title: Interaction-based discovery of functionally important genes in cancers.
abstract: A major challenge in cancer genomics is uncovering genes with an active role in tumorigenesis from a potentially large pool of mutated genes across patient samples. Here we focus on the interactions that proteins make with nucleic acids, small molecules, ions and peptides, and show that residues within proteins that are involved in these interactions are more frequently affected by mutations observed in large-scale cancer genomic data than are other residues. We leverage this observation to predict genes that play a functionally important role in cancers by introducing a computational pipeline (http://canbind.princeton.edu) for mapping large-scale cancer exome data across patients onto protein structures, and automatically extracting proteins with an enriched number of mutations affecting their nucleic acid, small molecule, ion or peptide binding sites. Using this computational approach, we show that many previously known genes implicated in cancers are enriched in mutations within the binding sites of their encoded proteins. By focusing on functionally relevant portions of proteins--specifically those known to be involved in molecular interactions--our approach is particularly well suited to detect infrequent mutations that may nonetheless be important in cancer, and should aid in expanding our functional understanding of the genomic landscape of cancer.
authors.affiliation: Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA and Department of Computer Science, Princeton University, Princeton, NJ 08544, USA.
authors.forename: Dario
authors.initials: D
authors.lastname: Ghersi
authors.forename: Mona
authors.initials: M
authors.lastname: Singh
mesh_terms: D001665:Binding Sites / Q000235:genetics; D053487:DEAD-box RNA Helicases / Q000737:chemistry / Q000235:genetics; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics; D052138:Genes, Neoplasm; D006801:Humans; D020125:Mutation, Missense; D009369:Neoplasms / Q000235:genetics; D011110:Polymorphism, Genetic; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry / Q000235:genetics; D043244:Ribonuclease III / Q000737:chemistry / Q000235:genetics; D012984:Software; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000235:genetics; D044844:beta-Transducin Repeat-Containing Proteins / Q000737:chemistry / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C471645:FBXW11 protein, human; C066141:MBD1 protein, human; D011506:Proteins; D014157:Transcription Factors; D044844:beta-Transducin Repeat-Containing Proteins; D044767:Ubiquitin-Protein Ligases; C491754:AKT3 protein, human; D051057:Proto-Oncogene Proteins c-akt; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases