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

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. JohnsonJia 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

Research output: Contribution to journal › Article › peer-review

193 Scopus citations

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. Ng et al. develop a moderate-throughput functional genomic platform and use it to annotate >1,000 cancer variants of unknown significance. The approach is sufficiently sensitive to identify weak drivers, potentially doubling the number of driver mutations characterized in clinically actionable genes.

Original language	English
Pages (from-to)	450-462.e10
Journal	Cancer Cell
Volume	33
Issue number	3
DOIs	https://doi.org/10.1016/j.ccell.2018.01.021
State	Published - Mar 12 2018

Keywords

TCGA
cellular assay
clinical marker
driver mutation
drug sensitivity
functional genomics
functional proteomics
therapeutic target

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10.1016/j.ccell.2018.01.021

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Ng, P. K. S., Li, J., Jeong, K. J., Shao, S., Chen, H., Tsang, Y. H., Sengupta, S., Wang, Z., Bhavana, V. H., Tran, R., Soewito, S., Minussi, D. C., Moreno, D., Kong, K., Dogruluk, T., Lu, H., Gao, J., Tokheim, C., Zhou, D. C., ... Mills, G. B. (2018). Systematic Functional Annotation of Somatic Mutations in Cancer. Cancer Cell, 33(3), 450-462.e10. https://doi.org/10.1016/j.ccell.2018.01.021

@article{0c973fea00724526b2420117fa3ec7d8,

title = "Systematic Functional Annotation of Somatic Mutations in Cancer",

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. Ng et al. develop a moderate-throughput functional genomic platform and use it to annotate >1,000 cancer variants of unknown significance. The approach is sufficiently sensitive to identify weak drivers, potentially doubling the number of driver mutations characterized in clinically actionable genes.",

keywords = "TCGA, cellular assay, clinical marker, driver mutation, drug sensitivity, functional genomics, functional proteomics, therapeutic target",

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

note = "Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",

year = "2018",

month = mar,

day = "12",

doi = "10.1016/j.ccell.2018.01.021",

language = "English",

volume = "33",

pages = "450--462.e10",

journal = "Cancer Cell",

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Ng, PKS, Li, J, Jeong, KJ, Shao, S, Chen, H, Tsang, YH, Sengupta, S, Wang, Z, Bhavana, VH, Tran, R, Soewito, S, Minussi, DC, Moreno, D, Kong, K, Dogruluk, T, Lu, H, Gao, J, Tokheim, C, Zhou, DC, Johnson, AM, Zeng, J, Ip, CKM, Ju, Z, Wester, M, Yu, S, Li, Y, Vellano, CP, Schultz, N, Karchin, R, Ding, L, Lu, Y, Cheung, LWT, Chen, K, Shaw, KR, Meric-Bernstam, F, Scott, KL, Yi, S, Sahni, N, Liang, H & Mills, GB 2018, 'Systematic Functional Annotation of Somatic Mutations in Cancer', Cancer Cell, vol. 33, no. 3, pp. 450-462.e10. https://doi.org/10.1016/j.ccell.2018.01.021

TY - JOUR

T1 - Systematic Functional Annotation of Somatic Mutations in Cancer

AU - Ng, Patrick Kwok Shing

AU - Li, Jun

AU - Jeong, Kang Jin

AU - Shao, Shan

AU - Chen, Hu

AU - Tsang, Yiu Huen

AU - Sengupta, Sohini

AU - Wang, Zixing

AU - Bhavana, Venkata Hemanjani

AU - Tran, Richard

AU - Soewito, Stephanie

AU - Minussi, Darlan Conterno

AU - Moreno, Daniela

AU - Kong, Kathleen

AU - Dogruluk, Turgut

AU - Lu, Hengyu

AU - Gao, Jianjiong

AU - Tokheim, Collin

AU - Zhou, Daniel Cui

AU - Johnson, Amber M.

AU - Zeng, Jia

AU - Ip, Carman Ka Man

AU - Ju, Zhenlin

AU - Wester, Matthew

AU - Yu, Shuangxing

AU - Li, Yongsheng

AU - Vellano, Christopher P.

AU - Schultz, Nikolaus

AU - Karchin, Rachel

AU - Ding, Li

AU - Lu, Yiling

AU - Cheung, Lydia Wai Ting

AU - Chen, Ken

AU - Shaw, Kenna R.

AU - Meric-Bernstam, Funda

AU - Scott, Kenneth L.

AU - Yi, Song

AU - Sahni, Nidhi

AU - Liang, Han

AU - Mills, Gordon B.

PY - 2018/3/12

Y1 - 2018/3/12

N2 - 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. Ng et al. develop a moderate-throughput functional genomic platform and use it to annotate >1,000 cancer variants of unknown significance. The approach is sufficiently sensitive to identify weak drivers, potentially doubling the number of driver mutations characterized in clinically actionable genes.

AB - 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. Ng et al. develop a moderate-throughput functional genomic platform and use it to annotate >1,000 cancer variants of unknown significance. The approach is sufficiently sensitive to identify weak drivers, potentially doubling the number of driver mutations characterized in clinically actionable genes.

KW - TCGA

KW - cellular assay

KW - clinical marker

KW - driver mutation

KW - drug sensitivity

KW - functional genomics

KW - functional proteomics

KW - therapeutic target

UR - http://www.scopus.com/inward/record.url?scp=85042855288&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2018.01.021

DO - 10.1016/j.ccell.2018.01.021

M3 - Article

C2 - 29533785

AN - SCOPUS:85042855288

SN - 1535-6108

VL - 33

SP - 450-462.e10

JO - Cancer Cell

JF - Cancer Cell

IS - 3

ER -

Systematic Functional Annotation of Somatic Mutations in Cancer

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Keywords

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