Systematic functional interrogation of rare cancer variants identifies oncogenic alleles

Eejung Kim, Nina Ilic, Yashaswi Shrestha, Lihua Zou, Atanas Kamburov, Cong Zhu, Xiaoping Yang, Rakela Lubonja, Nancy Tran, Cindy Nguyen, Michael S. Lawrence, Federica Piccioni, Mukta Bagul, John G. Doench, Candace R. Chouinard, Xiaoyun Wu, Larson Hogstrom, Ted Natoli, Pablo Tamayo, Heiko HornSteven M. Corsello, Kasper Lage, David E. Root, Aravind Subramanian, Todd R. Golub, Gad Getz, Jesse S. Boehm, William C. Hahn*

*Corresponding author for this work

Research output: Contribution to journalArticle

54 Scopus citations

Abstract

Cancer genome characterization efforts now provide an initial view of the somatic alterations in primary tumors. However, most point mutations occur at low frequency, and the function of these alleles remains undefined. We have developed a scalable systematic approach to interrogate the function of cancer-associated gene variants. We subjected 474 mutant alleles curated from 5,338 tumors to pooled in vivo tumor formation assays and gene expression profiling. We identified 12 transforming alleles, including two in genes (PIK3CB, POT1) that have not been shown to be tumorigenic. One rare KRAS allele, D33E, displayed tumorigenicity and constitutive activation of known RAS effector pathways. By comparing gene expression changes induced upon expression of wild-type and mutant alleles, we inferred the activity of specific alleles. Because alleles found to be mutated only once in 5,338 tumors rendered cells tumorigenic, these observations underscore the value of integrating genomic information with functional studies. SIGNIFICANCE: Experimentally inferring the functional status of cancer-associated mutations facilitates the interpretation of genomic information in cancer. Pooled in vivo screen and gene expression profiling identified functional variants and demonstrated that expression of rare variants induced tumorigenesis. Variant phenotyping through functional studies will facilitate defining key somatic events in cancer.

Original languageEnglish (US)
Pages (from-to)714-726
Number of pages13
JournalCancer discovery
Volume6
Issue number7
DOIs
StatePublished - Jul 2016

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Kim, E., Ilic, N., Shrestha, Y., Zou, L., Kamburov, A., Zhu, C., Yang, X., Lubonja, R., Tran, N., Nguyen, C., Lawrence, M. S., Piccioni, F., Bagul, M., Doench, J. G., Chouinard, C. R., Wu, X., Hogstrom, L., Natoli, T., Tamayo, P., ... Hahn, W. C. (2016). Systematic functional interrogation of rare cancer variants identifies oncogenic alleles. Cancer discovery, 6(7), 714-726. https://doi.org/10.1158/2159-8290.CD-16-0160