of disease-causing mutations. We identified small-effect genetic variants associated with allelic expression differences in BRCA2 which could possibly affect the risk in mutation carriers through altering expression levels of the wildtype allele.
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TL;DR: The IRS1 Gly972Arg single-nucleotide polymorphism, which affects insulin-like growth factor and insulin signaling, modifies ovarian cancer risk in BRCA1 and BRCa2 mutation carriers and breast cancer riskIn carriers with class II mutations than class I mutations, these findings may prove useful for risk prediction for breast and ovarian cancers.
Abstract: Background: We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk in women carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were associated with breast cancer risk in a larger cohort of BRCA1 and BRCA2 mutation carriers. Methods: IRS1 rs1801123, rs1330645, and rs1801278 were genotyped in samples from 36 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analyzed by a retrospective cohort approach modeling the associations with breast and ovarian cancer risks simultaneously. Analyses were stratified by BRCA1 and BRCA2 status and mutation class in BRCA1 carriers. Results: Rs1801278 (Gly972Arg) was associated with ovarian cancer risk for both BRCA1 (HR, 1.43; 95% confidence interval (CI), 1.06-1.92; P = 0.019) and BRCA2 mutation carriers (HR, 2.21; 95% CI, 1.39-3.52, P = 0.0008). For BRCA1 mutation carriers, the breast cancer risk was higher in carriers with class II mutations than class I mutations (class II HR, 1.86; 95% CI, 1.28-2.70; class I HR, 0.86; 95%CI, 0.69-1.09; P-difference, 0.0006). Rs13306465 was associated with ovarian cancer risk in BRCA1 class II mutation carriers (HR, 2.42; P = 0.03). Conclusion: The IRS1 Gly972Arg single-nucleotide polymorphism, which affects insulin-like growth factor and insulin signaling, modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers and breast cancer risk in BRCA1 class II mutation carriers. Impact: These findings may prove useful for risk prediction for breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev; 21(8); 1362-70. (C)2012 AACR.
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TL;DR: The study demonstrates the usefulness of CGH-array in routine genetic analysis and indicates there is a very low incidence of large rearrangements in BRCA1/2 and in the other eight candidate genes in families already explored for BRCHereditary breast cancers.
Abstract: Hereditary breast cancers account for up to 5-10 % of breast cancers and a majority are related to the BRCA1 and BRCA2 genes. However, many families with breast cancer predisposition do not carry any known mutations for BRCA1 and BRCA2 genes. We explored the incidence of rare large rearrangements in the coding, noncoding and flanking regions of BRCA1/2 and in eight other candidate genes--CHEK2, BARD1, ATM, RAD50, RAD51, BRIP1, RAP80 and PALB2. A dedicated zoom-in CGH-array was applied to screen for rearrangements in 472 unrelated French individuals from breast-ovarian cancer families that were being followed in eight French oncogenetic laboratories. No new rearrangement was found neither in the genomic regions of BRCA1/2 nor in candidate genes, except for the CHEK2 and BARD1 genes. Three heterozygous deletions were detected in the 5' and 3' flanking regions of BRCA1. One large deletion introducing a frameshift was identified in the CHEK2 gene in two families and one heterozygous deletion was detected within an intron of BARD1. The study demonstrates the usefulness of CGH-array in routine genetic analysis and, aside from the CHEK2 rearrangements, indicates there is a very low incidence of large rearrangements in BRCA1/2 and in the other eight candidate genes in families already explored for BRCA1/2 mutations. Finally, next-generation sequencing should bring new information about point mutations in intronic and flanking regions and also medium size rearrangements.
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TL;DR: In this cohort of French women carrying BRCA1/2 mutations, prophylactic mastectomy was a rarely used option, however, good compliance with prophyllactic salpingo-oophorectomy was observed and confirms the high breast cancer risk in these women.
Abstract: Description of the various modalities of breast and ovarian cancer risk management, patient choices and their outcome in a single-center cohort of 158 unaffected women carrying a BRCA1 or BRCA2 germline mutation. Between 1998 and 2009, 158 unaffected women carrying a BRCA1 or BRCA2 gene mutation were prospectively followed. The following variables were studied: general and gynecological characteristics, data concerning any prophylactic procedures, and data concerning the outcome of these patients. Median age at inclusion was 37 years and median follow-up was 54 months. Among the 156 women who received systematic information about prophylactic mastectomy, 5.3 % decided to undergo surgery within 36 months after disclosure of genetic results. Prophylactic salpingo-oophorectomy was performed in 68 women. Among women in whom follow-up started between the ages of 40 and 50 years, prophylactic salpingo-oophorectomy was performed, within 24 months after start of follow-up, in 83.7 and 52 % of women with BRCA1 and BRCA2 mutations, respectively. Twenty four women developed breast cancer. Ovarian cancer was detected during prophylactic salpingo-oophorectomy in two women (2.9 %). In this cohort of French women carrying BRCA1/2 mutations, prophylactic mastectomy was a rarely used option. However, good compliance with prophylactic salpingo-oophorectomy was observed. This study confirms the high breast cancer risk in these women.
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TL;DR: L’une des applications majeures attendues du NGS sera l’identification de mutations tumorales pouvant constituer des cibles thérapeutiques chez un patient donné.
Abstract: > Le séquençage de nouvelle génération (NGS) est une révolution technologique qui a un retentissement majeur sur la connaissance de la variabilité, non seulement celle du génome, mais aussi celle du transcriptome, et sur l’appréhension de l’hétérogénéité des maladies génétiques mendéliennes [1-3]. L’accès en une session à des centaines de gigabases permet de séquencer : le génome complet d’une personne ; l’exome d’une dizaine ; ou encore la séquence d’un ensemble de gènes impliqués dans une maladie génétique hétérogène chez une centaine. Le NGS va ainsi augmenter considérablement les capacités d’analyse des laboratoires de génétique médicale. Il va autoriser pour des maladies fréquentes l’exploration clinique de nouveaux gènes, siège de mutations rares et dont la contribution génétique est faible. Le NGS va permettre d’élargir les indications de tests génétiques. À titre d’exemple, les indications familiales actuelles des tests de prédisposition aux cancers du sein via l’analyse in extenso des gènes BRCA1/2 ont une sensibilité de 64 % ; en d’autres termes, 36 % des femmes ayant une mutation BRCA1/2 sont en dehors de ces indications [4]. Le NGS va aussi permettre de rassurer un couple s’interrogeant sur le risque d’avoir un enfant atteint d’une maladie récessive grave et rare, lorsque l’un des membres du couple est porteur d’une mutation mono-allélique, alors qu’aujourd’hui le séquençage du gène en cause chez le conjoint n’est pas réalisé ; l’argument est la fréquence faible des porteurs dans la population générale et, par là, le risque faible d’avoir un enfant atteint (risque de 1/600 si la fréquence de la maladie est de 1/90 000 et la fréquence des porteurs dans la population de 1/150). Enfin, l’une des applications majeures attendues du NGS sera l’identification de mutations tumorales pouvant constituer des cibles thérapeutiques chez un patient donné. Le NGS devrait en effet avoir raison de la complexité de la génomique tumorale (mutations ponctuelles, délétions, amplifications de régions chromosomiques, translocations) [5, 6]. On peut pressentir que, très rapidement, le séquençage de l’exome, voire de l’ensemble du génome, va être techniquement plus simple et moins coûteux que la sélection et l’analyse à façon de quelques gènes. Aura-t-on une lecture sélective des seuls gènes en lien avec la maladie étudiée ou, au contraire, aurat-on une lecture exhaustive des séquences générées ? Voudrons-nous « tout voir », identifier des données fortuites (incidentes), sans lien avec la maladie étudiée ? N’est-ce pas déjà ce qui est proposé dans la période préconceptionnelle, avec la détection de mutations des gènes de près de 500 maladies récessives [7] ? N’allons-nous pas vers une généralisation de l’analyse de nos génomes, vers un check-up de notre make-up génétique ? Pourquoi pas ? La question qui doit rester cependant centrale, avant d’ouvrir le champ des questions éthiques posées par l’accès à ce savoir génétique encombrant, est précisément : de quel savoir parlons-nous ? Avant l’avènement du NGS, les études génétiques classiques se fondaient sur des histoires personnelles, familiales particulières, en quête d’un génotype : les mutations d’un gène choisi qui pourraient expliquer, au moins partiellement, le phénotype observé. On sait cependant que les maladies mendéliennes ne sont plus si mendéliennes que cela, leurs phénotypes étant influencés par des facteurs modificateurs, génétiques et non génétiques environnementaux. On va pas à pas du phénotype au génotype, randonnée fatigante, parfois même épuisante, notamment pour les patients. Sans connaissance exhaustive des facteurs modificateurs, les gènes majeurs des maladies mendéliennes constituent aujourd’hui l’essentiel des tests génétiques chez les apparentés. L’histoire familiale résume alors un ensemble de facteurs modificateurs qui ont plus de chance d’être présents chez les apparentés testés. Désormais, le NGS nous invite, dans le domaine de la génétique médicale, à avoir une démarche inverse : d’un génotype à un phénotype, d’un génotype à la prédiction d’une maladie. La réponse est plus complexe, les risques d’erreurs de prédiction sont plus élevés du fait précisément de l’absence de point d’appel. Le généticien est déjà confronté, lors de l’analyse de ses gènes préférés, aux difficultés d’interprétation de
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TL;DR: The aim of this review is to indicate cancer risks associated with the hereditary forms of ovarian adenocarcinomas and Lynch syndrome, to evaluate their contribution in the pathogenesis of ovarian cancers and to indicate the clinical data suggestive of these diagnoses, the validated indications for genetic analyses and the current management guidelines.
Abstract: Approximately 5 to 10 % of all ovarian cancers arise in the setting of a major genetic predisposition. The two main hereditary forms of ovarian adenocarcinomas are the hereditary breast/ovarian cancers associated with a BRCA1 or BRCA2 gene mutation and the Lynch syndrome associated with a MLH1, MSH2, MSH6 or PMS2 gene mutation. Their identification and the characterization of a causative germline mutation are crucial and have a major impact for affected women and their relatives in terms of medical management. The aim of this review is to indicate cancer risks associated with these two entities, to evaluate their contribution in the pathogenesis of ovarian cancers and to indicate the clinical data suggestive of these diagnoses, the validated indications for genetic analyses and the current management guidelines. We will also illustrate the diagnostic strategy by reporting a clinical observation.
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TL;DR: One-third of the female carriers not affected by breast/ovarian cancer disclosed their BRCA1/2 genetic test results spontaneously to their employers, mainly to inform them that they were disease-free but required medical surveillance or a surgical intervention to reduce the risk of cancer.
Abstract: The aim of this study was to examine the patterns of disclosure of BRCA1/2 genetic test results to employers by unaffected carriers. In a national prospective cohort study on unaffected BRCA1/2 mutation carriers, disclosure to employers was assessed prospectively, using self-administered questionnaires, up to 2 years after their test results were delivered by cancer geneticists. Kaplan–Meier curves and Cox-regression analysis were used to assess the factors associated with time to disclosure to the employer. Mean age of the 146 women BRCA1/2 carriers who were employed when their test results were delivered was 37.1 years (range: 19–57). At the end of the second year of follow-up, 47 of them (32.2%) had disclosed their results to their employers; median time to disclosure was 6 months. Reasons spontaneously expressed were first to inform the employer that medical surveillance/surgery was necessary for cancer risk management although these carriers did not actually have cancer. After multivariate adjustment on age, women with a lower educational level (HRadj=2.00, P=0.026) and those who had undergone prophylactic surgery during the 2 years of follow-up (HRadj=2.18, P=0.019) had disclosed their BRCA status to their employers earlier and more frequently. One-third of the female carriers not affected by breast/ovarian cancer disclosed their BRCA1/2 genetic test results spontaneously to their employers, mainly to inform them that they were disease-free but required medical surveillance or a surgical intervention to reduce the risk of cancer.
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Mayo Clinic1, National Institutes of Health2, University of Toronto3, University of Southern Denmark4, University of Pisa5, University of Pennsylvania6, Pomeranian Medical University7, Carlos III Health Institute8, German Cancer Research Center9, University of Kansas10, Paris Descartes University11, University of Melbourne12, University of Utah13, Medical University of Vienna14, University of Copenhagen15, University of Iceland16, Memorial Sloan Kettering Cancer Center17, Roswell Park Cancer Institute18, Latvian Biomedical Research and Study centre19, University of California, San Francisco20, City of Hope National Medical Center21, University of Delaware22, Laval University23, QIMR Berghofer Medical Research Institute24, Peter MacCallum Cancer Centre25, Belfast Health and Social Care Trust26, University of Cambridge27
TL;DR: This follow-up study suggests that, contrary to the initial report, this variant is not associated with breast cancer risk among individuals with germline BRCA2 mutations.
Abstract: Several common germline variants identified through genome-wide association studies of breast cancer risk in the general population have recently been shown to be associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. When combined, these variants can identify marked differences in the absolute risk of developing breast cancer for mutation carriers, suggesting that additional modifier loci may further enhance individual risk assessment for BRCA1 and BRCA2 mutation carriers. Recently, a common variant on 6p22 (rs9393597) was found to be associated with increased breast cancer risk for BRCA2 mutation carriers [hazard ratio (HR) = 1.55, 95 % confidence interval (CI) 1.25-1.92, p = 6.0 × 10(-5)]. This observation was based on data from GWAS studies in which, despite statistical correction for multiple comparisons, the possibility of false discovery remains a concern. Here, we report on an analysis of this variant in an additional 6,165 BRCA1 and 3,900 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). In this replication analysis, rs9393597 was not associated with breast cancer risk for BRCA2 mutation carriers (HR = 1.09, 95 % CI 0.96-1.24, p = 0.18). No association with ovarian cancer risk for BRCA1 or BRCA2 mutation carriers or with breast cancer risk for BRCA1 mutation carriers was observed. This follow-up study suggests that, contrary to our initial report, this variant is not associated with breast cancer risk among individuals with germline BRCA2 mutations.
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TL;DR: Quand l’adequation de the perception du risque de predisposition devrait favoriser une prise de decision eclairee quant au test genetique et a l�’anticipation du resultat, nombre of consultantes n’apprehendent pas correctement ce risque.
Abstract: Resume Cette etude vise a determiner l’adequation entre la perception du risque de predisposition genetique et l’estimation objective de ce risque, et ses facteurs associes, chez des femmes, cas index, atteintes de cancer du sein. La perception de ce risque, absolue et comparative, a ete confrontee a l’estimation objective. La detresse emotionnelle et les connaissances sur le risque genetique de cancer du sein, postconsultation, ont ete mesurees respectivement par l’Hospital Anxiety and Depression Scale (HADS), l’Impact of Event Scale (IES) et le Breast Genetic Counseling Knowledge Questionnaire (BGKQ). Sur 213 consultantes eligibles, les 173 questionnaires (81,2 %) analyses revelent une inadequation de la perception du risque absolu et comparatif dans 50 et 55,3 % respectivement. Une tendance a la surestimation du risque absolu ( p =0,08) et une sous-estimation significative du risque comparatif ( p β =0,150) et un niveau moindre d’education ( β =-0,164). Celle du risque comparatif est associee a plus de connaissances ( β =0,208), un niveau d’etudes superieur ( β =0,176) et un Âge plus jeune ( β =-0,151). Le fait de vivre en couple est facteur d’inadequation des deux formes d’evaluation du risque ( β =0,189 ; β =0,147). Quand l’adequation de la perception du risque de predisposition devrait favoriser une prise de decision eclairee quant au test genetique et a l’anticipation du resultat, nombre de consultantes n’apprehendent pas correctement ce risque lorsqu’elles presentent une detresse emotionnelle et malgre des connaissances sur le risque de cancer du sein.
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TL;DR: In this paper, the authors developed a study to determine molecular signatures of BRCA1 and BRCa2-mutated breast cancers and identified specific genomic rearrangements in these breast cancers, which could be used to find new markers for such breast cancers.
Abstract: Background: Germline mutation screening of BRCA1 and BRCA2 genes is performed in suspected familial breast cancer cases, but a causative mutation is found in only 30% of patients. The development of additional methods to identify good candidates for BRCA1 and BRCA2 analysis would therefore increase the efficacy of diagnostic mutation screening. With this in mind, we developed a study to determine molecular signatures of BRCA1—or BRCA2—mutated breast cancers. Materials and Methods: Array-cgh (comparative genomic hybridization) and transcriptomic analysis were performed on a series of 103 familial breast cancers. The series included 7 breast cancers with a BRCA1 mutation and 5 breast cancers with a BRCA2 mutation. The remaining 91 cases were obtained from 73 families selected on the basis of at least 3 affected first-degree relatives or at least 2 affected first-degree relatives with breast cancer at an average age of 45 years. Array-cgh analyses were performed on a 4407 BAC-array (CIT-V8) manufactured by IntegraGen. Transcriptomic analyses were performed using an Affymetrix Human Genome U133 Plus 2.0 chip. Results: Using supervised clustering analyses we identified two transcriptomic signatures: one for BRCA1-mutated breast cancers consisting of 600 probe sets and another for BRCA2-mutated breast cancers also consisting of 600 probes sets. We also defined cgh-array signatures, based on the presence of specific genomic rearrangements, one for BRCA1-mutated breast cancers and one for BRCA2-mutated breast cancers. Conclusions: This study identified molecular signatures of breast cancers with BRCA1 or BRCA2 germline mutations. Genes present in these signatures could be exploited to find new markers for such breast cancers. We also identified specific genomic rearrangements in these breast cancers, which could be screened for in a diagnostic setting using fluorescence in situ hybridization, thus improving patient selection for BRCA1 and BRCA2 molecular genetic analysis.