@article {460, title = {A Pan-Cancer Catalogue of Cancer Driver Protein Interaction Interfaces.}, journal = {PLoS Comput Biol}, volume = {11}, year = {2015}, month = {2015 Oct}, pages = {e1004518}, abstract = {

Despite their importance in maintaining the integrity of all cellular pathways, the role of mutations on protein-protein interaction (PPI) interfaces as cancer drivers has not been systematically studied. Here we analyzed the mutation patterns of the PPI interfaces from 10,028 proteins in a pan-cancer cohort of 5,989 tumors from 23 projects of The Cancer Genome Atlas (TCGA) to find interfaces enriched in somatic missense mutations. To that end we use e-Driver, an algorithm to analyze the mutation distribution of specific protein functional regions. We identified 103 PPI interfaces enriched in somatic cancer mutations. 32 of these interfaces are found in proteins coded by known cancer driver genes. The remaining 71 interfaces are found in proteins that have not been previously identified as cancer drivers even that, in most cases, there is an extensive literature suggesting they play an important role in cancer. Finally, we integrate these findings with clinical information to show how tumors apparently driven by the same gene have different behaviors, including patient outcomes, depending on which specific interfaces are mutated.

}, keywords = {Animals, Base Sequence, Biomarkers, Tumor, Catalogs as Topic, Chromosome Mapping, Computer Simulation, DNA Mutational Analysis, Genetic Predisposition to Disease, Humans, Models, Genetic, Molecular Sequence Data, mutation, Neoplasm Proteins, Neoplasms, Polymorphism, Single Nucleotide, Protein Interaction Mapping, Signal Transduction}, issn = {1553-7358}, doi = {10.1371/journal.pcbi.1004518}, author = {Porta-Pardo, Eduard and Garc{\'\i}a-Alonso, Luz and Hrabe, Thomas and Dopazo, Joaquin and Godzik, Adam} } @article {495, title = {Pathways systematically associated to Hirschsprung{\textquoteright}s disease.}, journal = {Orphanet J Rare Dis}, volume = {8}, year = {2013}, month = {2013 Dec 02}, pages = {187}, abstract = {

Despite it has been reported that several loci are involved in Hirschsprung{\textquoteright}s disease, the molecular basis of the disease remains yet essentially unknown. The study of collective properties of modules of functionally-related genes provides an efficient and sensitive statistical framework that can overcome sample size limitations in the study of rare diseases. Here, we present the extension of a previous study of a Spanish series of HSCR trios to an international cohort of 162 HSCR trios to validate the generality of the underlying functional basis of the Hirschsprung{\textquoteright}s disease mechanisms previously found. The Pathway-Based Analysis (PBA) confirms a strong association of gene ontology (GO) modules related to signal transduction and its regulation, enteric nervous system (ENS) formation and other processes related to the disease. In addition, network analysis recovers sub-networks significantly associated to the disease, which contain genes related to the same functionalities, thus providing an independent validation of these findings. The functional profiles of association obtained for patients populations from different countries were compared to each other. While gene associations were different at each series, the main functional associations were identical in all the five populations. These observations would also explain the reported low reproducibility of associations of individual disease genes across populations.

}, keywords = {Female, Genetic Predisposition to Disease, Genotype, Hirschsprung Disease, Humans, Male, Polymorphism, Single Nucleotide}, issn = {1750-1172}, doi = {10.1186/1750-1172-8-187}, author = {Fern{\'a}ndez, Raquel M and Bleda, Marta and Luz{\'o}n-Toro, Berta and Garc{\'\i}a-Alonso, Luz and Arnold, Stacey and Sribudiani, Yunia and Besmond, Claude and Lantieri, Francesca and Doan, Betty and Ceccherini, Isabella and Lyonnet, Stanislas and Hofstra, Robert Mw and Chakravarti, Aravinda and Anti{\v n}olo, Guillermo and Dopazo, Joaquin and Borrego, Salud} } @article {515, title = {Four new loci associations discovered by pathway-based and network analyses of the genome-wide variability profile of Hirschsprung{\textquoteright}s disease.}, journal = {Orphanet J Rare Dis}, volume = {7}, year = {2012}, month = {2012 Dec 28}, pages = {103}, abstract = {

Finding gene associations in rare diseases is frequently hampered by the reduced numbers of patients accessible. Conventional gene-based association tests rely on the availability of large cohorts, which constitutes a serious limitation for its application in this scenario. To overcome this problem we have used here a combined strategy in which a pathway-based analysis (PBA) has been initially conducted to prioritize candidate genes in a Spanish cohort of 53 trios of short-segment Hirschsprung{\textquoteright}s disease. Candidate genes have been further validated in an independent population of 106 trios. The study revealed a strong association of 11 gene ontology (GO) modules related to signal transduction and its regulation, enteric nervous system (ENS) formation and other HSCR-related processes. Among the preselected candidates, a total of 4 loci, RASGEF1A, IQGAP2, DLC1 and CHRNA7, related to signal transduction and migration processes, were found to be significantly associated to HSCR. Network analysis also confirms their involvement in the network of already known disease genes. This approach, based on the study of functionally-related gene sets, requires of lower sample sizes and opens new opportunities for the study of rare diseases.

}, keywords = {Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Hirschsprung Disease, Humans, Male}, issn = {1750-1172}, doi = {10.1186/1750-1172-7-103}, author = {Fern{\'a}ndez, Raquel Ma and Bleda, Marta and N{\'u}{\~n}ez-Torres, Roc{\'\i}o and Medina, Ignacio and Luz{\'o}n-Toro, Berta and Garc{\'\i}a-Alonso, Luz and Torroglosa, Ana and Marb{\`a}, Martina and Enguix-Riego, Ma Valle and Montaner, David and Anti{\v n}olo, Guillermo and Dopazo, Joaquin and Borrego, Salud} }