ORCID Profile
0000-0001-8361-0936
Current Organisation
INSERM
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Publisher: Elsevier BV
Date: 05-2019
Publisher: Springer Science and Business Media LLC
Date: 14-01-2019
DOI: 10.1038/S41467-018-08078-W
Abstract: The original version of this Article contained errors in the spelling of the authors Fan Liu and M. Arfan Ikram, which were incorrectly given as Fan Lui and Arfan M. Ikram. In addition, the original version of this Article also contained errors in the author affiliations which are detailed in the associated Publisher Correction.
Publisher: Springer Science and Business Media LLC
Date: 22-12-2017
Publisher: Springer Science and Business Media LLC
Date: 03-07-2020
DOI: 10.1038/S41467-020-16483-3
Abstract: Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that s le sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence.
Publisher: Elsevier BV
Date: 07-2014
Publisher: Springer Science and Business Media LLC
Date: 08-05-2018
DOI: 10.1038/S41467-018-04086-Y
Abstract: The skin’s tendency to sunburn rather than tan is a major risk factor for skin cancer. Here we report a large genome-wide association study of ease of skin tanning in 176,678 subjects of European ancestry. We identify significant association with tanning ability at 20 loci. We confirm previously identified associations at six of these loci, and report 14 novel loci, of which ten have never been associated with pigmentation-related phenotypes. Our results also suggest that variants at the AHR/AGR3 locus, previously associated with cutaneous malignant melanoma the underlying mechanism of which is poorly understood, might act on disease risk through modulation of tanning ability.
Publisher: Springer Science and Business Media LLC
Date: 13-01-2010
Publisher: Elsevier BV
Date: 08-2019
Publisher: Cold Spring Harbor Laboratory
Date: 17-10-2018
Abstract: Most expression quantitative trait locus (eQTL) studies to date have been performed in heterogeneous tissues as opposed to specific cell types. To better understand the cell-type–specific regulatory landscape of human melanocytes, which give rise to melanoma but account for % of typical human skin biopsies, we performed an eQTL analysis in primary melanocyte cultures from 106 newborn males. We identified 597,335 cis -eQTL SNPs prior to linkage disequilibrium (LD) pruning and 4997 eGenes (FDR 0.05). Melanocyte eQTLs differed considerably from those identified in the 44 GTEx tissue types, including skin. Over a third of melanocyte eGenes, including key genes in melanin synthesis pathways, were unique to melanocytes compared to those of GTEx skin tissues or TCGA melanomas. The melanocyte data set also identified trans -eQTLs, including those connecting a pigmentation-associated functional SNP with four genes, likely through cis -regulation of IRF4 . Melanocyte eQTLs are enriched in cis -regulatory signatures found in melanocytes as well as in melanoma-associated variants identified through genome-wide association studies. Melanocyte eQTLs also colocalized with melanoma GWAS variants in five known loci. Finally, a transcriptome-wide association study using melanocyte eQTLs uncovered four novel susceptibility loci, where imputed expression levels of five genes ( ZFP90 , HEBP1 , MSC , CBWD1 , and RP11-383H13.1 ) were associated with melanoma at genome-wide significant P -values. Our data highlight the utility of lineage-specific eQTL resources for annotating GWAS findings, and present a robust database for genomic research of melanoma risk and melanocyte biology.
Publisher: Springer Science and Business Media LLC
Date: 03-08-2015
DOI: 10.1038/NG.3373
Publisher: Public Library of Science (PLoS)
Date: 02-02-2016
Publisher: Wiley
Date: 07-06-2019
DOI: 10.1111/JDV.15680
Publisher: Elsevier BV
Date: 02-2012
DOI: 10.1038/JID.2011.322
Publisher: Oxford University Press (OUP)
Date: 17-09-2011
DOI: 10.1093/HMG/DDR415
Publisher: Elsevier BV
Date: 12-2018
Publisher: Springer Science and Business Media LLC
Date: 2012
Publisher: Springer Science and Business Media LLC
Date: 06-11-2015
DOI: 10.1038/NCOMMS9804
Abstract: Eczema often precedes the development of asthma in a disease course called the ‘atopic march’. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27 P= 2.1 × 10 −8 ) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58 P= 5.3 × 10 −9 ). Additional susceptibility loci identified at genome-wide significance are FLG (1q21.3), IL4/KIF3A (5q31.1), AP5B1/OVOL1 (11q13.1), C11orf30/LRRC32 (11q13.5) and IKZF3 (17q21). We show that predominantly eczema loci increase the risk for the atopic march. Our findings suggest that eczema may play an important role in the development of asthma after eczema.
Publisher: Springer Science and Business Media LLC
Date: 18-05-2008
DOI: 10.1038/NG.163
Publisher: Springer Science and Business Media LLC
Date: 19-10-2011
DOI: 10.1038/NATURE10539
Abstract: So far, no common environmental and/or phenotypic factor has been associated with melanoma and renal cell carcinoma (RCC). The known risk factors for melanoma include sun exposure, pigmentation and nevus phenotypes risk factors associated with RCC include smoking, obesity and hypertension. A recent study of coexisting melanoma and RCC in the same patients supports a genetic predisposition underlying the association between these two cancers. The microphthalmia-associated transcription factor (MITF) has been proposed to act as a melanoma oncogene it also stimulates the transcription of hypoxia inducible factor (HIF1A), the pathway of which is targeted by kidney cancer susceptibility genes. We therefore proposed that MITF might have a role in conferring a genetic predisposition to co-occurring melanoma and RCC. Here we identify a germline missense substitution in MITF (Mi-E318K) that occurred at a significantly higher frequency in genetically enriched patients affected with melanoma, RCC or both cancers, when compared with controls. Overall, Mi-E318K carriers had a higher than fivefold increased risk of developing melanoma, RCC or both cancers. Codon 318 is located in a small-ubiquitin-like modifier (SUMO) consensus site (ΨKXE) and Mi-E318K severely impaired SUMOylation of MITF. Mi-E318K enhanced MITF protein binding to the HIF1A promoter and increased its transcriptional activity compared to wild-type MITF. Further, we observed a global increase in Mi-E318K-occupied loci. In an RCC cell line, gene expression profiling identified a Mi-E318K signature related to cell growth, proliferation and inflammation. Lastly, the mutant protein enhanced melanocytic and renal cell clonogenicity, migration and invasion, consistent with a gain-of-function role in tumorigenesis. Our data provide insights into the link between SUMOylation, transcription and cancer.
Publisher: Springer Science and Business Media LLC
Date: 16-12-2020
Publisher: Elsevier BV
Date: 12-2016
Publisher: Springer Science and Business Media LLC
Date: 02-12-2015
DOI: 10.1038/NATURE16158
Publisher: Springer Science and Business Media LLC
Date: 27-04-2020
Publisher: Springer Science and Business Media LLC
Date: 1996
DOI: 10.1038/NG0196-58
Abstract: The changes in the type of haemoglobin (Hb) produced during embryonic, fetal and adult life, have served as a paradigm for understanding the developmental regulation of human genes. A genetically determined persistence of fetal Hb synthesis has an ameliorating effect on beta thalassaemia and sickle cell anaemia, globally the commonest single gene disorders. The search for the putative gene(s) controlling the level of fetal Hb production has been extremely difficult because this trait may be influenced by several factors. We have studied a large kindred with hereditary persistence of fetal haemoglobin (HPFH). Using a genetic mapping strategy and statistical methods that account simultaneously for the effects of several genetic factors, we have demonstrated that in addition to the two factors (beta thalassaemia and Xmn I-G gamma site) on chromosome 11p, there is a third major genetic determinant for fetal Hb production localized on chromosome 6q.
Publisher: Elsevier BV
Date: 12-2017
Publisher: Springer Science and Business Media LLC
Date: 06-2020
DOI: 10.1038/S41467-020-16590-1
Abstract: Genome-wide association studies (GWAS) have identified ~20 melanoma susceptibility loci, most of which are not functionally characterized. Here we report an approach integrating massively-parallel reporter assays (MPRA) with cell-type-specific epigenome and expression quantitative trait loci (eQTL) to identify susceptibility genes/variants from multiple GWAS loci. From 832 high-LD variants, we identify 39 candidate functional variants from 14 loci displaying allelic transcriptional activity, a subset of which corroborates four colocalizing melanocyte cis -eQTL genes. Among these, we further characterize the locus encompassing the HIV-1 restriction gene, MX2 (Chr21q22.3), and validate a functional intronic variant, rs398206. rs398206 mediates the binding of the transcription factor, YY1, to increase MX2 levels, consistent with the cis -eQTL of MX2 in primary human melanocytes. Melanocyte-specific expression of human MX2 in a zebrafish model demonstrates accelerated melanoma formation in a BRAF V600E background. Our integrative approach streamlines GWAS follow-up studies and highlights a pleiotropic function of MX2 in melanoma susceptibility.
No related grants have been discovered for Florence Demenais.