TY - JOUR T1 - Association of a single nucleotide polymorphism in the ubxn6 gene with long-term non-progression phenotype in HIV-positive individuals. JF - Clin Microbiol Infect Y1 - 2020 A1 - Díez-Fuertes, F A1 - De La Torre-Tarazona, H E A1 - Calonge, E A1 - Pernas, M A1 - Bermejo, M A1 - García-Pérez, J A1 - Álvarez, A A1 - Capa, L A1 - García-García, F A1 - Saumoy, M A1 - Riera, M A1 - Boland-Auge, A A1 - López-Galíndez, C A1 - Lathrop, M A1 - Dopazo, J A1 - Sakuntabhai, A A1 - Alcamí, J KW - Adaptor Proteins, Vesicular Transport KW - Autophagy-Related Proteins KW - Caveolin 1 KW - Cohort Studies KW - Dendritic Cells KW - Disease Progression KW - Gene Frequency KW - Gene Knockdown Techniques KW - Genetic Association Studies KW - HeLa Cells KW - HIV Infections KW - HIV Long-Term Survivors KW - HIV-1 KW - Humans KW - Macrophages KW - Oligonucleotide Array Sequence Analysis KW - Phenotype KW - Polymorphism, Single Nucleotide KW - whole exome sequencing AB -

OBJECTIVES: The long-term non-progressors (LTNPs) are a heterogeneous group of HIV-positive individuals characterized by their ability to maintain high CD4 T-cell counts and partially control viral replication for years in the absence of antiretroviral therapy. The present study aims to identify host single nucleotide polymorphisms (SNPs) associated with non-progression in a cohort of 352 individuals.

METHODS: DNA microarrays and exome sequencing were used for genotyping about 240 000 functional polymorphisms throughout more than 20 000 human genes. The allele frequencies of 85 LTNPs were compared with a control population. SNPs associated with LTNPs were confirmed in a population of typical progressors. Functional analyses in the affected gene were carried out through knockdown experiments in HeLa-P4, macrophages and dendritic cells.

RESULTS: Several SNPs located within the major histocompatibility complex region previously related to LTNPs were confirmed in this new cohort. The SNP rs1127888 (UBXN6) surpassed the statistical significance of these markers after Bonferroni correction (q = 2.11 × 10). An uncommon allelic frequency of rs1127888 among LTNPs was confirmed by comparison with typical progressors and other publicly available populations. UBXN6 knockdown experiments caused an increase in CAV1 expression and its accumulation in the plasma membrane. In vitro infection of different cell types with HIV-1 replication-competent recombinant viruses caused a reduction of the viral replication capacity compared with their corresponding wild-type cells expressing UBXN6.

CONCLUSIONS: A higher prevalence of Ala31Thr in UBXN6 was found among LTNPs within its N-terminal region, which is crucial for UBXN6/VCP protein complex formation. UBXN6 knockdown affected CAV1 turnover and HIV-1 replication capacity.

VL - 26 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/31158522?dopt=Abstract ER - TY - JOUR T1 - Fibroblast activation and abnormal extracellular matrix remodelling as common hallmarks in three cancer-prone genodermatoses. JF - Br J Dermatol Y1 - 2019 A1 - Chacón-Solano, E A1 - León, C A1 - Díaz, F A1 - García-García, F A1 - García, M A1 - Escámez, M J A1 - Guerrero-Aspizua, S A1 - Conti, C J A1 - Mencía, Á A1 - Martínez-Santamaría, L A1 - Llames, S A1 - Pévida, M A1 - Carbonell-Caballero, J A1 - Puig-Butillé, J A A1 - Maseda, R A1 - Puig, S A1 - de Lucas, R A1 - Baselga, E A1 - Larcher, F A1 - Dopazo, J A1 - Del Rio, M KW - Adolescent KW - Adult KW - Biopsy KW - Blister KW - Case-Control Studies KW - Cells, Cultured KW - Child KW - Child, Preschool KW - Epidermolysis Bullosa KW - Epidermolysis Bullosa Dystrophica KW - Extracellular Matrix KW - Extracellular Matrix Proteins KW - Female KW - Fibroblasts KW - Fibrosis KW - Gene Expression Regulation KW - Healthy Volunteers KW - Humans KW - Infant KW - Infant, Newborn KW - Male KW - Middle Aged KW - mutation KW - Periodontal Diseases KW - Photosensitivity Disorders KW - Primary Cell Culture KW - RNA-seq KW - Skin KW - Xeroderma Pigmentosum KW - Young Adult AB -

BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB), Kindler syndrome (KS) and xeroderma pigmentosum complementation group C (XPC) are three cancer-prone genodermatoses whose causal genetic mutations cannot fully explain, on their own, the array of associated phenotypic manifestations. Recent evidence highlights the role of the stromal microenvironment in the pathology of these disorders.

OBJECTIVES: To investigate, by means of comparative gene expression analysis, the role played by dermal fibroblasts in the pathogenesis of RDEB, KS and XPC.

METHODS: We conducted RNA-Seq analysis, which included a thorough examination of the differentially expressed genes, a functional enrichment analysis and a description of affected signalling circuits. Transcriptomic data were validated at the protein level in cell cultures, serum samples and skin biopsies.

RESULTS: Interdisease comparisons against control fibroblasts revealed a unifying signature of 186 differentially expressed genes and four signalling pathways in the three genodermatoses. Remarkably, some of the uncovered expression changes suggest a synthetic fibroblast phenotype characterized by the aberrant expression of extracellular matrix (ECM) proteins. Western blot and immunofluorescence in situ analyses validated the RNA-Seq data. In addition, enzyme-linked immunosorbent assay revealed increased circulating levels of periostin in patients with RDEB.

CONCLUSIONS: Our results suggest that the different causal genetic defects converge into common changes in gene expression, possibly due to injury-sensitive events. These, in turn, trigger a cascade of reactions involving abnormal ECM deposition and underexpression of antioxidant enzymes. The elucidated expression signature provides new potential biomarkers and common therapeutic targets in RDEB, XPC and KS. What's already known about this topic? Recessive dystrophic epidermolysis bullosa (RDEB), Kindler syndrome (KS) and xeroderma pigmentosum complementation group C (XPC) are three genodermatoses with high predisposition to cancer development. Although their causal genetic mutations mainly affect epithelia, the dermal microenvironment likely contributes to the physiopathology of these disorders. What does this study add? We disclose a large overlapping transcription profile between XPC, KS and RDEB fibroblasts that points towards an activated phenotype with high matrix-synthetic capacity. This common signature seems to be independent of the primary causal deficiency, but reflects an underlying derangement of the extracellular matrix via transforming growth factor-β signalling activation and oxidative state imbalance. What is the translational message? This study broadens the current knowledge about the pathology of these diseases and highlights new targets and biomarkers for effective therapeutic intervention. It is suggested that high levels of circulating periostin could represent a potential biomarker in RDEB.

VL - 181 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/30693469?dopt=Abstract ER - TY - JOUR T1 - Highly sensitive and ultrafast read mapping for RNA-seq analysis. JF - DNA Res Y1 - 2016 A1 - Medina, I A1 - Tárraga, J A1 - Martínez, H A1 - Barrachina, S A1 - Castillo, M I A1 - Paschall, J A1 - Salavert-Torres, J A1 - Blanquer-Espert, I A1 - Hernández-García, V A1 - Quintana-Ortí, E S A1 - Dopazo, J KW - Genomics KW - High-Throughput Nucleotide Sequencing KW - Humans KW - Sensitivity and Specificity KW - Sequence Analysis, RNA KW - Transcriptome AB -

As sequencing technologies progress, the amount of data produced grows exponentially, shifting the bottleneck of discovery towards the data analysis phase. In particular, currently available mapping solutions for RNA-seq leave room for improvement in terms of sensitivity and performance, hindering an efficient analysis of transcriptomes by massive sequencing. Here, we present an innovative approach that combines re-engineering, optimization and parallelization. This solution results in a significant increase of mapping sensitivity over a wide range of read lengths and substantial shorter runtimes when compared with current RNA-seq mapping methods available.

VL - 23 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/26740642?dopt=Abstract ER - TY - JOUR T1 - Human DNA methylomes of neurodegenerative diseases show common epigenomic patterns. JF - Transl Psychiatry Y1 - 2016 A1 - Sanchez-Mut, J V A1 - Heyn, H A1 - Vidal, E A1 - Moran, S A1 - Sayols, S A1 - Delgado-Morales, R A1 - Schultz, M D A1 - Ansoleaga, B A1 - Garcia-Esparcia, P A1 - Pons-Espinal, M A1 - de Lagran, M M A1 - Dopazo, J A1 - Rabano, A A1 - Avila, J A1 - Dierssen, M A1 - Lott, I A1 - Ferrer, I A1 - Ecker, J R A1 - Esteller, M KW - Adult KW - Aged KW - Aged, 80 and over KW - DNA Methylation KW - Epigenomics KW - Female KW - Humans KW - Male KW - Middle Aged KW - neurodegenerative diseases KW - Prefrontal Cortex KW - Tissue Array Analysis AB -

Different neurodegenerative disorders often show similar lesions, such as the presence of amyloid plaques, TAU-neurotangles and synuclein inclusions. The genetically inherited forms are rare, so we wondered whether shared epigenetic aberrations, such as those affecting DNA methylation, might also exist. The studied samples were gray matter samples from the prefrontal cortex of control and neurodegenerative disease-associated cases. We performed the DNA methylation analyses of Alzheimer's disease, dementia with Lewy bodies, Parkinson's disease and Alzheimer-like neurodegenerative profile associated with Down's syndrome samples. The DNA methylation landscapes obtained show that neurodegenerative diseases share similar aberrant CpG methylation shifts targeting a defined gene set. Our findings suggest that neurodegenerative disorders might have similar pathogenetic mechanisms that subsequently evolve into different clinical entities. The identified aberrant DNA methylation changes can be used as biomarkers of the disorders and as potential new targets for the development of new therapies.

VL - 6 U1 - https://www.ncbi.nlm.nih.gov/pubmed/26784972?dopt=Abstract ER - TY - JOUR T1 - Identification of the Photoreceptor Transcriptional Co-Repressor SAMD11 as Novel Cause of Autosomal Recessive Retinitis Pigmentosa. JF - Sci Rep Y1 - 2016 A1 - Corton, M A1 - Avila-Fernández, A A1 - Campello, L A1 - Sánchez, M A1 - Benavides, B A1 - López-Molina, M I A1 - Fernández-Sánchez, L A1 - Sánchez-Alcudia, R A1 - da Silva, L R J A1 - Reyes, N A1 - Martín-Garrido, E A1 - Zurita, O A1 - Fernández-San José, P A1 - Pérez-Carro, R A1 - García-García, F A1 - Dopazo, J A1 - García-Sandoval, B A1 - Cuenca, N A1 - Ayuso, C KW - Aged KW - Animals KW - Co-Repressor Proteins KW - Codon, Nonsense KW - Cohort Studies KW - Comparative Genomic Hybridization KW - Consanguinity KW - DNA Mutational Analysis KW - Exome KW - Eye Proteins KW - Female KW - Gene Expression Regulation KW - Genes, Recessive KW - Homeodomain Proteins KW - Homozygote KW - Humans KW - Male KW - Mice KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Protein Interaction Mapping KW - Retina KW - Retinal Dystrophies KW - Retinal Rod Photoreceptor Cells KW - Retinitis pigmentosa KW - Spain KW - Trans-Activators KW - Transcription Factors AB -

Retinitis pigmentosa (RP), the most frequent form of inherited retinal dystrophy is characterized by progressive photoreceptor degeneration. Many genes have been implicated in RP development, but several others remain to be identified. Using a combination of homozygosity mapping, whole-exome and targeted next-generation sequencing, we found a novel homozygous nonsense mutation in SAMD11 in five individuals diagnosed with adult-onset RP from two unrelated consanguineous Spanish families. SAMD11 is ortholog to the mouse major retinal SAM domain (mr-s) protein that is implicated in CRX-mediated transcriptional regulation in the retina. Accordingly, protein-protein network analysis revealed a significant interaction of SAMD11 with CRX. Immunoblotting analysis confirmed strong expression of SAMD11 in human retina. Immunolocalization studies revealed SAMD11 was detected in the three nuclear layers of the human retina and interestingly differential expression between cone and rod photoreceptors was observed. Our study strongly implicates SAMD11 as novel cause of RP playing an important role in the pathogenesis of human degeneration of photoreceptors.

VL - 6 U1 - https://www.ncbi.nlm.nih.gov/pubmed/27734943?dopt=Abstract ER - TY - JOUR T1 - Deregulation of key signaling pathways involved in oocyte maturation in FMR1 premutation carriers with Fragile X-associated primary ovarian insufficiency. JF - Gene Y1 - 2015 A1 - Alvarez-Mora, M I A1 - Rodriguez-Revenga, L A1 - Madrigal, I A1 - García-García, F A1 - Duran, M A1 - Dopazo, J A1 - Estivill, X A1 - Milà, M KW - Adult KW - Aged KW - Female KW - Fragile X Mental Retardation Protein KW - Fragile X Syndrome KW - Gene Expression Profiling KW - Gene Expression Regulation, Developmental KW - Gene ontology KW - Genome-Wide Association Study KW - Heterozygote KW - Humans KW - Middle Aged KW - Models, Genetic KW - mutation KW - Oligonucleotide Array Sequence Analysis KW - Oocytes KW - Primary Ovarian Insufficiency KW - Signal Transduction AB -

FMR1 premutation female carriers are at risk for Fragile X-associated primary ovarian insufficiency (FXPOI). Insights from knock-in mouse model have recently demonstrated that FXPOI is due to an increased rate of follicle depletion or an impaired development of the growing follicles. Molecular mechanisms responsible for this reduced viability are still unknown. In an attempt to provide new data on the mechanisms that lead to FXPOI, we report the first investigation involving transcription profiling of total blood from FMR1 premutation female carriers with and without FXPOI. A total of 16 unrelated female individuals (6 FMR1 premutated females with FXPOI; 6 FMR1 premutated females without FXPOI; and 4 no-FXPOI females) were studied by whole human genome oligonucleotide microarray (Agilent Technologies). Fold change analysis did not show any genes with significant differential gene expression. However, functional profiling by gene set analysis showed large number of statistically significant deregulated GO annotations as well as numerous KEGG pathways in FXPOI females. These results suggest that the impairment of fertility in these females might be due to a generalized deregulation of key signaling pathways involved in oocyte maturation. In particular, the vasoendotelial growth factor signaling, the inositol phosphate metabolism, the cell cycle, and the MAPK signaling pathways were found to be down-regulated in FXPOI females. Furthermore, a high statistical enrichment of biological processes involved in cell death and survival were found deregulated among FXPOI females. Our results provide new strategic approaches to further investigate the molecular mechanisms and potential therapeutic targets for FXPOI not focused in a single gene but rather in the set of genes involved in these pathways.

VL - 571 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/26095811?dopt=Abstract ER - TY - JOUR T1 - Differential Features Between Chronic Skin Inflammatory Diseases Revealed in Skin-Humanized Psoriasis and Atopic Dermatitis Mouse Models. JF - J Invest Dermatol Y1 - 2015 A1 - Carretero, M A1 - Guerrero-Aspizua, S A1 - Illera, N A1 - Galvez, V A1 - Navarro, M A1 - García-García, F A1 - Dopazo, J A1 - Jorcano, J L A1 - Larcher, F A1 - Del Rio, M AB -

Psoriasis (PS) and atopic dermatitis (AD) are chronic and relapsing inflammatory diseases of the skin affecting a large number of patients worldwide. Psoriasis is characterized by a Th1/Th17 immunological response whereas acute AD lesions exhibit Th2-dominant inflammation. Current single gene and signaling pathways-based models of inflammatory skin diseases are incomplete. Previous work allowed us to model psoriasis in skin-humanized mice through proper combinations of inflammatory cell components and disruption of barrier function. Herein we describe and characterize an animal model for AD using similar bioengineered-based approaches, by intradermal injection of human Th2 lymphocytes in regenerated human skin after partial removal of stratum corneum. In the present work we have extensively compared this model with the previous and an improved version of the PS model, in which Th17/Th1 lymphocytes replace exogenous cytokines. Comparative expression analyses revealed marked differences in specific epidermal proliferation and differentiation markers and immune-related molecules including antimicrobial peptides. Likewise, the composition of the dermal inflammatory infiltrate presented important differences. Availability of accurate and reliable animal models for these diseases will contribute to the understanding of the pathogenesis and provide valuable tools for drug development and testing.Journal of Investigative Dermatology accepted article preview online, 23 September 2015. doi:10.1038/jid.2015.362.

U1 - https://www.ncbi.nlm.nih.gov/pubmed/26398345?dopt=Abstract ER - TY - JOUR T1 - The EGR2 gene is involved in axonal Charcot-Marie-Tooth disease. JF - Eur J Neurol Y1 - 2015 A1 - Sevilla, T A1 - Sivera, R A1 - Martínez-Rubio, D A1 - Lupo, V A1 - Chumillas, M J A1 - Calpena, E A1 - Dopazo, J A1 - Vílchez, J J A1 - Palau, F A1 - Espinós, C KW - Adult KW - Aged KW - Aged, 80 and over KW - Axons KW - Charcot-Marie-Tooth Disease KW - Early Growth Response Protein 2 KW - Exome KW - Female KW - Humans KW - Male KW - Middle Aged KW - mutation KW - Pedigree KW - Phenotype KW - Severity of Illness Index KW - Young Adult AB -

BACKGROUND AND PURPOSE: A three-generation family affected by axonal Charcot-Marie-Tooth disease (CMT) was investigated with the aim of discovering genetic defects and to further characterize the phenotype.

METHODS: The clinical, nerve conduction studies and muscle magnetic resonance images of the patients were reviewed. A whole exome sequencing was performed and the changes were investigated by genetic studies, in silico analysis and luciferase reporter assays.

RESULTS: A novel c.1226G>A change (p.R409Q) in the EGR2 gene was identified. Patients presented with a typical, late-onset axonal CMT phenotype with variable severity that was confirmed in the ancillary tests. The in silico studies showed that the residue R409 is an evolutionary conserved amino acid. The p.R409Q mutation, which is predicted as probably damaging, would alter the conformation of the protein slightly and would cause a decrease of gene expression.

CONCLUSIONS: This is the first report of an EGR2 mutation presenting as an axonal CMT phenotype with variable severity. This study broadens the phenotype of the EGR2-related neuropathies and suggests that the genetic testing of patients suffering from axonal CMT should include the EGR2 gene.

VL - 22 IS - 12 U1 - https://www.ncbi.nlm.nih.gov/pubmed/26204789?dopt=Abstract ER - TY - JOUR T1 - Differential gene-expression analysis defines a molecular pattern related to olive pollen allergy. JF - J Biol Regul Homeost Agents Y1 - 2013 A1 - Aguerri, M A1 - Calzada, D A1 - Montaner, D A1 - Mata, M A1 - Florido, F A1 - Quiralte, J A1 - Dopazo, J A1 - Lahoz, C A1 - Cardaba, B KW - Adult KW - Female KW - Gene Expression Profiling KW - Humans KW - Male KW - Middle Aged KW - Olea KW - Principal Component Analysis KW - Rhinitis, Allergic, Seasonal AB -

Analysis of gene-expression profiles by microarrays is useful for characterization of candidate genes, key regulatory networks, and to define phenotypes or molecular signatures which improve the diagnosis and/or classification of the allergic processes. We have used this approach in the study of olive pollen response in order to find differential molecular markers among responders and non-responders to this allergenic source. Five clinical groups, non-allergic, asymptomatic, allergic but not to olive pollen, untreated-olive-pollen allergic patients and olive-pollen allergic patients (under specific-immunotherapy), were assessed during and outside pollen seasons. Whole-genome gene expression analysis was performed in RNAs extracted from PBMCs. After assessment of data quality and principal components analysis (PCA), differential gene-expression, by multiple testing and, functional analyses by KEGG, for pathways and Gene-Ontology for biological processes were performed. Relevance was defined by fold change and corrected P values (less than 0.05). The most differential genes were validated by qRT-PCR in a larger set of individuals. Interestingly, gene-expression profiling obtained by PCA clearly showed five clusters of samples that correlated with the five clinical groups. Furthermore, differential gene expression and functional analyses revealed differential genes and pathways in the five clinical groups. The 93 most significant genes found were validated, and one set of 35 genes was able to discriminate profiles of olive pollen response. Our results, in addition to providing new information on allergic response, define a possible molecular signature for olive pollen allergy which could be useful for the diagnosis and treatment of this and other sensitizations.

VL - 27 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/23830385?dopt=Abstract ER - TY - JOUR T1 - Functional analysis of multiple genomic signatures demonstrates that classification algorithms choose phenotype-related genes. JF - Pharmacogenomics J Y1 - 2010 A1 - Shi, W A1 - Bessarabova, M A1 - Dosymbekov, D A1 - Dezso, Z A1 - Nikolskaya, T A1 - Dudoladova, M A1 - Serebryiskaya, T A1 - Bugrim, A A1 - Guryanov, A A1 - Brennan, R J A1 - Shah, R A1 - Dopazo, J A1 - Chen, M A1 - Deng, Y A1 - Shi, T A1 - Jurman, G A1 - Furlanello, C A1 - Thomas, R S A1 - Corton, J C A1 - Tong, W A1 - Shi, L A1 - Nikolsky, Y KW - Algorithms KW - Databases, Genetic KW - Endpoint Determination KW - Gene Expression Profiling KW - Genomics KW - Humans KW - Neural Networks, Computer KW - Oligonucleotide Array Sequence Analysis KW - Phenotype KW - Predictive Value of Tests KW - Proteins KW - Quality Control AB -

Gene expression signatures of toxicity and clinical response benefit both safety assessment and clinical practice; however, difficulties in connecting signature genes with the predicted end points have limited their application. The Microarray Quality Control Consortium II (MAQCII) project generated 262 signatures for ten clinical and three toxicological end points from six gene expression data sets, an unprecedented collection of diverse signatures that has permitted a wide-ranging analysis on the nature of such predictive models. A comprehensive analysis of the genes of these signatures and their nonredundant unions using ontology enrichment, biological network building and interactome connectivity analyses demonstrated the link between gene signatures and the biological basis of their predictive power. Different signatures for a given end point were more similar at the level of biological properties and transcriptional control than at the gene level. Signatures tended to be enriched in function and pathway in an end point and model-specific manner, and showed a topological bias for incoming interactions. Importantly, the level of biological similarity between different signatures for a given end point correlated positively with the accuracy of the signature predictions. These findings will aid the understanding, and application of predictive genomic signatures, and support their broader application in predictive medicine.

VL - 10 IS - 4 U1 - https://www.ncbi.nlm.nih.gov/pubmed/20676069?dopt=Abstract ER - TY - JOUR T1 - Molecular profiling related to poor prognosis in thyroid carcinoma. Combining gene expression data and biological information. JF - Oncogene Y1 - 2008 A1 - Montero-Conde, C A1 - Martín-Campos, J M A1 - Lerma, E A1 - Gimenez, G A1 - Martínez-Guitarte, J L A1 - Combalía, N A1 - Montaner, D A1 - Matías-Guiu, X A1 - Dopazo, J A1 - de Leiva, A A1 - Robledo, M A1 - Mauricio, D KW - Adenoma KW - Adolescent KW - Adult KW - Aged KW - Biomarkers, Tumor KW - Carcinoma KW - Carcinoma, Papillary KW - Cell Differentiation KW - Female KW - Gene Expression Profiling KW - Gene Expression Regulation, Neoplastic KW - Humans KW - Male KW - Middle Aged KW - Oligonucleotide Array Sequence Analysis KW - Prognosis KW - Reverse Transcriptase Polymerase Chain Reaction KW - RNA, Neoplasm KW - Signal Transduction KW - Thyroid Neoplasms AB -

Undifferentiated and poorly differentiated thyroid tumors are responsible for more than half of thyroid cancer patient deaths in spite of their low incidence. Conventional treatments do not obtain substantial benefits, and the lack of alternative approaches limits patient survival. Additionally, the absence of prognostic markers for well-differentiated tumors complicates patient-specific treatments and favors the progression of recurrent forms. In order to recognize the molecular basis involved in tumor dedifferentiation and identify potential markers for thyroid cancer prognosis prediction, we analysed the expression profile of 44 thyroid primary tumors with different degrees of dedifferentiation and aggressiveness using cDNA microarrays. Transcriptome comparison of dedifferentiated and well-differentiated thyroid tumors identified 1031 genes with >2-fold difference in absolute values and false discovery rate of <0.15. According to known molecular interaction and reaction networks, the products of these genes were mainly clustered in the MAPkinase signaling pathway, the TGF-beta signaling pathway, focal adhesion and cell motility, activation of actin polymerization and cell cycle. An exhaustive search in several databases allowed us to identify various members of the matrix metalloproteinase, melanoma antigen A and collagen gene families within the upregulated gene set. We also identified a prognosis classifier comprising just 30 transcripts with an overall accuracy of 95%. These findings may clarify the molecular mechanisms involved in thyroid tumor dedifferentiation and provide a potential prognosis predictor as well as targets for new therapies.

VL - 27 IS - 11 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17873908?dopt=Abstract ER -