02784nas a2200301   4500008004100000245006900041210006800110300000800178490000600186520165900192653002501851653002201876653001901898653006101917653007001978653003402048653013602082100001802218700002102236700001702257700002402274700001402298700001402312700001602326700001502342700001902357856010602376       2007                        eng d00aEvidence for systems-level molecular mechanisms of tumorigenesis0 aEvidence for systemslevel molecular mechanisms of tumorigenesis  a1850 v83 aBACKGROUND: Cancer arises from the consecutive acquisition of genetic alterations. Increasing evidence suggests that as a consequence of these alterations, molecular interactions are reprogrammed in the context of highly connected and regulated cellular networks. Coordinated reprogramming would allow the cell to acquire the capabilities for malignant growth. RESULTS: Here, we determine the coordinated function of cancer gene products (i.e., proteins encoded by differentially expressed genes in tumors relative to healthy tissue counterparts, hereafter referred to as "CGPs") defined as their topological properties and organization in the interactome network. We show that CGPs are central to information exchange and propagation and that they are specifically organized to promote tumorigenesis. Centrality is identified by both local (degree) and global (betweenness and closeness) measures, and systematically appears in down-regulated CGPs. Up-regulated CGPs do not consistently exhibit centrality, but both types of cancer products determine the overall integrity of the network structure. In addition to centrality, down-regulated CGPs show topological association that correlates with common biological processes and pathways involved in tumorigenesis. CONCLUSION: Given the current limited coverage of the human interactome, this study proposes that tumorigenesis takes place in a specific and organized way at the molecular systems-level and suggests a model that comprises the precise down-regulation of groups of topologically-associated proteins involved in particular functions, orchestrated with the up-regulation of specific proteins.10a*Cell Transformation10aBiological Models10aGenetic Models10aMessenger/metabolism Signal Transduction Systems Biology10aNeoplastic *Gene Expression Profiling *Gene Expression Regulation10aNeoplastic Humans Male Models10aStatistical Neoplasm Proteins/*physiology Neoplasms/etiology/*genetics Prostatic Neoplasms/genetics Protein Interaction Mapping RNA1 aHernandez, P.1 aHuerta-Cepas, J.1 aMontaner, D.1 aAl-Shahrour, Fatima1 aValls, J.1 aGomez, L.1 aCapella, G.1 aDopazo, J.1 aPujana, M., A.  uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1758491502859nas a2200301   4500008004100000245009400041210006900135300001300204490000800217520172300225653007401948653002202022653001902044653002402063653002802087653002002115653015502135653002502290100001502315700001402330700001702344700001602361700002202377700002202399700001502421700001502436856010602451       2006                        eng d00aSelective pressures at a codon-level predict deleterious mutations in human disease genes0 aSelective pressures at a codonlevel predict deleterious mutation  a1390-4040 v3583 aDeleterious mutations affecting biological function of proteins are constantly being rejected by purifying selection from the gene pool. The non-synonymous/synonymous substitution rate ratio (omega) is a measure of selective pressure on amino acid replacement mutations for protein-coding genes. Different methods have been developed in order to predict non-synonymous changes affecting gene function. However, none has considered the estimation of selective constraints acting on protein residues. Here, we have used codon-based maximum likelihood models in order to estimate the selective pressures on the individual amino acid residues of a well-known model protein: p53. We demonstrate that the number of residues under strong purifying selection in p53 is much higher than those that are strictly conserved during the evolution of the species. In agreement with theoretical expectations, residues that have been noted to be of structural relevance, or in direct association with DNA, were among those showing the highest signals of purifying selection. Conversely, those changing according to a neutral, or nearly neutral mode of evolution, were observed to be irrelevant for protein function. Finally, using more than 40 human disease genes, we demonstrate that residues evolving under strong selective pressures (omega<0.1) are significantly associated (p<0.01) with human disease. We hypothesize that non-synonymous change on amino acids showing omega<0.1 will most likely affect protein function. The application of this evolutionary prediction at a genomic scale will provide an a priori hypothesis of the phenotypic effect of non-synonymous coding single nucleotide polymorphisms (SNPs) in the human genome.10aAmino Acid Sequence Amino Acid Substitution Codon/*genetics Databases10aGenetic Evolution10aGenetic Models10aHuman Humans Models10aInborn/*genetics Genome10aMolecular Genes10aMolecular Molecular Sequence Data *Mutation Neoplasms/genetics Proteins/genetics *Selection (Genetics) Tumor Suppressor Protein p53/chemistry/genetics10ap53 Genetic Diseases1 aArbiza, L.1 aDuchi, S.1 aMontaner, D.1 aBurguet, J.1 aPantoja-Uceda, D.1 aPineda-Lucena, A.1 aDopazo, J.1 aDopazo, H.  uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16584746