High-throughput Phenotyping of Lung Cancer Somatic Mutations

Alice H. Berger; Angela N. Brooks; Xiaoyun Wu; Yashaswi Shrestha; Candace Chouinard; Federica Piccioni; Mukta Bagul; Atanas Kamburov; Marcin Imielinski; Larson Hogstrom; Cong Zhu; Xiaoping Yang; Sasha Pantel; Ryo Sakai; Jacqueline Watson; Nathan Kaplan; Joshua D. Campbell; Shantanu Singh; David E. Root; Rajiv Narayan; Ted Natoli; David L. Lahr; Itay Tirosh; Pablo Tamayo; Gad Getz; Bang Wong; John Doench; Aravind Subramanian; Todd R. Golub; Matthew Meyerson; Jesse S. Boehm

doi:10.1016/j.ccell.2016.06.022

High-throughput Phenotyping of Lung Cancer Somatic Mutations

Alice H. Berger, Angela N. Brooks, Xiaoyun Wu, Yashaswi Shrestha, Candace Chouinard, Federica Piccioni, Mukta Bagul, Atanas Kamburov, Marcin Imielinski, Larson Hogstrom, Cong Zhu, Xiaoping Yang, Sasha Pantel, Ryo Sakai, Jacqueline Watson, Nathan Kaplan, Joshua D. Campbell, Shantanu Singh, David E. Root, Rajiv NarayanTed Natoli, David L. Lahr, Itay Tirosh, Pablo Tamayo, Gad Getz, Bang Wong, John Doench, Aravind Subramanian, Todd R. Golub, Matthew Meyerson, Jesse S. Boehm

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92 Scopus citations

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.

Original language	English (US)
Pages (from-to)	214-228
Number of pages	15
Journal	Cancer Cell
Volume	30
Issue number	2
DOIs	https://doi.org/10.1016/j.ccell.2016.06.022
State	Published - Aug 8 2016
Externally published	Yes

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

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10.1016/j.ccell.2016.06.022

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Berger, A. H., Brooks, A. N., Wu, X., Shrestha, Y., Chouinard, C., Piccioni, F., Bagul, M., Kamburov, A., Imielinski, M., Hogstrom, L., Zhu, C., Yang, X., Pantel, S., Sakai, R., Watson, J., Kaplan, N., Campbell, J. D., Singh, S., Root, D. E., ... Boehm, J. S. (2016). High-throughput Phenotyping of Lung Cancer Somatic Mutations. Cancer Cell, 30(2), 214-228. https://doi.org/10.1016/j.ccell.2016.06.022

Berger, AH, Brooks, AN, Wu, X, Shrestha, Y, Chouinard, C, Piccioni, F, Bagul, M, Kamburov, A, Imielinski, M, Hogstrom, L, Zhu, C, Yang, X, Pantel, S, Sakai, R, Watson, J, Kaplan, N, Campbell, JD, Singh, S, Root, DE, Narayan, R, Natoli, T, Lahr, DL, Tirosh, I, Tamayo, P, Getz, G, Wong, B, Doench, J, Subramanian, A, Golub, TR, Meyerson, M & Boehm, JS 2016, 'High-throughput Phenotyping of Lung Cancer Somatic Mutations', Cancer Cell, vol. 30, no. 2, pp. 214-228. https://doi.org/10.1016/j.ccell.2016.06.022

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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.",

author = "Berger, {Alice H.} and Brooks, {Angela N.} and Xiaoyun Wu and Yashaswi Shrestha and Candace Chouinard and Federica Piccioni and Mukta Bagul and Atanas Kamburov and Marcin Imielinski and Larson Hogstrom and Cong Zhu and Xiaoping Yang and Sasha Pantel and Ryo Sakai and Jacqueline Watson and Nathan Kaplan and Campbell, {Joshua D.} and Shantanu Singh and Root, {David E.} and Rajiv Narayan and Ted Natoli and Lahr, {David L.} and Itay Tirosh and Pablo Tamayo and Gad Getz and Bang Wong and John Doench and Aravind Subramanian and Golub, {Todd R.} and Matthew Meyerson and Boehm, {Jesse S.}",

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AU - Berger, Alice H.

AU - Brooks, Angela N.

AU - Wu, Xiaoyun

AU - Shrestha, Yashaswi

AU - Chouinard, Candace

AU - Piccioni, Federica

AU - Bagul, Mukta

AU - Kamburov, Atanas

AU - Imielinski, Marcin

AU - Hogstrom, Larson

AU - Zhu, Cong

AU - Yang, Xiaoping

AU - Pantel, Sasha

AU - Sakai, Ryo

AU - Watson, Jacqueline

AU - Kaplan, Nathan

AU - Campbell, Joshua D.

AU - Singh, Shantanu

AU - Root, David E.

AU - Narayan, Rajiv

AU - Natoli, Ted

AU - Lahr, David L.

AU - Tirosh, Itay

AU - Tamayo, Pablo

AU - Getz, Gad

AU - Wong, Bang

AU - Doench, John

AU - Subramanian, Aravind

AU - Golub, Todd R.

AU - Meyerson, Matthew

AU - Boehm, Jesse S.

PY - 2016/8/8

Y1 - 2016/8/8

N2 - 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.

AB - 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.

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High-throughput Phenotyping of Lung Cancer Somatic Mutations

Abstract

ASJC Scopus subject areas

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