Systematic Functional Annotation of Somatic Mutations in Cancer

Patrick Kwok-Shing Ng; Jun Li; Kang Jin Jeong; Shan Shao; Hu Chen; Yiu Huen Tsang; Sohini Sengupta; Zixing Wang; Venkata Hemanjani Bhavana; Richard Tran; Stephanie Soewito; Darlan Conterno Minussi; Daniela Moreno; Kathleen Kong; Turgut Dogruluk; Hengyu Lu; Jianjiong Gao; Collin Tokheim; Daniel Cui Zhou; Amber M Johnson; Jia Zeng; Carman Ka Man Ip; Zhenlin Ju; Matthew Wester; Shuangxing Yu; Yongsheng Li; Christopher P Vellano; Nikolaus Schultz; Rachel Karchin; Li Ding; Yiling Lu; Lydia Wai Ting Cheung; Ken Chen; Kenna R Shaw; Funda Meric-Bernstam; Kenneth L Scott; Song Yi; Nidhi Sahni; Han Liang; Gordon B Mills

doi:10.1016/j.ccell.2018.01.021

Systematic Functional Annotation of Somatic Mutations in Cancer

Cancer Cell. 2018 Mar 12;33(3):450-462.e10. doi: 10.1016/j.ccell.2018.01.021.

Authors

Patrick Kwok-Shing Ng¹, Jun Li², Kang Jin Jeong³, Shan Shao¹, Hu Chen⁴, Yiu Huen Tsang⁵, Sohini Sengupta⁶, Zixing Wang², Venkata Hemanjani Bhavana⁵, Richard Tran¹, Stephanie Soewito¹, Darlan Conterno Minussi⁷, Daniela Moreno⁵, Kathleen Kong⁵, Turgut Dogruluk⁵, Hengyu Lu⁵, Jianjiong Gao⁸, Collin Tokheim⁹, Daniel Cui Zhou⁶, Amber M Johnson¹, Jia Zeng¹, Carman Ka Man Ip³, Zhenlin Ju², Matthew Wester³, Shuangxing Yu³, Yongsheng Li³, Christopher P Vellano³, Nikolaus Schultz⁸, Rachel Karchin¹⁰, Li Ding¹¹, Yiling Lu³, Lydia Wai Ting Cheung¹², Ken Chen², Kenna R Shaw¹, Funda Meric-Bernstam¹³, Kenneth L Scott⁵, Song Yi¹⁴, Nidhi Sahni¹⁵, Han Liang¹⁶, Gordon B Mills³

Affiliations

¹ Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
² Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
³ Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁴ Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Graduate Program in Quantitative and Computational Biosciences, Baylor College of Medicine, Houston, TX 77030, USA.
⁵ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
⁶ Division of Oncology, Department of Medicine, Washington University, St. Louis, MO 63108, USA.
⁷ Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁸ Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
⁹ Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA; Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD 21218, USA.
¹⁰ Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA; Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD 21218, USA; Department of Oncology, Johns Hopkins Medicine, Baltimore, MD 21287, USA.
¹¹ Division of Oncology, Department of Medicine, Washington University, St. Louis, MO 63108, USA; Siteman Cancer Center, Washington University, St. Louis, MO 63108, USA.
¹² HKU Shenzhen Institute of Research and Innovation, Shenzhen, China; School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR.
¹³ Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁴ Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: [email protected].
¹⁵ Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Graduate Program in Quantitative and Computational Biosciences, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: [email protected].
¹⁶ Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Graduate Program in Quantitative and Computational Biosciences, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: [email protected].

Abstract

The functional impact of the vast majority of cancer somatic mutations remains unknown, representing a critical knowledge gap for implementing precision oncology. Here, we report the development of a moderate-throughput functional genomic platform consisting of efficient mutant generation, sensitive viability assays using two growth factor-dependent cell models, and functional proteomic profiling of signaling effects for select aberrations. We apply the platform to annotate >1,000 genomic aberrations, including gene amplifications, point mutations, indels, and gene fusions, potentially doubling the number of driver mutations characterized in clinically actionable genes. Further, the platform is sufficiently sensitive to identify weak drivers. Our data are accessible through a user-friendly, public data portal. Our study will facilitate biomarker discovery, prediction algorithm improvement, and drug development.

Keywords: TCGA; cellular assay; clinical marker; driver mutation; drug sensitivity; functional genomics; functional proteomics; therapeutic target.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Algorithms
Biomarkers, Tumor / genetics*
Genomics
High-Throughput Nucleotide Sequencing / methods
Humans
Mutation / genetics*
Neoplasms / diagnosis*
Neoplasms / genetics*
Precision Medicine
Proteomics

Substances

Biomarkers, Tumor

Abstract

Publication types

MeSH terms

Substances

Grants and funding