title: 3D clusters of somatic mutations in cancer reveal numerous rare mutations as functional targets.
abstract: Many mutations in cancer are of unknown functional significance. Standard methods use statistically significant recurrence of mutations in tumor samples as an indicator of functional impact. We extend such analyses into the long tail of rare mutations by considering recurrence of mutations in clusters of spatially close residues in protein structures. Analyzing 10,000 tumor exomes, we identify more than 3000 rarely mutated residues in proteins as potentially functional and experimentally validate several in RAC1 and MAP2K1. These potential driver mutations (web resources: 3dhotspots.org and cBioPortal.org) can extend the scope of genomically informed clinical trials and of personalized choice of therapy.
authors.affiliation: Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. jgao@cbio.mskcc.org.
authors.forename: Jianjiong
authors.identifier: 0000-0002-5739-1781
authors.initials: J
authors.lastname: Gao
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Departments of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Chang
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Hannah C
authors.initials: HC
authors.lastname: Johnsen
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Sizhi Paul
authors.initials: SP
authors.lastname: Gao
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Brooke E
authors.initials: BE
authors.lastname: Sylvester
authors.affiliation: Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Selcuk Onur
authors.initials: SO
authors.lastname: Sumer
authors.affiliation: Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Hongxin
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Weill Cornell Medical College, Cornell University, New York, NY, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Solit
authors.affiliation: Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Barry S
authors.initials: BS
authors.lastname: Taylor
authors.affiliation: Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Schultz
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA, USA.|cBio Center, Dana-Farber Cancer Institute, Boston, MA, USA.|Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Sander
mesh_terms: D004252:DNA Mutational Analysis / Q000379:methods*; D059472:Exome; D023281:Genomics / Q000379:methods*; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D020830:rac1 GTP-Binding Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D009363:Neoplasm Proteins; C107953:RAC1 protein, human; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D020830:rac1 GTP-Binding Protein
keywords: Cancer genomics; Driver mutations; Precision medicine; Protein structures