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 & 20 others 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 Mills

Research output: Contribution to journalArticle

22 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)450-462.e10
JournalCancer Cell
Volume33
Issue number3
DOIs
StatePublished - Mar 12 2018
Externally publishedYes

Fingerprint

Mutation
Neoplasms
Gene Amplification
Gene Fusion
Point Mutation
Proteomics
Genes
Intercellular Signaling Peptides and Proteins
Biomarkers
Pharmaceutical Preparations

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

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

In: Cancer Cell, Vol. 33, No. 3, 12.03.2018, p. 450-462.e10.

Research output: Contribution to journalArticle

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, G 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
Ng, Patrick Kwok Shing ; Li, Jun ; Jeong, Kang Jin ; Shao, Shan ; Chen, Hu ; Tsang, Yiu Huen ; Sengupta, Sohini ; Wang, Zixing ; Bhavana, Venkata Hemanjani ; Tran, Richard ; Soewito, Stephanie ; Minussi, Darlan Conterno ; Moreno, Daniela ; Kong, Kathleen ; Dogruluk, Turgut ; Lu, Hengyu ; Gao, Jianjiong ; Tokheim, Collin ; Zhou, Daniel Cui ; Johnson, Amber M. ; Zeng, Jia ; Ip, Carman Ka Man ; Ju, Zhenlin ; Wester, Matthew ; Yu, Shuangxing ; Li, Yongsheng ; Vellano, Christopher P. ; Schultz, Nikolaus ; Karchin, Rachel ; Ding, Li ; Lu, Yiling ; Cheung, Lydia Wai Ting ; Chen, Ken ; Shaw, Kenna R. ; Meric-Bernstam, Funda ; Scott, Kenneth L. ; Yi, Song ; Sahni, Nidhi ; Liang, Han ; Mills, Gordon. / Systematic Functional Annotation of Somatic Mutations in Cancer. In: Cancer Cell. 2018 ; Vol. 33, No. 3. pp. 450-462.e10.
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