A Pan-Cancer Catalogue of Cancer Driver Protein Interaction Interfaces.
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.
Bioinformatics and Systems Biology Program, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.
Eduard
E
Porta-Pardo
European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Cambridge, United Kingdom.
Luz
L
Garcia-Alonso
Bioinformatics and Systems Biology Program, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.
Thomas
T
Hrabe
Computational Genomics Department, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain; Functional Genomics Node, (INB) at CIPF, Valencia, Spain; Bioinformatics of Rare Diseases (BIER), CIBER de Enfermedades Raras (CIBERER), Valencia, Spain.
Joaquin
J
Dopazo
Bioinformatics and Systems Biology Program, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.
Adam
A
Godzik
D000818:Animals; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics; D002377:Catalogs as Topic; D002874:Chromosome Mapping; D003198:Computer Simulation; D004252:DNA Mutational Analysis / Q000379:methods*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D025941:Protein Interaction Mapping / Q000379:methods*; D015398:Signal Transduction / Q000235:genetics*
D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins