Identification of a BRCA2-Specific modifier locus at 6p24 related to breast cancer risk

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9×10−8). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat

Identification of parameters of cartilage for hip joint mechanical model

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Viscoelastic modeling and quantitative experimental characterization of normal and osteoarthritic human articular cartilage using indentation

International audienceThe viscoelastic behavior of articular cartilage changes with progression of osteoarthritis. The objective of this study is to quantify this progression and to propose a viscoelastic model of articular cartilage taking into account the degree of osteoarthritis that which be easily used in predictive numerical simulations of the hip joint behavior. To quantify the effects of osteoarthritis (OA) on the viscoelastic behavior of human articular cartilage, samples were obtained from the hip arthroplasty due to femoral neck fracture (normal cartilage) or advanced coxarthrosis (OA cartilage). Experimental data were obtained from instrumented indentation tests on unfrozen femoral cartilage collected and studied in the day following the prosthetic hip surgery pose. By using an inverse method coupled with a numerical modeling (FEM) of all experimental data of the indentation tests, the viscoelastic properties of the two states were quantified. Mean values of viscoelastic parameters were significantly lower for OA cartilage than normal (instantaneous and relaxed tension moduli, viscosity coefficient). Based on the results and in the thermodynamic framework, a constitutive viscoelastic model taking into account the degree of osteoarthritis as an internal variable of damage is proposed. The isotropic phenomenological viscoelastic model including degradation provides an accurate prediction of the mechanical response of the normal human cartilage and OA cartilage with advanced coxarthrosis but should be further validated for intermediate degrees of osteoarthritis

Identification of material parameters of cartilage for hip joint mechanical model

International audienceCartilage is an essential element of joint. It allows the joint surfaces to slide against one another and to distribute the pressure between them. Without cartilage, many movements would be impossible or at least painful. Understanding the mechanical behaviour of cartilage andassociated parameters would allow, through appropriate modelling, to better understand the onset of certain diseases such as osteoarthritis or efficiently analyse the pressure distribution in the joint. Many studies have been conducted on the mechanical properties of cartilage

Comportement viscoélastique endommageable du cartilage articulaire humain normal et arthrosique : modélisation et caractérisation à l´aide d´essais d´indentation instrumentée. Vers une quantification des effets de l'arthrose et de la viscosité du cartilage

Le comportement viscoélastique du cartilage articulaire se modifie avec le degré d'arthrose. L'objectif de cette étude est de quantifier cette modification et de proposer un modèle viscoélastique du cartilage articulaire prenant en compte le degré d'arthrose et pouvant être aisément utilisé dans des simulations numériques de prévision du comportement l’articulation coxo-fémorale. Pour quantifier les effets de l'arthrose sur le comportement viscoélastique du cartilage articulaire humain, des échantillons ont été prélevé suite à des arthroplasties de la hanche : fractures de col du fémur pour le cartilage normal et opérations de pose de prothèse de hanche pour le cartilage arthrosique avancé. Les mesures d’indentation sur les échantillons ont été obtenues à l’aide d’essais d’indentation instrumentée effectués dans les 24 heures suivant le prélèvement. En utilisant une méthode inverse couplant les mesures expérimentales à une modélisation numérique par éléments finis des essais, les propriétés viscoélastiques des deux états (normal et arthrosique avancé) ont été quantifiées. Les valeurs moyennes des paramètres viscoélastiques sont significativement plus faibles pour le cartilage arthrosique que la normale (modules instantané, relaxé et coefficient de viscosité). Sur la base des résultats d’identification et dans le cadre de la thermodynamique des processus irréversibles, un modèle viscoélastique de comportement prenant en compte le degré d'arthrose comme une variable interne d'endommagement est proposé. Le modèle phénoménologique proposé fournit une bonne prévision de la réponse viscoélastique du cartilage humain pour les deux états (normal et arthrosique avancée). A titre d’exemple d’application, ce comportement est introduit dans une modélisation de l’articulation de la hanche et les effets de l’arthrose et de la viscosité sur les pressions et les aires de contact sont quantifiés pour une simulation d’un mouvement de la vie quotidienne

Identification of geometrical parameters of femoral heads for hip joint mechanical model

International audienceThe femoral head is a protrusion that fits together with the acetabulum of the pelvis. This joint called hip joint is an important joint in the body. It transmits the body weight to the lower limb and allows humans to move. In most textbooks, there is an excellent congruence between thearticular surfaces, thus describing the femoral head and the acetabulum as perfect spheres

Micro-indentation and coupling test-calculations for identification by inverse method of non linear behavior of human femoral head cartilage

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