Agency: European Commission | Branch: FP7 | Program: ERC-CG | Phase: ERC-CG-2013-LS8 | Award Amount: 2.00M | Year: 2014
By far, most evolutionary research has focused on the changes that occur in the germline of individuals across generations, within and between species. For different reasons, much less attention has been given to the process of change within the somatic line of a multicellular individual. The formation of cancer tumors due to uncontrolled cell proliferation is one of the most prominent forms of somatic evolution. The evolution of cancer tumors in a body can be likened with the evolution of populations in more or less fragmented habitats. The tumor is usually a expanding population of clonal cells, which may differentiate to a bigger or lesser extent (population structure) and disperse to contiguous (range expansion) or more distant tissues (long distance colonization). During tumor progression, this population of cells is subject to distinct somatic evolutionary processes like mutation, drift, selection or migration, which can act at different points in time and geographical space. Very recently, the discovery of extensive intratumor heterogeneity, together with the rise of single cell genomics, has created an unique opportunity to study the phylogeography of cancer tumor cells. So far evolutionary inferences drawn from cancer genomes have been mostly qualitative. Here we propose to study a thousand single cell genomes from different regions in primary tumors and matched metastases. We will develop and apply state-of-the-art statistical and computational techniques from phylogenetics, phylogeography and population genomics to understand the tempo and mode of evolution of cell lineages within and between cancer tumors. By doing so we aim to construct a robust theoretical and methodological evolutionary framework that can contribute to a better understanding of the process of somatic evolution and shed light into the biology of cancer.
Agency: European Commission | Branch: H2020 | Program: RIA | Phase: PHC-32-2014 | Award Amount: 2.95M | Year: 2015
Cancer sequencing studies have extensively investigated the landscape of somatic mutations that drive tumor development, however the importance of germline variation for cancer susceptibility has been neglected. We hypothesize that for cancer types affecting a large proportion of the population, a shared set of genes with variants of different levels of penetrance leads to the clinical phenotype. While rare germline variants are not interrogated by array-based genome-wide association studies (GWAS), these can be effectively studied by whole-genome or whole-exome sequencing. Here, we propose in-depth pan-cancer analyses, which will be implemented as part of the International Cancer Genome Consortium (ICGC) initiative, as a model to develop and apply the necessary bioinformatics tools and pipelines to fully exploit the cancer-genome datasets, and to harness the diagnostic power of genome sequencing in day-to-day clinical practice. Our proposal addresses the full chain of computational and statistical tools that are needed for clinically relevant diagnosis and intervention, including discovery in large cohorts, validation of putative causal sites in model systems and development of targeted cancer-risk panels. The consortium combines complementary expertise to extend the computational discovery of novel variants that influence cancer susceptibility to intergenic and regulatory variants; to integrate genomic, molecular phenotype, biomarker and clinical data; and to develop novel statistical methods for variant association and eQTL analysis. The project will deal with essential aspects on how data are collected, stored, organized, integrated, analyzed and exploited in cancer genetic clinics. We aim to provide a concerted, cross-disciplinary framework for a better understanding, integration and use of cancer clinical data in the evaluation of the multitude of genetic variants and mutations involved in cancer susceptibility, for the direct benefit of cancer patients.
Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2013.2.4.1-3 | Award Amount: 7.82M | Year: 2013
Long-term side-effects of radiotherapy impact on the quality-of-life (QoL) of cancer survivors. These side-effects could be reduced if predicted in advance. Previous work identified clinical and biological predictors but a major, coordinated approach is needed to validate them so they can be used clinically. The EU has ~17.8 million people living with a prior diagnosis of cancer of whom ~7 million received radiotherapy. In the long-term, potentially 20% of those suffering with mild to severe side-effects (~1.4 million) might benefit from alleviation of symptoms, with resulting reductions in the cost of care in the EU. REQUITE aims to develop validated clinical models and incorporate biomarkers to identify before treatment cancer patients at risk of side-effects and use the models to design interventional trials aimed at reducing side-effects and improving QoL in cancer survivors who underwent radiotherapy. REQUITE will: 1. carry out a multi-centre, longitudinal, observational study to collect standardised data and samples in breast, prostate and lung cancer patients; 2. validate biomarkers with published evidence of predictive value; 3. replicate published clinical models and incorporate replicated biomarkers to create validated predictive algorithms; 4. use the prospectively validated models and biomarkers to design interventional trial protocols aiming to reduce side-effects and improve QoL in high-risk patients. REQUITE builds on collaborations with a proven history of data sharing, enlarged to a consortium with expertise in patient recruitment, knowledge management, biomarker testing and predictive model development. SME involvement for biomarker assays will facilitate future clinical implementation and commercial exploitation. The outcome of this project will be validated predictive models for three common cancers and trial protocols using the models to investigate interventions aimed at reducing long-term side-effects and improving the QoL of cancer survivors.
Rodriguez-Rodriguez C.,Autonomous University of Barcelona |
Rimola A.,University of Turin |
Rodriguez-Santiago L.,Autonomous University of Barcelona |
Ugliengo P.,University of Turin |
And 4 more authors.
Chemical Communications | Year: 2010
Combining X-ray data on thioflavin-T and theoretical calculations on its binding to a peptide model for Aβ1-42 fibrils gives evidence of main stabilizing interactions, which influence the dihedral angle between the two moieties of thioflavin-T and thereby its fluorescence properties; these results shed new light on possible strategies for the design of dyes to bind amyloid fibrils more specifically. © 2010 The Royal Society of Chemistry.
Kohlrausch F.B.,Federal University of Fluminense |
Kohlrausch F.B.,Federal University of Rio Grande do Sul |
Carracedo A.,Fundacion Publica Galega de Medicina Xenomica |
Hutz M.H.,Federal University of Rio Grande do Sul
Molecular Biology Reports | Year: 2014
Potential causes of variability in drug response include intrinsic factors such as ethnicity and genetic differences in the expression of enzymes that metabolize drugs, such as those from Cytochrome P450 (CYPs) superfamily. Pharmacogenetic studies search for genetic differences between populations since relevant alleles occur with varying frequencies among different ethnic populations. The Brazilian population is one of the most heterogeneous in the world, resulting from multiethnic admixture of Amerindians, Europeans, and Africans across centuries. Since the knowledge of CYP allele frequency distributions is relevant to pharmacogenetic strategies and these data are scarce in the Brazilian population, this study aimed to describe genotype and allele distributions of 15 single nucleotide polymorphisms (SNPs) at CYP 1A2, 2C19, 3A4, and 3A5 genes in African and European descents from South Brazil. A sample of 179 healthy individuals of European and African ancestry was genotyped by the MassARRAY SNP genotyping system. CYP3A5*3, CYP1A2*1F, CYP3A4*1B, and CYP2C19*2 were the most frequent alleles found in our sample. Significant differences in genotype and allelic distribution between African and European descents were observed for CYP3A4 and CYP3A5 genes. CYP3A4*1B was observed in higher frequency in African descents (0.379) than in European descents (0.098), and European descents showed higher frequency of CYP3A5*3 (0.810) than African descents (0.523). Our results indicate that only a few polymorphisms would have impact in pharmacogenetic testing in South Brazilians. Further studies with larger sample sizes are required also among other Brazilian regions. © 2014 Springer Science+Business Media.
Fachal L.,Fundacion Publica Galega de Medicina Xenomica |
Fachal L.,University of Santiago de Compostela |
Gomez-Caamano A.,University of Santiago de Compostela |
Barnett G.C.,University of Cambridge |
And 20 more authors.
Nature Genetics | Year: 2014
There is increasing evidence supporting the role of genetic variants in the development of radiation-induced toxicity. However, previous candidate gene association studies failed to elucidate the common genetic variation underlying this phenotype, which could emerge years after the completion of treatment. We performed a genome-wide association study on a Spanish cohort of 741 individuals with prostate cancer treated with external beam radiotherapy (EBRT). The replication cohorts consisted of 633 cases from the UK4 and 368 cases from North America. One locus comprising TANC1 (lowest unadjusted P value for overall late toxicity = 6.85 × 10-9, odds ratio (OR) = 6.61, 95% confidence interval (CI) = 2.23-19.63) was replicated in the second stage (lowest unadjusted P value for overall late toxicity = 2.08 × 1 -4, OR = 6.17, 95% CI = 2.25-16.95; Pcombined= 4.16 × 10-10). The inclusion of the third cohort gave unadjusted Pcombined= 4.64 × 10-9. These results, together with the role of TANC1 in regenerating damaged muscle, suggest that the TANC1 locus influences the development of late radiation-induced damage. © 2014 Nature America, Inc.
Martinon-Torres N.,University of Santiago de Compostela |
Vazquez-Donsion M.,University of Santiago de Compostela |
Loidi L.,Fundacion Publica Galega de Medicina Xenomica |
Couselo J.M.,University of Santiago de Compostela
Pediatric Blood and Cancer | Year: 2011
Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare disorder characterized by thrombocytopenia and absence or decline in the number of megakaryocytic precursors in the bone marrow. It is caused by mutations in the thrombopoietin receptor gene, c-mpl, involved in the proliferation and differentiation of megakaryocytes and platelets. The association between CAMT and central nervous system (CNS) anomalies has been reported in the literature, albeit not very frequently. Here we present a unique case where CAMT appeared associated to cerebellum agenesis, hypoplasia of the corpus callosum and brainstem, facial malformations, and developmental delay. © 2010 Wiley-Liss, Inc.
Gonzalez-Quintela A.,Complejo Hospitalario Universitario |
Alonso M.,Complejo Hospitalario Universitario |
Campos J.,Complejo Hospitalario Universitario |
Vizcaino L.,Complejo Hospitalario Universitario |
And 2 more authors.
PLoS ONE | Year: 2013
Background and Aim: Assessment of serum concentration of lipopolysaccharide (LPS)-binding protein (LBP) has been suggested as a useful biomarker to indicate activation of innate immune responses to microbial products. We investigated LBP concentrations and associations with demographics, lifestyle factors, and common metabolic abnormalities in adults. We also examined if LBP concentrations were associated with common polymorphisms in genes coding for LBP (rs2232618), CD14 (rs2569190), and TLR4 (rs4986790), the molecules responsible for the innate immune response to LPS, or serum levels of soluble CD14 (sCD14) and proinflammatory cytokines. Methods: Serum LBP was measured with a commercial immunoassay in a random sample of the adult population (n = 420, 45% males, age 18-92 years) from a single municipality. Results: Serum LBP concentrations increased with age (P<0.001) and were higher in individuals who were overweight or obese than in normal-weight individuals (P<0.001). Similarly, LBP concentrations were higher in individuals with metabolic syndrome than in individuals without it (P<0.001). Among metabolic syndrome components, LBP concentrations were independently associated with abdominal obesity (P = 0.002) and low concentrations of HDL-cholesterol (P<0.001). Serum LBP concentrations tended to be independently associated with smoking (P = 0.05), but not with alcohol consumption. Likewise, there was not significant association between LBP concentrations and gene polymorphisms. Concentrations of LBP significantly correlated with serum levels of proinflammatory cytokines (IL-6 and IL-8), sCD14, and with liver enzymes. Conclusions: Serum LBP concentrations increased with age. Overweight, obesity, and having metabolic syndrome (particularly, low HDL cholesterol levels) were associated with higher LBP concentrations. These findings are consistent with microbial exposure playing a role in these inflammatory, metabolic abnormalities. © 2013 Gonzalez-Quintela et al.
University of Santiago de Compostela, Fundacion Pedro Barrie De La Maza and Fundacion Publica Galega De Medicina Xenomica | Date: 2012-01-06
Methods for diagnosing follicular thyroid cancer, providing a prognosis for follicular thyroid cancer, and monitoring treatment of follicular thyroid cancer, using biomarkers that are differentially expressed in follicular thyroid cancer are provided.
Allones J.L.,University of Santiago de Compostela |
Taboada M.,University of Santiago de Compostela |
Martinez D.,University of Santiago de Compostela |
Sobrido M.J.,Fundacion Publica Galega de Medicina Xenomica |
Sobrido M.J.,Institute of Health Carlos III
Journal of Biomedical Informatics | Year: 2013
Objective: To explore semantic search to improve management and user navigation in clinical archetype repositories. Methods: In order to support semantic searches across archetypes, an automated method based on SNOMED CT modularization is implemented to transform clinical archetypes into SNOMED CT extracts. Concurrently, query terms are converted into SNOMED CT concepts using the search engine Lucene. Retrieval is then carried out by matching query concepts with the corresponding SNOMED CT segments. Results: A test collection of the 16 clinical archetypes, including over 250 terms, and a subset of 55 clinical terms from two medical dictionaries, MediLexicon and MedlinePlus, were used to test our method. The keyword-based service supported by the OpenEHR repository offered us a benchmark to evaluate the enhancement of performance. In total, our approach reached 97.4% precision and 69.1% recall, providing a substantial improvement of recall (more than 70%) compared to the benchmark. Conclusions: Exploiting medical domain knowledge from ontologies such as SNOMED CT may overcome some limitations of the keyword-based systems and thus improve the search experience of repository users. An automated approach based on ontology segmentation is an efficient and feasible way for supporting modeling, management and user navigation in clinical archetype repositories. © 2013 Elsevier Inc.