Cancer Cell. 2018 Mar 12;33(3):450-462.e10. doi: 10.1016/j.ccell.2018.01.021.
Systematic Functional Annotation of Somatic Mutations in Cancer.
Ng PK1, Li J2, Jeong KJ3, Shao S1, Chen H4, Tsang YH5, Sengupta S6, Wang Z2, Bhavana VH5, Tran R1, Soewito S1, Minussi DC7, Moreno D5, Kong K5, Dogruluk T5, Lu H5, Gao J8, Tokheim C9, Zhou DC6, Johnson AM1, Zeng J1, Ip CKM3, Ju Z2, Wester M3, Yu S3, Li Y3, Vellano CP3, Schultz N8, Karchin R10, Ding L11, Lu Y3, Cheung LWT12, Chen K2, Shaw KR1, Meric-Bernstam F13, Scott KL5, Yi S14, Sahni N15, Liang H16, Mills GB3.
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.
TCGA; cellular assay; clinical marker; driver mutation; drug sensitivity; functional genomics; functional proteomics; therapeutic target