title: High-throughput Phenotyping of Lung Cancer Somatic Mutations.
abstract: Recent genome sequencing efforts have identified millions of somatic mutations in cancer. However, the functional impact of most variants is poorly understood. Here we characterize 194 somatic mutations identified in primary lung adenocarcinomas. We present an expression-based variant-impact phenotyping (eVIP) method that uses gene expression changes to distinguish impactful from neutral somatic mutations. eVIP identified 69% of mutations analyzed as impactful and 31% as functionally neutral. A subset of the impactful mutations induces xenograft tumor formation in mice and/or confers resistance to cellular EGFR inhibition. Among these impactful variants are rare somatic, clinically actionable variants including EGFR S645C, ARAF S214C and S214F, ERBB2 S418T, and multiple BRAF variants, demonstrating that rare mutations can be functionally important in cancer.
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA.|Broad Institute of MIT and Harvard, Cambridge, MA.|Harvard Medical School, Boston, MA.
authors.forename: Alice H
authors.initials: AH
authors.lastname: Berger
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA.|Broad Institute of MIT and Harvard, Cambridge, MA.|Harvard Medical School, Boston, MA.
authors.forename: Angela N
authors.initials: AN
authors.lastname: Brooks
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Wu
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA.
authors.forename: Yashaswi
authors.initials: Y
authors.lastname: Shrestha
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA.
authors.forename: Candace
authors.initials: C
authors.lastname: Chouinard
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA.
authors.forename: Federica
authors.initials: F
authors.lastname: Piccioni
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA.
authors.forename: Mukta
authors.initials: M
authors.lastname: Bagul
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA.|Harvard Medical School, Boston, MA.|Department of Pathology and Cancer Center, Massachusetts General Hospital, Boston, MA.
authors.forename: Atanas
authors.initials: A
authors.lastname: Kamburov
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA.|Broad Institute of MIT and Harvard, Cambridge, MA.|Harvard Medical School, Boston, MA.
authors.forename: Marcin
authors.initials: M
authors.lastname: Imielinski
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA.
authors.forename: Larson
authors.initials: L
authors.lastname: Hogstrom
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA.
authors.forename: Cong
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Yang
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA.
authors.forename: Sasha
authors.initials: S
authors.lastname: Pantel
authors.affiliation: KU Leuven, Leuven, Belgium.
authors.forename: Ryo
authors.initials: R
authors.lastname: Sakai
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA.|Broad Institute of MIT and Harvard, Cambridge, MA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Watson
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Kaplan
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA.|Broad Institute of MIT and Harvard, Cambridge, MA.|Harvard Medical School, Boston, MA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Campbell
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA.
authors.forename: Shantanu
authors.initials: S
authors.lastname: Singh
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA.
authors.forename: David E
authors.initials: DE
authors.lastname: Root
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Narayan
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA.
authors.forename: Ted
authors.initials: T
authors.lastname: Natoli
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA.
authors.forename: David L
authors.initials: DL
authors.lastname: Lahr
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA.
authors.forename: Itay
authors.initials: I
authors.lastname: Tirosh
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA.
authors.forename: Pablo
authors.initials: P
authors.lastname: Tamayo
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA.|Harvard Medical School, Boston, MA.|Department of Pathology and Cancer Center, Massachusetts General Hospital, Boston, MA.
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA.
authors.forename: Bang
authors.initials: B
authors.lastname: Wong
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA.
authors.forename: John
authors.initials: J
authors.lastname: Doench
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA.
authors.forename: Aravind
authors.initials: A
authors.lastname: Subramanian
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA.|Broad Institute of MIT and Harvard, Cambridge, MA.
authors.forename: Todd R
authors.initials: TR
authors.lastname: Golub
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA.|Broad Institute of MIT and Harvard, Cambridge, MA.|Harvard Medical School, Boston, MA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA.
authors.forename: Jesse S
authors.initials: JS
authors.lastname: Boehm
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D064593:Heterografts; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D051379:Mice; D009154:Mutation; D009857:Oncogenes; D010641:Phenotype