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Journal Article

Systematic Functional Interrogation of Rare Cancer Variants Identifies Oncogenic Alleles

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.

Eejung Kim
Nina Ilic
Yashaswi Shrestha
Lihua Zou
Atanas Kamburov
Cong Zhu
Xiaoping Yang
Rakela Lubonja
Nancy Tran
Cindy Nguyen
Michael Lawrence
Federica Piccioni
Mukta Bagul
John Doench
Candace Chouinard
Xiaoyun Wu
Larson Hogstrom
Ted Natoli
Pablo Tamayo
Heiko Horn
Steven Corsello
Kasper Lage
David Root
Aravind Subramanian
Todd Golub
Gad Getz
Jesse Boehm
William Hahn
Journal Name
Cancer Discovery
Publication Date
July, 2016