title: Systematic analysis of somatic mutations in phosphorylation signaling predicts novel cancer drivers.
abstract: Large-scale cancer genome sequencing has uncovered thousands of gene mutations, but distinguishing tumor driver genes from functionally neutral passenger mutations is a major challenge. We analyzed 800 cancer genomes of eight types to find single-nucleotide variants (SNVs) that precisely target phosphorylation machinery, important in cancer development and drug targeting. Assuming that cancer-related biological systems involve unexpectedly frequent mutations, we used novel algorithms to identify genes with significant phosphorylation-associated SNVs (pSNVs), phospho-mutated pathways, kinase networks, drug targets, and clinically correlated signaling modules. We highlight increased survival of patients with TP53 pSNVs, hierarchically organized cancer kinase modules, a novel pSNV in EGFR, and an immune-related network of pSNVs that correlates with prolonged survival in ovarian cancer. Our findings include multiple actionable cancer gene candidates (FLNB, GRM1, POU2F1), protein complexes (HCF1, ASF1), and kinases (PRKCZ). This study demonstrates new ways of interpreting cancer genomes and presents new leads for cancer research.
authors: The Donnelly Centre, University of Toronto, Toronto, Canada. Juri.Reimand@utoronto.ca
authors: Jüri
authors: J
authors: Reimand
authors: Gary D
authors: GD
authors: Bader
mesh_terms: D000465:Algorithms; D003285:Contractile Proteins / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D064448:Filamins; D016158:Genes, p53; D005909:Glioblastoma / Q000235:genetics; D006801:Humans; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D015233:Models, Statistical; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000401:mortality*; D050811:Octamer Transcription Factor-1 / Q000235:genetics / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics / Q000401:mortality; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D000099221:Protein Kinase C zeta
chemical_list: D003285:Contractile Proteins; D066246:ErbB Receptors; D064448:Filamins; D008840:Microfilament Proteins; D050811:Octamer Transcription Factor-1; D011493:Protein Kinase C; D011494:Protein Kinases; D011506:Proteins; D000099221:Protein Kinase C zeta; C578662:FLNB protein, human; C494165:POU2F1 protein, human; C512478:EGFR protein, human