title: Patient-specific driver gene prediction and risk assessment through integrated network analysis of cancer omics profiles.
abstract: Extensive and multi-dimensional data sets generated from recent cancer omics profiling projects have presented new challenges and opportunities for unraveling the complexity of cancer genome landscapes. In particular, distinguishing the unique complement of genes that drive tumorigenesis in each patient from a sea of passenger mutations is necessary for translating the full benefit of cancer genome sequencing into the clinic. We address this need by presenting a data integration framework (OncoIMPACT) to nominate patient-specific driver genes based on their phenotypic impact. Extensive in silico and in vitro validation helped establish OncoIMPACT's robustness, improved precision over competing approaches and verifiable patient and cell line specific predictions (2/2 and 6/7 true positives and negatives, respectively). In particular, we computationally predicted and experimentally validated the gene TRIM24 as a putative novel amplified driver in a melanoma patient. Applying OncoIMPACT to more than 1000 tumor samples, we generated patient-specific driver gene lists in five different cancer types to identify modes of synergistic action. We also provide the first demonstration that computationally derived driver mutation signatures can be overall superior to single gene and gene expression based signatures in enabling patient stratification and prognostication. Source code and executables for OncoIMPACT are freely available from http://sourceforge.net/projects/oncoimpact.
authors.affiliation: Computational and Systems Biology, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Denis
authors.initials: D
authors.lastname: Bertrand
authors.affiliation: Computational and Systems Biology, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Kern Rei
authors.initials: KR
authors.lastname: Chng
authors.affiliation: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Faranak Ghazi
authors.initials: FG
authors.lastname: Sherbaf
authors.affiliation: Computational and Systems Biology, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Anja
authors.initials: A
authors.lastname: Kiesel
authors.affiliation: Computational and Systems Biology, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Burton K H
authors.initials: BK
authors.lastname: Chia
authors.affiliation: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Yee Yen
authors.initials: YY
authors.lastname: Sia
authors.affiliation: Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, CA 90404, USA.
authors.forename: Sharon K
authors.initials: SK
authors.lastname: Huang
authors.affiliation: Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, CA 90404, USA.
authors.forename: Dave S B
authors.initials: DS
authors.lastname: Hoon
authors.affiliation: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore 138672, Singapore The Jackson Laboratory for Genomic Medicine, Farmington, CT 06030, USA.
authors.forename: Edison T
authors.initials: ET
authors.lastname: Liu
authors.affiliation: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Axel
authors.initials: A
authors.lastname: Hillmer
authors.affiliation: Computational and Systems Biology, Genome Institute of Singapore, Singapore 138672, Singapore nagarajann@gis.a-star.edu.sg.
authors.forename: Niranjan
authors.initials: N
authors.lastname: Nagarajan
mesh_terms: D000465:Algorithms; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000503:physiopathology; D009154:Mutation; D018570:Risk Assessment; D016019:Survival Analysis