title: Prediction and prioritization of rare oncogenic mutations in the cancer Kinome using novel features and multiple classifiers.
abstract: Cancer is a genetic disease that develops through a series of somatic mutations, a subset of which drive cancer progression. Although cancer genome sequencing studies are beginning to reveal the mutational patterns of genes in various cancers, identifying the small subset of "causative" mutations from the large subset of "non-causative" mutations, which accumulate as a consequence of the disease, is a challenge. In this article, we present an effective machine learning approach for identifying cancer-associated mutations in human protein kinases, a class of signaling proteins known to be frequently mutated in human cancers. We evaluate the performance of 11 well known supervised learners and show that a multiple-classifier approach, which combines the performances of individual learners, significantly improves the classification of known cancer-associated mutations. We introduce several novel features related specifically to structural and functional characteristics of protein kinases and find that the level of conservation of the mutated residue at specific evolutionary depths is an important predictor of oncogenic effect. We consolidate the novel features and the multiple-classifier approach to prioritize and experimentally test a set of rare unconfirmed mutations in the epidermal growth factor receptor tyrosine kinase (EGFR). Our studies identify T725M and L861R as rare cancer-associated mutations inasmuch as these mutations increase EGFR activity in the absence of the activating EGF ligand in cell-based assays.
authors.affiliation: Department of Computer Science, University of Georgia, Athens, Georgia, United States of America.
authors.forename: ManChon
authors.initials: M
authors.lastname: U
authors.affiliation: Department of Dermatology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Eric
authors.initials: E
authors.lastname: Talevich
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Georgia, Athens, Georgia, United States of America.
authors.forename: Samiksha
authors.initials: S
authors.lastname: Katiyar
authors.affiliation: Department of Computer Science, University of Georgia, Athens, Georgia, United States of America.
authors.forename: Khaled
authors.initials: K
authors.lastname: Rasheed
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Georgia, Athens, Georgia, United States of America; Institute of Bioinformatics, University of Georgia, Athens, Georgia, United States of America.
authors.forename: Natarajan
authors.initials: N
authors.lastname: Kannan
mesh_terms: D001185:Artificial Intelligence; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000201:enzymology*; D009857:Oncogenes; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D011494:Protein Kinases
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