title: Identification of significantly mutated regions across cancer types highlights a rich landscape of functional molecular alterations.
abstract: Cancer sequencing studies have primarily identified cancer driver genes by the accumulation of protein-altering mutations. An improved method would be annotation independent, sensitive to unknown distributions of functions within proteins and inclusive of noncoding drivers. We employed density-based clustering methods in 21 tumor types to detect variably sized significantly mutated regions (SMRs). SMRs reveal recurrent alterations across a spectrum of coding and noncoding elements, including transcription factor binding sites and untranslated regions mutated in up to ∼ 15% of specific tumor types. SMRs demonstrate spatial clustering of alterations in molecular domains and at interfaces, often with associated changes in signaling. Mutation frequencies in SMRs demonstrate that distinct protein regions are differentially mutated across tumor types, as exemplified by a linker region of PIK3CA in which biophysical simulations suggest that mutations affect regulatory interactions. The functional diversity of SMRs underscores both the varied mechanisms of oncogenic misregulation and the advantage of functionally agnostic driver identification.
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Carlos L
authors.identifier: http://orcid.org/0000-0002-5512-3062
authors.initials: CL
authors.lastname: Araya
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Can
authors.initials: C
authors.lastname: Cenik
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Reuter
authors.affiliation: Department of Chemistry, Stanford University, Stanford, California, USA.
authors.forename: Gert
authors.initials: G
authors.lastname: Kiss
authors.affiliation: Department of Chemistry, Stanford University, Stanford, California, USA.
authors.forename: Vijay S
authors.initials: VS
authors.lastname: Pande
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Snyder
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.|Department of Applied Physics, Stanford University, Stanford, California, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Greenleaf
mesh_terms: D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*