Institute Of Medicina Predictiva I Personalitzada Del Cancer Imppc

Badalona, Spain

Institute Of Medicina Predictiva I Personalitzada Del Cancer Imppc

Badalona, Spain
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Messiaen L.,University of Alabama at Birmingham | Vogt J.,University of Ulm | Bengesser K.,University of Ulm | Fu C.,University of Alabama at Birmingham | And 6 more authors.
Human Mutation | Year: 2011

Mosaicism is an important feature of type-1 neurofibromatosis (NF1) on account of its impact upon both clinical manifestations and transmission risk. Using FISH and MLPA to screen 3500 NF1 patients, we identified 146 individuals harboring gross NF1 deletions, 14 of whom (9.6%) displayed somatic mosaicism. The high rate of mosaicism in patients with NF1 deletions supports the postulated idea of a direct relationship between the high new mutation rate in this cancer predisposition syndrome and the frequency of mosaicism. Seven of the 14 mosaic NF1 deletions were type-2, whereas four were putatively type-1, and three were atypical. Two of the four probable type-1 deletions were confirmed as such by breakpoint-spanning PCR or SNP analysis. Both deletions were associated with a generalized manifestation of NF1. Independently, we identified a third patient with a mosaic type-1 NF1 deletion who exhibited segmental NF1. Together, these three cases constitute the first proven mosaic type-1 deletions so far reported. In two of these three mosaic type-1 deletions, the breakpoints were located within PRS1 and PRS2, previously identified as hotspots for nonallelic homologous recombination (NAHR) during meiosis. Hence, NAHR within PRS1 and PRS2 is not confined to meiosis but may also occur during postzygotic mitotic cell cycles. © 2011 Wiley-Liss, Inc.

Javierre B.M.,Chromatin | Fernandez A.F.,Lhospitalet Of Llobregat | Richter J.,University of Kiel | Al-Shahrour F.,Research Center Principe Felipe | And 23 more authors.
Genome Research | Year: 2010

Monozygotic (MZ) twins are partially concordant for most complex diseases, including autoimmune disorders. Whereas phenotypic concordance can be used to study heritability, discordance suggests the role of non-genetic factors. In autoimmune diseases, environmentally driven epigenetic changes are thought to contribute to their etiology. Here we report the first high-throughput and candidate sequence analyses of DNA methylation to investigate discordance for autoimmune disease in twins. We used a cohort of MZ twins discordant for three diseases whose clinical signs often overlap: systemic lupus erythematosus (SLE), rheumatoid arthritis, and dermatomyositis. Only MZ twins discordant for SLE featured widespread changes in the DNA methylation status of a significant number of genes. Gene ontology analysis revealed enrichment in categories associated with immune function. Individual analysis confirmed the existence of DNA methylation and expression changes in genes relevant to SLE pathogenesis. These changes occurred in parallel with a global decrease in the 5-methylcytosine content that was concomitantly accompanied with changes in DNA methylation and expression levels of ribosomal RNA genes, although no changes in repetitive sequences were found. Our findings not only identify potentially relevant DNA methylation markers for the clinical characterization of SLE patients but also support the notion that epigenetic changes may be critical in the clinical manifestations of autoimmune disease. Copyright © 2010 Cold Spring Harbor Laboratory Press.

Gomez-Diaz E.,Institute Of Biologia Evolutiva Ibe | Jorda M.,Institute Of Medicina Predictiva I Personalitzada Del Cancer Imppc | Peinado M.A.,Institute Of Medicina Predictiva I Personalitzada Del Cancer Imppc | Rivero A.,IRD Montpellier
PLoS Pathogens | Year: 2012

A growing body of evidence points towards epigenetic mechanisms being responsible for a wide range of biological phenomena, from the plasticity of plant growth and development to the nutritional control of caste determination in honeybees and the etiology of human disease (e.g., cancer). With the (partial) elucidation of the molecular basis of epigenetic variation and the heritability of certain of these changes, the field of evolutionary epigenetics is flourishing. Despite this, the role of epigenetics in shaping host-pathogen interactions has received comparatively little attention. Yet there is plenty of evidence supporting the implication of epigenetic mechanisms in the modulation of the biological interaction between hosts and pathogens. The phenotypic plasticity of many key parasite life-history traits appears to be under epigenetic control. Moreover, pathogen-induced effects in host phenotype may have transgenerational consequences, and the bases of these changes and their heritability probably have an epigenetic component. The significance of epigenetic modifications may, however, go beyond providing a mechanistic basis for host and pathogen plasticity. Epigenetic epidemiology has recently emerged as a promising area for future research on infectious diseases. In addition, the incorporation of epigenetic inheritance and epigenetic plasticity mechanisms to evolutionary models and empirical studies of host-pathogen interactions will provide new insights into the evolution and coevolution of these associations. Here, we review the evidence available for the role epigenetics on host-pathogen interactions, and the utility and versatility of the epigenetic technologies available that can be cross-applied to host-pathogen studies. We conclude with recommendations and directions for future research on the burgeoning field of epigenetics as applied to host-pathogen interactions. © 2012 Gómez-Díaz et al.

Yamamoto F.,Institute Of Medicina Predictiva I Personalitzada Del Cancer Imppc | Yamamoto F.,University Paul Sabatier | Cid E.,Institute Of Medicina Predictiva I Personalitzada Del Cancer Imppc | Cid E.,University Paul Sabatier | And 4 more authors.
Transfusion Medicine Reviews | Year: 2012

Research on ABO has advanced significantly in recent years. A database was established to manage the sequence information of an increasing number of novel alleles. Genome sequencings have identified ABO orthologues and paralogues in various organisms and enhanced the knowledge on the evolution of the ABO and related genes. The most prominent advancements include clarification of the association between ABO and different disease processes. For instance, ABO status affects the infectivity of certain strains of Helicobacter pylori and Noroviruses as well as the sequestration and rosetting of red blood cells infected with Plasmodium falciparum. Genome-wide association studies have conclusively linked the ABO locus to pancreatic cancer, venous thromboembolism, and myocardial infarction in the presence of coronary atherosclerosis. These findings suggest ABO's important role in determining an individual's susceptibility to such diseases. Furthermore, our understanding of the structures of A and B transferases and their enzymology has been dramatically improved. ABO has also become a research subject in neurobiology and the preparation of artificial/universal blood and became a topic in the pseudoscience of "blood type diets." With such new progress, it has become evident that ABO is a critical player in the modern era of genomic medicine. This article provides the most up-to-date information regarding ABO genomics. © 2012 Elsevier Inc.

Jorda M.,Institute Of Medicina Predictiva I Personalitzada Del Cancer Imppc | Peinado M.A.,Institute Of Medicina Predictiva I Personalitzada Del Cancer Imppc
Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis | Year: 2010

It is well established that epigenetic events, in an intimate cooperation with genetic events, are involved in every step of tumorigenesis. DNA methylation, which in mammals takes place in the cytosines that precede a guanine (CpG dinucleotide), is the most well-characterized epigenetic mark. The study of aberrant DNA methylation patterns, such as hypermethylation of CpG islands and global genomic hypomethylation, are common issues in the studies on all types of cancer, and as in other areas of molecular oncology, colorectal cancer has become a privileged target. Besides the great variety of technologies available for the analysis of DNA methylation, most methods are based on three principles: methylation-sensitive enzymes, bisulphite conversion of unmethylated cytosines and immunoprecipitation of 5-methylcytosines. By combining each one of these principles with other genomic methodologies, a large range of approaches aimed at the analysis of methylation from one specific CpG site to a large number of sequences on the genome scale and suitable for different research needs have been developed. The goal of this review is to describe the most widely used methylation methods in the study of cancer, as well as the potential clinical applications of DNA methylation biomarkers in colorectal cancer. © 2010 Elsevier B.V.

BACKGROUND: The α1,3-galactosyl epitope (α1-3Gal epitope), a major xenotransplant antigen, is synthesized by α1,3-galactosyltransferase (α1-3Gal transferase), which is evolutionarily related to the histo-blood group A/B transferases. STUDY DESIGN AND METHODS: We constructed structural chimeras between the human type A and murine α1-3Gal transferases and examined their activity and specificity. RESULTS: In many instances, a total loss of transferase activity was observed. Certain areas could be exchanged, with a potential diminishing of activity. With a few constructs, changes in acceptor substrate specificity were suspected. Unexpectedly, a functional conversion from A to B transferase activity was observed after replacing the short sequence of human A transferase with the corresponding sequence from murine α1-3Gal transferase. CONCLUSION: Because these two paralogous enzymes differ in 16 positions of the 38 amino acid residues in the replaced region, our finding may suggest that despite separate evolution and diversified acceptors, these glycosyltransferases still share the three-dimensional domain structure that is responsible for their sugar specificity, arguing against the functional requirement of a strong purifying selection playing a role in the evolution of the ABO family of genes. © 2009 American Association of Blood Banks.

Buj R.,Institute Dinvestigacions Biomediques Of Barcelona Iibb | Buj R.,Institute Of Medicina Predictiva I Personalitzada Del Cancer Imppc | Iglesias N.,Institute Dinvestigacions Biomediques Of Barcelona Iibb | Planas A.M.,Institute Dinvestigacions Biomediques Of Barcelona Iibb | And 3 more authors.
BMC Molecular Biology | Year: 2013

Background: Valuable clone collections encoding the complete ORFeomes for some model organisms have been constructed following the completion of their genome sequencing projects. These libraries are based on Gateway cloning technology, which facilitates the study of protein function by simplifying the subcloning of open reading frames (ORF) into any suitable destination vector. The expression of proteins of interest as fusions with functional modules is a frequent approach in their initial functional characterization. A limited number of Gateway destination expression vectors allow the construction of fusion proteins from ORFeome-derived sequences, but they are restricted to the possibilities offered by their inbuilt functional modules and their pre-defined model organism-specificity. Thus, the availability of cloning systems that overcome these limitations would be highly advantageous.Results: We present a versatile cloning toolkit for constructing fully-customizable three-part fusion proteins based on the MultiSite Gateway cloning system. The fusion protein components are encoded in the three plasmids integral to the kit. These can recombine with any purposely-engineered destination vector that uses a heterologous promoter external to the Gateway cassette, leading to the in-frame cloning of an ORF of interest flanked by two functional modules. In contrast to previous systems, a third part becomes available for peptide-encoding as it no longer needs to contain a promoter, resulting in an increased number of possible fusion combinations. We have constructed the kit's component plasmids and demonstrate its functionality by providing proof-of-principle data on the expression of prototype fluorescent fusions in transiently-transfected cells.Conclusions: We have developed a toolkit for creating fusion proteins with customized N- and C-term modules from Gateway entry clones encoding ORFs of interest. Importantly, our method allows entry clones obtained from ORFeome collections to be used without prior modifications. Using this technology, any existing Gateway destination expression vector with its model-specific properties could be easily adapted for expressing fusion proteins. © 2013 Buj et al.; licensee BioMed Central Ltd.

Vidal B.,University Pompeu Fabra | Vidal B.,Columbia University | Ardite E.,University Pompeu Fabra | Suelves M.,University Pompeu Fabra | And 8 more authors.
Human Molecular Genetics | Year: 2012

In Duchenne muscular dystrophy (DMD), a persistently altered and reorganizing extracellular matrix (ECM) within inflamed muscle promotes damage and dysfunction. However, the molecular determinants of the ECM that mediate inflammatory changes and faulty tissue reorganization remain poorly defined. Here, we show that fibrin deposition is a conspicuous consequence of muscle-vascular damage in dystrophic muscles of DMD patients and mdx mice and that elimination of fibrin(ogen) attenuated dystrophy progression in mdx mice. These benefits appear to be tied to: (i) a decrease in leukocyte integrin α. Mβ. 2-mediated proinflammatory programs, thereby attenuating counterproductive inflammation and muscle degeneration; and (ii) a release of satellite cells from persistent inhibitory signals, thereby promoting regeneration. Remarkably, Fib-gamma(390-396A) (Fibγ. 390-396A) mice expressing a mutant form of fibrinogen with normal clotting function, but lacking the α. Mβ. 2 binding motif, ameliorated dystrophic pathology. Delivery of a fibrinogen/α. Mβ. 2 blocking peptide was similarly beneficial. Conversely, intramuscular fibrinogen delivery sufficed to induce inflammation and degeneration in fibrinogen-null mice. Thus, local fibrin(ogen) deposition drives dystrophic muscle inflammation and dysfunction, and disruption of fibrin(ogen)-α. Mβ. 2 interactions may provide a novel strategy for DMD treatment. © The Author 2012. Published by Oxford University Press. All rights reserved.

Yamamoto F.,Institute Of Medicina Predictiva I Personalitzada Del Cancer Imppc | Cid E.,Institute Of Medicina Predictiva I Personalitzada Del Cancer Imppc | Yamamoto M.,Institute Of Medicina Predictiva I Personalitzada Del Cancer Imppc | Saitou N.,National Institute of Genetics | And 2 more authors.
Scientific Reports | Year: 2014

The ABO system is one of the most important blood group systems in transfusion/transplantation medicine. However, the evolutionary significance of the ABOgene and its polymorphism remained unknown. We took an integrative approach to gain insights into the significance of the evolutionary process of ABOgenes, including those related not only phylogenetically but also functionally. We experimentally created a code table correlating amino acid sequence motifs of the ABOgene-encoded glycosyltransferases with GalNAc (A)/galactose (B) specificity, and assigned A/B specificity to individual ABOgenes from various species thus going beyond the simple sequence comparison. Together with genome information and phylogenetic analyses, this assignment revealed early appearance of A and Bgene sequences in evolution and potentially non-allelic presence of both gene sequences in some animal species. We argue: Evolution may have suppressed the establishment of two independent, functional Aand Bgenes in most vertebrates and promoted A/B conversion through amino acid substitutions and/or recombination; A/Ballelism should have existed in common ancestors of primates; and bacterial ABOgenes evolved through horizontal and vertical gene transmission into 2 separate groups encoding glycosyltransferases with distinct sugar specificities.

Institute Of Medicina Predictiva I Personalitzada Del Cancer Imppc and Sanford Burnham Institute for Medical Research | Date: 2013-02-08

Disclosed herein are systems and methods for using demethylation of genomic DNA for diagnosing, predicting, and/or monitoring the status or outcome of a neoplasm or a cancer in a subject.

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