Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma.

Thirteen common susceptibility loci have been reproducibly associated with cutaneous malignant melanoma (CMM). We report the results of an international 2-stage meta-analysis of CMM genome-wide association studies (GWAS). This meta-analysis combines 11 GWAS (5 previously unpublished) and a further three stage 2 data sets, totaling 15,990 CMM cases and 26,409 controls. Five loci not previously associated with CMM risk reached genome-wide significance (P < 5 × 10(-8)), as did 2 previously reported but unreplicated loci and all 13 established loci. Newly associated SNPs fall within putative melanocyte regulatory elements, and bioinformatic and expression quantitative trait locus (eQTL) data highlight candidate genes in the associated regions, including one involved in telomere biology.[Please see the Supplementary Note for acknowledgments.]This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/ng.337

Multi-Marker Analytical Strategies to Identify Genes and Gene-Gene Interactions Associated with Cutaneous Melanoma

Le mélanome cutané est un cancer des cellules de la peau (mélanocytes) qui se situe, en France, au 11e rang des cancers les plus fréquents. Sa mortalité reste élevée lorsqu’il est diagnostiqué à un stade tardif. Ce cancer résulte de nombreux facteurs génétiques, environnementaux et des interactions entre ces facteurs. La susceptibilité génétique à ce cancer recouvre un large spectre de variabilité génétique, depuis des mutations rares conférant un risque élevé jusqu’à des variants fréquents conférant un risque modeste. C’est dans le cadre de l’identification de variants fréquents liés à l’apparition du mélanome et à son pronostic que se situe mon travail de thèse. À ce jour, les études d’associations pangénomiques du mélanome ont identifié des variants fréquents à effets relativement modestes qui expliquent seulement une part de la composante génétique. Les variants fonctionnels au sein des régions identifiées sont le plus souvent inconnus. Les études pangénomiques ont eu principalement recours à des analyses simple-marqueur qui peuvent manquer de puissance pour détecter des variants ayant un effet individuel faible ou interagissant avec d’autres variants. L’objectif principal de ce travail de thèse a été de proposer des stratégies d’analyse multi-marqueurs pour identifier de nouveaux gènes impliqués dans le mélanome et pour caractériser des variants potentiellement fonctionnels au sein des régions du génome associées au mélanome.Pour identifier de nouveaux gènes associés au risque de mélanome et à un facteur pronostique de ce cancer (l’indice de Breslow), nous avons proposé une stratégie d’analyse multi-marqueurs qui intègre une analyse de pathways biologiques basée sur la méthode GSEA (Gene Set Enrichment Analysis) et une analyse d’interactions entre gènes au sein des pathways associés au mélanome. Ces analyses ont été menées dans deux études : l’étude française MELARISK et l’étude américaine du MD Anderson Cancer Center (MDACC), totalisant 2 980 cas et 3 823 témoins. Nous avons identifié une interaction entre les gènes, TERF1 et AFAP1L2, pour le risque de mélanome et une interaction entre les gènes, CDC42 et SCIN, pour l’indice de Breslow. Ces gènes sont particulièrement pertinents sur le plan biologique du fait de leur rôle dans la biologie des télomères pour la première paire de gènes et dans la dynamique des filaments d’actine pour la seconde paire. Afin d’identifier les variants potentiellement fonctionnels au sein des régions du génome mises en évidence par études pangénomiques, nous avons proposé une stratégie de cartographie fine qui repose principalement sur une méthode de régression pénalisée (méthode HyperLasso) appliquée à tous les variants de la région étudiée. Par l’analyse de la région 16q24 qui contient le gène MC1R dont les variants fonctionnels sont connus, nous avons montré que cette stratégie était capable d’identifier ces variants parmi de nombreux variants associés au mélanome dans cette région. Nous avons contribué à identifier cinq nouvelles régions du génome associées au mélanome par méta-analyse d’études pangénomiques réalisées au niveau mondial (43 000 sujets) puis mené une étude de cartographie fine de toutes les régions associées au mélanome, en se basant sur la stratégie proposée et validée dans la région 16q24. Les stratégies d’analyses multi-marqueurs proposées dans le cadre de ce travail de thèse ont permis d’identifier de nouveaux gènes associés au risque de mélanome et à un facteur pronostique de ce cancer et de caractériser les variants génétiques potentiellement fonctionnels au sein des régions du génome identifiées par études pangénomiques.Cutaneous melanoma is a skin cancer developed from melanocytes. It is the 11th most common cancers in France. Mortality due to melanoma remains high when diagnosed at a late stage. This cancer results from many genetic, environmental factors and interactions between these factors. The genetic susceptibility to melanoma covers a broad spectrum of genetic variation, from rare mutations conferring high risk to common variants conferring low risk. My thesis was conducted in the framework of low-risk variants associated with melanoma occurrence and prognosis. To date, genome-wide association studies (GWAS) of melanoma have identified common variants with relatively modest effects which only explain a part of the genetic component of this cancer. Functional variants at the identified loci are mostly unknown. GWASs have been mainly conducted using single-marker analysis which may be underpowered to detect variants with small effect or interacting with each other. The main objective of this thesis was to propose multi-marker analysis strategies to identify novel genes involved in melanoma and to characterize potentially functional variants in chromosomal regions found associated with melanoma. To identify new genes associated with melanoma risk and a prognostic factor for this cancer (Breslow thickness), we proposed a multi-marker analysis strategy which integrates pathway analysis based on the GSEA (Gene Set Enrichment Analysis) method and gene-gene interaction analysis within melanoma-associated pathways. These analyses were conducted in two studies: the French MELARISK study and the North-American MD Anderson Cancer Center (MDACC) study, with a total of 2,980 cases and 3,823 controls. We identified gene-gene interactions between TERF1 and AFAP1L2 genes for melanoma risk and between CDC42 and SCIN genes for Breslow thickness. These genes are biologically relevant because of their role in telomere biology for the former gene pair and in actin dynamics for the latter pair. To identify potentially functional variants at loci identified by GWAS, we proposed a fine mapping strategy which is mainly based on a penalized regression approach (HyperLasso method) that can be applied to all variants of the region under study. By studying the 16q24 region which harbors the MC1R gene whose functional variants are known, we showed this strategy was able to identify those variants among many variants associated with melanoma in this region. We contributed to the identification of five novel regions associated with melanoma through a worldwide meta-analysis of melanoma GWASs (43,000 subjects) and conducted fine mapping of all melanoma-associated loci using the strategy we proposed and validated in the 16q24 region. The multi-marker strategies proposed in this work have allowed identifying new biologically relevant genes associated with risk of melanoma and a major melanoma prognostic factor and characterizing potentially functional genetic variants within regions identified by GWAS

Développement d'un automate de préparation des anticancéreux injectables

PARIS-BIUP (751062107) / SudocSudocFranceF

Comprimés flottants matriciels (optimisation de l'agent effervescent)

PARIS-BIUP (751062107) / SudocSudocFranceF

SigMod: an exact and efficient method to identify a strongly interconnected disease-associated module in a gene network

ISSN:1367-4803ISSN:1460-205

New susceptibility loci for cutaneous melanoma risk and progression revealed using a porcine model

International audienceDespite major advances, it is estimated that a large part of melanoma predisposing genes remains to be discovered. Animal models of spontaneous diseases are valuable tools and experimental crosses can be used to identify and fine-map new susceptibility loci associated with melanoma. We performed a Genome-Wide Association Study (GWAS) of melanoma occurrence and progression (clinical ulceration and presence of metastasis) in a porcine model of spontaneous melanoma, the MeLiM pig. Five loci on chromosomes 2, 5, 7, 8 and 16 showed genome-wide significant associations ( p < 5 × 10 –6 ) with either one of these phenotypes. Suggestive associations ( p < 5 × 10 –5 ) were also found at 16 additional loci. Moreover, comparison of the porcine results to those reported by human melanoma GWAS indicated shared association signals notably at CDKAL1 and TERT loci but also nearby CCND1 , FTO, PLA2G6 and TMEM 38B-RAD23B loci. Extensive search of the literature revealed a potential key role of genes at the identified porcine loci in tumor invasion ( DST , PLEKHA5, CBY1 , LIMK2 and ETV5 ) and immune response modulation ( ETV5 , HERC3 and DICER1 ) of the progression phenotypes. These biological processes are consistent with the clinico-pathological features of MeLiM tumors and can open new routes for future melanoma research in humans

A novel role for cilia function in atopy: ADGRV1 and DNAH5 interactions

International audienceBACKGROUND:Atopy, an endotype underlying allergic diseases, has a substantial genetic component.OBJECTIVE:Our goal was to identify novel genes associated with atopy in asthma-ascertained families.METHODS:We implemented a three-step analysis strategy in three datasets: The Epidemiological study on the Genetics and Environment of Asthma (EGEA) dataset: 1,660 subjects; The Saguenay-Lac-Saint-Jean (SLSJ) dataset: 1,138 subjects; and The Medical Research Council (MRC) dataset: 446 subjects). This strategy included a single-SNP genome-wide association study (GWAS), the selection of related gene pairs based on statistical filtering of GWAS results and text-mining filtering using GRAIL and SNP-SNP interaction analysis of selected gene pairs.RESULTS:We identified the 5q14 locus, harboring the adhesion G protein-coupled receptor V1 (ADGRV1) gene, that showed genome-wide significant association with atopy (rs4916831; Pmeta=6.8x10-9). Statistical filtering of GWAS results followed by text-mining filtering revealed relationships between ADGRV1 and three genes showing suggestive association with atopy (P≤10-4). SNP-SNP interaction analysis between ADGRV1 and these three genes showed significant interaction between ADGRV1 rs17554723 and two correlated SNPs (rs2134256 and rs1354187) within dynein axonemal heavy chain 5 (DNAH5) gene (Pmeta-int=3.6x10-5 and 6.1x10-5, that met the multiple-testing corrected threshold of 7.3x10-5). Further conditional analysis indicated that rs2134256 alone accounted for the interaction signal with rs17554723.CONCLUSION:As both DNAH5 and ADGRV1 contribute to function of cilia, this study suggests that cilia dysfunction may represent a novel mechanism underlying atopy. Combining GWAS and epistasis analysis driven by statistical and knowledge-based evidence represents a promising approach for identifying new genes involved in complex traits

Interactive effect between ATPase-related genes and early-life tobacco smoke exposure on bronchial hyper-responsiveness detected in asthma-ascertained families

International audienceBackground: A positional cloning study of bronchial hyper-responsiveness (BHR) at the 17p11 locus in the French Epidemiological study on the Genetics and Environment of Asthma (EGEA) families showed significant interaction between early life environmental tobacco smoke (ETS) exposure and genetic variants located in DNAH9. This gene encodes the heavy chain subunit of axonemal dynein, which is involved with adenosine triphosphate (ATP) in the motile cilia function. Our goal was to identify genetic variants at other genes interacting with ETS in BHR by investigating all genes belonging to the “ATP-binding” and “ATPase activity” pathways which include DNAH9, are targets of cigarette smoke and play a crucial role in the airway inflammation. Methods: Family-based interaction tests between ETS exposed versus unexposed BHR siblings were conducted in 388 EGEA families. Twenty SNPs showing interaction signals (P≤5.10-3) were tested in the 253 Saguenay-Lac-Saint-Jean (SLSJ) families. Results: One of these SNPs was significantly replicated for interaction with ETS in SLSJ families (P=0.003). Another SNP reached the significance threshold after correction for multiple testing in the combined analysis of the two samples (P=10-5). Results were confirmed using both a robust log-linear test and a gene-based interaction test.Conclusion: The SNPs showing interaction with ETS belong to the ATP8A1 and ABCA1 genes, which play a role in the maintenance of asymmetry and homeostasis of lung membrane lipids