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

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

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

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

Adhesive bond testing between composite laminates by laser shockwave loading

"Assembling materials by adhesive bonding has several advantages compared to other joining methods such as the use of fasteners or welding. Fasteners require drilling holes in the parts to be joined and both fastening and welding require significant investment in machinery. For metals, welded joints also generally produce a mechanically weaker heat affected zone. Adhesive bonding also has significant advantages for polymer-matrix composites. Drilling through composites has the drawback of cutting load-bearing fibers with adverse effects of possible delamination and excessive tool wear. It may also be economically advantageous to bond several small parts to make a large structure instead of having it co-cured. However, for all materials, the use of adhesive bonding for loadbearing structures is impeded by the absence of reliable nondestructive methods that can guarantee the strength of the joint, and in particular are able to very reliably identify the presence of near zerostrength \u201ckissing bonds\u201d [1]. Kissing bonds are undetectable by conventional ultrasonic inspection since the return echo from the interface in the pulse-echo technique does not depend upon the bond strength and only requires mechanical contact between the adherends. This is also the case for the transmitted echo. Although there have been many attempts to develop other ultrasonic approaches, such as using waves that propagate essentially along the bond line, none of these approaches has succeeded in detecting a weak bond other than those that are weakened by defects such disbonds or porosity [1-3]. These defects can be detected by the well established ultrasonic inspection technique and in the case of porosity, also by x-ray radiography. Among possible causes of weak bonds are contamination of surfaces prior to bonding, inadequate surface preparation, degradation of the adhesive from improper storage, and inadequate mixing ratio for two-part adhesives. In all these cases, there can be good mechanical contact without defects, combined with poor mechanical strength, undetectable by established ultrasonic inspection techniques. Ultrasonic techniques only apply weak stresses to the bond line and such weak stresses cannot reveal characteristics that are only apparent by applying significant stresses, like in destructive tests. Therefore, a reliable technique to identify such weak bonds requires application of a strong tensile stress across the bond line. A convenient approach that has been previously studied for evaluating the dhesion of coatings to their substrate and fibers to their matrix uses a pulsed laser to generate a large amplitude wave (shockwave) that propagates throughout the material [4-9]. This wave, being initially in compression, is converted by reflection on the back surface of the sample into a strong tensile wave that can pry apart the sample and disbond the assembly. This approach has been more recently extended to proof testing of adhesive bonds between carbon-epoxy laminates [10,11]. To probe bond strength, higher and higher tensile stress loading is applied by increasing the laser pulse energy step by step. A \u201cgood\u201d joint will be unaffected under a given stress level whereas a weaker one will be damaged, allowing this method to evaluate the bond strength. The principle of the method is described next in more detail. We then describe how the ethod is implemented, the instrumentation that has been developed and the fabrication of weak bond test specimens. Finally we present some results and indicate erspectives and future developments.Peer reviewed: YesNRC publication: Ye

Perspectives d'émergence d'une filière forêt-chimie des extractibles Points de vue des acteurs du Nord-Est de la France et du Sud-Ouest de l'Allemagne

International audienceForest biomass can be the source of molecules of interest for the purpose of substituting or supplementing molecules derived from oil. As a result, an innovative conversion of wood extractives may well present an economic, social and environmental opportunity. The aim of our study is to better assess the prospects for the emergence of a new chemical conversion of wood and wood by-products in the Grand Est region basing ourselves on opinions and feelings of players in the forestry and forest-based industry and on the chemicals sector in this region and neighbouring ones. Our results pertain to three areas: forest industry corporate strategies for processing wood by-products, the perceptions players have of the emergence of a forest/extractive chemicals industry and of the prospects for such an industry to become established in the medium term. We naturally believe these results need to be more thoroughly researched so as to more precisely spell out the conditions for such an industry to be born.La biomasse forestière peut être une source de molécules d’intérêt dans le but de substituer ou de compléter les molécules pétro-sourcées. Par conséquent, une valorisation innovante des extractibles du bois semble être une opportunité économique, sociale et environnementale. L’objectif de notre étude est de mieux cerner les perspectives d’émergence d’une nouvelle valorisation chimique des connexes bois pour la région Grand Est, à partir des avis et ressentis des acteurs de la filière forêt-bois et de la valorisation chimique de cette région ainsi que de territoires voisins. Nos résultats se portent sur trois axes : les stratégies de valorisation des connexes des entreprises de la filière forêt-bois, les perceptions des acteurs sur l’émergence d’une filière forêt-chimie, et les perspectives de mise en place d’une telle filière à moyen terme. Nous conviendrons tout de même que les résultats doivent être approfondis dans le cadre de perspectives de recherche pour préciser les conditions de la mise en œuvre de cette filière

Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2

Introduction: Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour. Methods: We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach. Results: The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 x 10(-6)). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status. Conclusions: The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers

Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2.

Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour