title: Comprehensive assessment of cancer missense mutation clustering in protein structures.
abstract: Large-scale tumor sequencing projects enabled the identification of many new cancer gene candidates through computational approaches. Here, we describe a general method to detect cancer genes based on significant 3D clustering of mutations relative to the structure of the encoded protein products. The approach can also be used to search for proteins with an enrichment of mutations at binding interfaces with a protein, nucleic acid, or small molecule partner. We applied this approach to systematically analyze the PanCancer compendium of somatic mutations from 4,742 tumors relative to all known 3D structures of human proteins in the Protein Data Bank. We detected significant 3D clustering of missense mutations in several previously known oncoproteins including HRAS, EGFR, and PIK3CA. Although clustering of missense mutations is often regarded as a hallmark of oncoproteins, we observed that a number of tumor suppressors, including FBXW7, VHL, and STK11, also showed such clustering. Beside these known cases, we also identified significant 3D clustering of missense mutations in NUF2, which encodes a component of the kinetochore, that could affect chromosome segregation and lead to aneuploidy. Analysis of interaction interfaces revealed enrichment of mutations in the interfaces between FBXW7-CCNE1, HRAS-RASA1, CUL4B-CAND1, OGT-HCFC1, PPP2R1A-PPP2R5C/PPP2R2A, DICER1-Mg2+, MAX-DNA, SRSF2-RNA, and others. Together, our results indicate that systematic consideration of 3D structure can assist in the identification of cancer genes and in the understanding of the functional role of their mutations.
authors.affiliation: Department of Pathology and Cancer Center, Massachusetts General Hospital, Boston, MA 02114; Harvard Medical School, Boston, MA 02115; Broad Institute of MIT and Harvard, Cambridge, MA 02142;
authors.forename: Atanas
authors.initials: A
authors.lastname: Kamburov
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142;
authors.forename: Michael S
authors.initials: MS
authors.lastname: Lawrence
authors.affiliation: Department of Pathology and Cancer Center, Massachusetts General Hospital, Boston, MA 02114; Harvard Medical School, Boston, MA 02115; Broad Institute of MIT and Harvard, Cambridge, MA 02142;
authors.forename: Paz
authors.initials: P
authors.lastname: Polak
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142;
authors.forename: Ignaty
authors.initials: I
authors.lastname: Leshchiner
authors.affiliation: Harvard Medical School, Boston, MA 02115; Broad Institute of MIT and Harvard, Cambridge, MA 02142; Department of Surgery, Massachusetts General Hospital, Boston, MA 02114.
authors.forename: Kasper
authors.initials: K
authors.lastname: Lage
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142;
authors.forename: Todd R
authors.initials: TR
authors.lastname: Golub
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142; lander@broadinstitute.org gadgetz@broadinstitute.org.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Lander
authors.affiliation: Department of Pathology and Cancer Center, Massachusetts General Hospital, Boston, MA 02114; Harvard Medical School, Boston, MA 02115; Broad Institute of MIT and Harvard, Cambridge, MA 02142; lander@broadinstitute.org gadgetz@broadinstitute.org.
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
mesh_terms: D000465:Algorithms; D020134:Catalytic Domain; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016000:Cluster Analysis; D030562:Databases, Protein; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D020125:Mutation, Missense; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism*; D015513:Oncogene Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D025941:Protein Interaction Mapping / Q000379:methods; D060066:Protein Interaction Maps / Q000235:genetics; D017434:Protein Structure, Tertiary
chemical_list: D018797:Cell Cycle Proteins; C490197:NUF2 protein, human; D015513:Oncogene Proteins
keywords: cancer; cancer genetics; interaction interfaces; mutation clustering; protein structures