title: Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity.
abstract: Mutational hotspots indicate selective pressure across a population of tumor samples, but their prevalence within and across cancer types is incompletely characterized. An approach to detect significantly mutated residues, rather than methods that identify recurrently mutated genes, may uncover new biologically and therapeutically relevant driver mutations. Here, we developed a statistical algorithm to identify recurrently mutated residues in tumor samples. We applied the algorithm to 11,119 human tumors, spanning 41 cancer types, and identified 470 somatic substitution hotspots in 275 genes. We find that half of all human tumors possess one or more mutational hotspots with widespread lineage-, position- and mutant allele-specific differences, many of which are likely functional. In total, 243 hotspots were novel and appeared to affect a broad spectrum of molecular function, including hotspots at paralogous residues of Ras-related small GTPases RAC1 and RRAS2. Redefining hotspots at mutant amino acid resolution will help elucidate the allele-specific differences in their function and could have important therapeutic implications.
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Departments of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California, USA.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Chang
authors.affiliation: Department of Medicine, University of California, San Francisco, California, USA.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Asthana
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Sizhi Paul
authors.initials: SP
authors.lastname: Gao
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Byron H
authors.initials: BH
authors.lastname: Lee
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, California, USA.
authors.forename: Jocelyn S
authors.initials: JS
authors.lastname: Chapman
authors.affiliation: Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Cyriac
authors.identifier: http://orcid.org/0000-0002-1345-3573
authors.initials: C
authors.lastname: Kandoth
authors.affiliation: Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: JianJiong
authors.initials: J
authors.lastname: Gao
authors.affiliation: Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Bioinformatics Core, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Socci
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Weill Cornel Medical College, Cornell University, New York, New York, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Solit
authors.affiliation: Epidemiology and Biostatistics, University of California, San Francisco, California, USA.|Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA.
authors.forename: Adam B
authors.initials: AB
authors.lastname: Olshen
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Schultz
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Barry S
authors.initials: BS
authors.lastname: Taylor
mesh_terms: D000465:Algorithms; D019295:Computational Biology; D004252:DNA Mutational Analysis / Q000379:methods*; D006801:Humans; D009154:Mutation / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics*