| 1. |
- Figlioli, G, et al.
(författare)
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The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer
- 2019
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Ingår i: NPJ breast cancer. - : Springer Science and Business Media LLC. - 2374-4677. ; 5, s. 38-
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Tidskriftsartikel (refereegranskat)abstract
- Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.
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| 2. |
- Lawrenson, Kate, et al.
(författare)
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Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 4. |
- Aldred, M. A., et al.
(författare)
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BMPR2 gene rearrangements account for a significant proportion of mutations in familial and idiopathic pulmonary arterial hypertension
- 2006
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Ingår i: Hum Mutat.. ; 27:2, s. 212-3.
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Tidskriftsartikel (refereegranskat)abstract
- Mutations of the BMPR2 gene predispose to pulmonary arterial hypertension (PAH), a serious, progressive disease of the pulmonary vascular system. However, despite the fact that most PAH families are consistent with linkage to the BMPR2 locus, sequencing only identifies mutations in some 55% of familial cases and between 10% and 40% of cases without a family history (idiopathic or IPAH). We therefore conducted a systematic analysis for larger gene rearrangements in panels of both familial and idiopathic PAH cases that were negative on sequencing of coding regions. Analysis of exon dosage across the entire gene using Multiplex Ligation-dependent Probe Amplification identified nine novel rearrangements and enabled full characterization at the exon level of previously reported deletions. Overall, BMPR2 rearrangements were identified in 7 of 58 families and 6 of 126 IPAH cases, suggesting that gross rearrangements underlie around 12% of all FPAH cases and 5% of IPAH. Importantly, two deletions encompassed all functional protein domains and are predicted to result in null mutations, providing the strongest support yet that the predominant molecular mechanism for disease predisposition is haploinsufficiency. Dosage analysis should now be considered an integral of part of the molecular work-up of PAH patients. (c) 2006 Wiley-Liss, Inc.
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| 5. |
- Ternant, D, et al.
(författare)
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TROUGH CONCENTRATION AND ESTIMATED CLEARANCE CAN DETECT IMMUNOGENICITY TO ADALIMUMAB IN RA PATIENTS: A PROSPECTIVE LONGITUDINAL MULTICENTRE STUDY
- 2020
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 79, s. 1449-1450
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Anti-Drug Antibodies (ADA) to adalimumab increase drug clearance in rheumatoid arthritis (RA).Objectives:To study the ability of drug concentration or estimating clearance to identify ADA to adalimumab.Methods:Adalimumab concentration was measured with a validated ELISA. ADA was measured using a capture ELISA (Theradiag®) and the Meso scale discovery (MSD) platform. Using a bayesian PK model, adalimumab clearance was estimated at 1, 3, 6 and 12 months. Predictions for ADA presence were calculated, and the correlation between ADA and adalimumab clearance was analysed.Results:We analyzed 108 samples from 53 RA patients. Serum concentrations and clearance estimates showed good prediction performance for ADA presence (Table 1). There was a correlation between adalimumab clearance and ADA (Figure 1).Table 1.Immunogenicity prediction of adalimumab, using trough concentration or estimated clearanceTime of visitADA methodAdalimumab trough concentrationAdalimumab estimated clearanceAUC ROCp-valueAUC ROCp-valueMonth 1THER.55.6411.52.8358MSD.65.0821.61.1872Month 3THER.89.0006.91.0003MSD.73.0096.72.0131Month 6THER.95.0035.95.0035MSD.85.0004.84.0006Month 12THER.87.0045.86.0057MSD.88.0002.88.0002Figure 1.correlation between adalimumab estimated clearance and ADA as provided by the Meso scale discovery (MSD) plateformConclusion:Adalimumab concentration and clearance should be considered as reliable predictors for ADA presence in RA patients.Acknowledgments:Measurement of adalimumab serum concentrations was performed within the ‘Centre pilote de suivi biologique des anticorps thérapeutiques’ (CePiBAc)– Pilot centre for therapeutic antibodies monitoring platform of Tours University Hospital, which was cofinanced by the European Regional Development Fund (ERDF). We thank Oscar Knight, Delphine Delord and Fabien Giannoni (ABIRISK lab technician), Caroline Brochon and Anne Claire Duveau (CePIBAc), Aliette Decock-Giraudaud (Centre de ressource-Biobank), Sophie Tourdot (ABRISIK Project manager), Aline Doublet (Assistance Publique Hopitaux de Paris, Agnès Hincelin-Méry (Sanofi, Chilly-Mazarin, France). This work has received support from the Innovative Medicines Initiative Joint Undertaking (IMI JU) under grant agreement no. 115303, the resources of which are composed of financial contributions from the European Union’s Seventh Framework Programme (FP7/2007-2013) and European Federation of Pharmaceutical Industries and Associations (EFPIA) companies’ in-kind contributions.Disclosure of Interests:David Ternant Consultant of: Sanofi and Amgen., Jamal Elhasnaoui: None declared, Natacha Szely: None declared, Salima Hacein-Bey: None declared, Aude Gleizes: None declared, Christophe Richez Consultant of: Abbvie, Amgen, Mylan, Pfizer, Sandoz and UCB., Jessica Manson: None declared, Martin SOUBRIER: None declared, Olilvier Brocq: None declared, Jérôme Avouac: None declared, Anna Fogdell-Hahn Grant/research support from: Biogen Idec and Pfizer., Consultant of: Pfizer, Biogen, Merck-Serono, and Sanofi-Genzyme., Pierre Dönnes: None declared, Gilles Paintaud Grant/research support from: Amgen, Genzyme (Sanofi), Lilly, Merck, Novartis, and Roche Pharma., Consultant of: Chugai, Novartis and Shire (Takeda), with remunerations received by his institution., Céline Desvignes: None declared, Florian Deisenhammer: None declared, Sebastian Spindeldreher Employee of: Novartis, Marc Pallardy: None declared, Xavier Mariette Consultant of: BMS, Gilead, Medimmune, Novartis, Pfizer, Servier, UCB, Denis Mulleman Grant/research support from: Non-governmental organisation Lions Club Tours Val de France, French Society for Rheumatology., Consultant of: Pfizer, Novartis.
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