Systematic Functional Interrogation of Rare Cancer Variants Identifies Oncogenic Alleles.

Cancer Discov
Authors
Keywords
Abstract

UNLABELLED: 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. Cancer Discov; 6(7); 714-26. ©2016 AACR.See related commentary by Cho and Collisson, p. 694This article is highlighted in the In This Issue feature, p. 681.

Year of Publication
2016
Journal
Cancer Discov
Volume
6
Issue
7
Pages
714-26
Date Published
2016 07
ISSN
2159-8290
URL
DOI
10.1158/2159-8290.CD-16-0160
PubMed ID
27147599
PubMed Central ID
PMC4930723
Links
Grant list
P01 CA154303 / CA / NCI NIH HHS / United States
P30 CA023100 / CA / NCI NIH HHS / United States
U01 CA176058 / CA / NCI NIH HHS / United States
U01 CA199253 / CA / NCI NIH HHS / United States