High-throughput Phenotyping of Lung Cancer Somatic Mutations

被引：153

作者：

Berger, Alice H. ^{[1
,2
,3
]}

Brooks, Angela N. ^{[1
,2
,3
,11
]}

Wu, Xiaoyun ^{[2
]}

Shrestha, Yashaswi ^{[2
]}

Chouinard, Candace ^{[2
]}

Piccioni, Federica ^{[4
]}

Bagul, Mukta ^{[4
]}

Kamburov, Atanas ^{[2
,3
,5
,6
]}

Imielinski, Marcin ^{[1
,2
,3
]}

Hogstrom, Larson ^{[2
]}

Zhu, Cong ^{[4
]}

Yang, Xiaoping ^{[4
]}

Pantel, Sasha ^{[4
]}

Sakai, Ryo ^{[7
]}

Watson, Jacqueline ^{[1
,2
]}

Kaplan, Nathan ^{[1
]}

Campbell, Joshua D. ^{[1
,2
,3
]}

Singh, Shantanu ^{[8
]}

Root, David E. ^{[4
]}

Narayan, Rajiv ^{[2
]}

Natoli, Ted ^{[2
]}

Lahr, David L. ^{[2
]}

Tirosh, Itay ^{[9
]}

Tamayo, Pablo ^{[2
]}

Getz, Gad ^{[2
,3
,5
,6
]}

Wong, Bang ^{[2
]}

Doench, John ^{[4
]}

Subramanian, Aravind ^{[2
]}

Golub, Todd R. ^{[1
,2
,10
]}

Meyerson, Matthew ^{[1
,2
,3
]}

Boehm, Jesse S. ^{[2
]}

机构：

[1] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[2] Broad Inst MIT & Harvard, Canc Program, Cambridge, MA 02142 USA

[3] Harvard Med Sch, Dept Pathol, Boston, MA 02115 USA

[4] Broad Inst MIT & Harvard, Genet Perturbat Platform, Cambridge, MA 02142 USA

[5] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA

[6] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA

[7] Katholieke Univ Leuven, Dept Elect Engn ESAT STADIUS, B-3000 Leuven, Belgium

[8] Broad Inst MIT & Harvard, Imaging Platform, Cambridge, MA 02142 USA

[9] Broad Inst MIT & Harvard, Cell Circuits & Epigen Program, Cambridge, MA 02142 USA

[10] Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA

[11] Univ Calif Santa Cruz, Santa Cruz, CA 95064 USA

来源：

CANCER CELL | 2016年 / 30卷 / 02期

关键词：

RNA INTERFERENCE SCREEN; TUMOR SAMPLES; LIVER-CANCER; HUMAN-CELLS; GENOME; GENES; IDENTIFICATION; ADENOCARCINOMA; INHIBITION; GEFITINIB;

D O I：

10.1016/j.ccell.2016.06.022

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：214 / 228

页数：15

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