Systematic Functional Interrogation of Rare Cancer Variants Identifies Oncogenic Alleles.

Cancer Discov 2016 07 4;6(7):714-26. Epub 2016 May 4.

Broad Institute of MIT and Harvard, Cambridge, Massachusetts. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

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.

Download full-text PDF

Source
http://dx.doi.org/10.1158/2159-8290.CD-16-0160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4930723PMC
July 2016

Publication Analysis

Top Keywords

gene expression
12
mutant alleles
8
pooled vivo
8
5338 tumors
8
expression profiling
8
profiling identified
8
alleles
7
cancer
5
expression
5
specific alleles
4
alleles alleles
4
activity specific
4
wild-type mutant
4
induced expression
4
expression wild-type
4
alleles mutated
4
alleles inferred
4
inferred activity
4
rendered cells
4
underscore integrating
4

Similar Publications