Novel Common Genetic Susceptibility Loci for Colorectal Cancer

BACKGROUND: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. METHODS: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided. RESULTS: The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0. CONCLUSIONS: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screenin

Recherche de mutations du gène ADAMTS13 dans deux cohortes de patients suspects de Syndrome d'Upschaw-Schulman

Le syndrome d'Upshaw-Schulman ou purpura thrombotique thrombocytopénique héréditaire (PTT) est une pathologie génétique autosomique récessive rare, engageant le pronostic vital, dont le mécanisme physiopathologique réside dans l'altération constitutionnelle de la protéase du facteur de von Willebrand, ADAMTS13 (a desintegrin and metalloproteinase with thrombospondin type 1 repeats). Des mutations hétérozygotes composites ou homozygotes du gène ADAMTS13 ont été impliquées dans la survenue de la maladie. Ce mémoire expose les résultats du séquençage des régions codantes du gène ADAMTS13 chez 35 patients suspects de syndrome d Upschaw-Schulman, répartis en deux cohortes distinctes, qui diffèrent par l'âge du début de la pathologie. Nous avons mis en évidence 25 mutations non décrites dans la littérature internationale, et souligné les effets fonctionnels fins de certains modulateurs de l'activité ADAMTS13.NANTES-BU Médecine pharmacie (441092101) / SudocSudocFranceF

Étude du gène SHOX et de la région PAR1 sur une cohorte de 125 patients avec retard de croissance

Les phénotypes de petite taille touche 3% de la population et représentent l'un des plus fréquents motifs de suivi médical pendant l'enfance. Le gène SHOX est fréquemment impliqué dans la dyschondrostéose (Syndrome de Léri-Weill), mais aussi dans un certain nombre de cas de petites tailles idiopathiques, c'est pourquoi l'exploration de ce gène est de plus en plus prescrite. Ce mémoire retrace l'étude nantaise d'une cohorte de 125 patients aboutissant sur la mise au point d'un séquençage des régions codantes du gène, ainsi que sur la réalisation d'une fiche d informations cliniques devant permettre, à l'avenir, une meilleure sélection des patients pour l'exploration du gène SHOX.NANTES-BU Médecine pharmacie (441092101) / SudocSudocFranceF

Identification d'un gène humain localisé en 17q12, codant pour un membre de la famille F-box (Fbxo47) (étude des caractéristiques de la protéine )

Les altérations chromosomiques dans la région 17q surviennent dans de nombreux cancers, incluant les tumeurs papillaires rénales (pRCC), suggérant la présence d'un gène impliqué dans l'oncogenèse. Une analyse de perte d'hétérozygotie sur 15 cas de pRCC nous a permis de définir une zone minimale de délétion autour du marqueur D17S250 (17q12), dans laquelle nous avons isolé un nouveau gène, FBXO47. Ce transcrit apparaît fortement exprimé dans le testicule. La recherche de domaines protéiques caractéristiques a permis de montrer la présence: d'un domaine F-box, dont nous avons démontré la fonctionnalité; d'un motif Leucine-zipper ; d'une séquence d'adressage mitochondrial. Le motif F-box définit une famille de protéines dont la majorité des membres appartient à la voie de dégradation ubiquitine-protéasome dépendante. Afin de déterminer le rôle de Fbxo47 au sein de la cellule, nous avons cherché à identifier ses protéines partenaires. La technique de double-hybride nous a permis d'identifier Gfm1, facteur d'élongation principal de la traduction mitochondriale. Ce travail de thèse représente donc la première description de la présence du système F-box dans la matrice mitochondriale chez l'homme.Genetic alterations of chromosome arm 17q occur in numerous tumor types, including papillary renal cell carcinoma (pRCC). It suggests the presence of a tumor suppressor gene on the long arm of chromosome 17, which is critical for carcinogenesis. In this study, we analyzed 15 cases of pRCC for LOH. We identified a minimal deleted region in which the D17S250 marker (17q12). We isolated the cDNA of a novel gene named FBXO47. FBXO47 cDNA is preferentially expressed in normal tissue, particularly in the testis. The search of characteristic protein domains showed the presence of: a F-box domain, that we showed the functionality in vitro and in vivo; a Leucine-zipper; and a sequence of addressing mitochondrial. Most proteins of the family defined by the F-box motif belong to the ubiquitine-proteasome pathway. In order to determine the cellular function of Fbxo47, we sought to identify its protein partners. A screening in two- hybrid system enabled us to identify the protein Gfm1, the principal elongation factor of the mitochondrial translation. This thesis work represents indeed the first description of the presence of F-box system in mitochondrial matrix in human.NANTES-BU Médecine pharmacie (441092101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

High HFE mutation incidence in idiopathic erythrocytosis

IF 5.128International audienc

Acute cytotoxicity of MIRA-1/NSC19630, a mutant p53-reactivating small molecule, against human normal and cancer cells via a caspase-9-dependent apoptosis

International audienceAlthough numerous studies have focused on the mechanisms of action of the candidate chemotherapeutic drug MIRA-1/NSC19630, initially described as a mutant p53-reactivating small molecule, the issue of its toxicological evaluation remains open. Here, we devised a strategy to examine the effects of MIRA-1 on a variety of human normal cells and cancer cell lines. First, we demonstrated a massive and rapid (within 2 hours) MIRA-1 apoptotic effect on human normal primary epithelial cells as shown using an intestinal mucosa explant assay. MIRA-1 was also cytotoxic to primary and subcultured human mesenchymal cells. Interestingly these effects were restricted to actively proliferating cells. Second, MIRA-1 acute toxicity was independent of p53, since it occurred in human normal cells with increased or silenced p53 expression level, in cancer cells derived from solid or liquid tumors, with either mutated or wt TP53, and in cancer cells devoid of p53. Third, combined pharmacological and genetic approaches showed that MIRA-1 acute cytotoxicity was mediated by a caspase-9-dependent apoptosis. In conclusion, our strategy unveils the limitations of the targeted action of a small molecule designed to reactivate mutant p53

Two novel variants of uncertain significance in GP9 associated with Bernard–Soulier syndrome: Are they true mutations?

International audienceBernard–Soulier syndrome (BSS) is an autosomal recessive major thrombocytopathy, the symptoms of which are mainly marked by mucocutaneous bleeding. This rare disease, initially described in the 1970s, is the result of an abnormal formation of the glycoprotein complex Ib-IX-V (GP Ib-IX-V), a platelet receptor of von Willebrand factor. A large number of mutations, sometimes involving the GP9 gene, have been described as possibly responsible for the disease. We report here the case of a BSS patient who presented with persistent thrombocytopenia (31x10[9]/L) and decreased surface expression of GPIb-IX-V on large platelets with anisocytosis. Thorough molecular analyses disclosed two previously unreported GP9 variants, respectively c.230T>A (p.Leu77Gln) and c.255C>A (p.Asn85Lys). Both are likely to modify the conformation of GP-IX interactions with other glycoproteins of the Ib-IX-V complex and thus proper expression of this complex on the membrane of platelets

The density of Tbet+ tumor-infiltrating T lymphocytes reflects an effective and druggable preexisting adaptive antitumor immune response in colorectal cancer, irrespective of the microsatellite status

International audiencePurpose: The recent success of anti-PD1 antibody in metastatic colorectal cancer (CRC) patients with microsatellite instability (MSI), known to be associated with an upregulated Th1/Tc1 gene signature, provides new promising therapeutic strategies. However, the partial objective response highlights a crucial need for relevant, easily evaluable, predictive biomarkers. Here we explore whether in situ assessment of Tbet+ tumor infiltrating lymphocytes (TILs) reflects a pre-existing functional antitumor Th1/Tc1/IFNγ response, in relation with clinicopathological features, microsatellite status and expression of immunoregulatory molecules (PD1, PDL1, IDO-1). Methodology: In two independent cohorts of CRC (retrospective n = 80; prospective n = 27) we assessed TILs density (CD3, Tbet, PD1) and expression profile of PDL1 and IDO-1 by immunohistochemistry/image analysis. Furthermore, the prospective cohort allowed to perform ex vivo CRC explant cultures and measure by Elisa the IFNγ response, at baseline and upon anti-PD1 treatment. Results: The density of Tbet+ TILs was significantly higher in MSI CRC, especially in the medullary subtype but also in a subgroup of MSS (microsatellite stable), and positively correlated with PD1 and PDL1 expression, but not with IDO-1. Finally, a high number of Tbet+ TILs was associated with a favorable overall survival. These Tbet+ TILs were functional as their density positively correlated with basal IFNγ levels. In addition, the combined score of Tbet+ PD1+ TILs coupled with IDO-1 expression predicted the magnitude of the IFNγ response upon anti-PD1. Conclusion: Altogether, immunohistochemical quantification of Tbet+ TILs is a reliable and accurate tool to recapitulate a preexisting Th1/Tc1/IFNγ antitumor response that can be reinvigorated by anti-PD1 treatment

Burden of rare variants in arrhythmogenic cardiomyopathy with right dominant form associated genes provides new insights for molecular diagnosis and clinical management.

International audienc