@article {574, title = {Multidimensional gene set analysis of genomic data.}, journal = {PLoS One}, volume = {5}, year = {2010}, month = {2010 Apr 27}, pages = {e10348}, abstract = {

Understanding the functional implications of changes in gene expression, mutations, etc., is the aim of most genomic experiments. To achieve this, several functional profiling methods have been proposed. Such methods study the behaviour of different gene modules (e.g. gene ontology terms) in response to one particular variable (e.g. differential gene expression). In spite to the wealth of information provided by functional profiling methods, a common limitation to all of them is their inherent unidimensional nature. In order to overcome this restriction we present a multidimensional logistic model that allows studying the relationship of gene modules with different genome-scale measurements (e.g. differential expression, genotyping association, methylation, copy number alterations, heterozygosity, etc.) simultaneously. Moreover, the relationship of such functional modules with the interactions among the variables can also be studied, which produces novel results impossible to be derived from the conventional unidimensional functional profiling methods. We report sound results of gene sets associations that remained undetected by the conventional one-dimensional gene set analysis in several examples. Our findings demonstrate the potential of the proposed approach for the discovery of new cell functionalities with complex dependences on more than one variable.

}, keywords = {Databases, Genetic, Gene Expression Profiling, Gene Regulatory Networks, Genome, Human, Genomics, Humans, Models, Statistical}, issn = {1932-6203}, doi = {10.1371/journal.pone.0010348}, author = {Montaner, David and Dopazo, Joaquin} } @article {604, title = {Evidence for systems-level molecular mechanisms of tumorigenesis.}, journal = {BMC Genomics}, volume = {8}, year = {2007}, month = {2007 Jun 20}, pages = {185}, abstract = {

BACKGROUND: 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.

}, keywords = {Cell Transformation, Neoplastic, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Male, Models, Biological, Models, Genetic, Models, Statistical, Neoplasm Proteins, Neoplasms, Prostatic Neoplasms, Protein Interaction Mapping, RNA, Messenger, Signal Transduction, Systems biology}, issn = {1471-2164}, doi = {10.1186/1471-2164-8-185}, author = {Hern{\'a}ndez, Pilar and Huerta-Cepas, Jaime and Montaner, David and Al-Shahrour, F{\'a}tima and Valls, Joan and G{\'o}mez, Laia and Capell{\`a}, Gabriel and Dopazo, Joaquin and Pujana, Miguel Angel} }