RT Journal Article
SR Electronic
T1 Convergence of dispersed regulatory mutations predicts driver genes in prostate cancer
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 097451
DO 10.1101/097451
A1 Sallari, Richard C.
A1 Sinnott-Armstrong, Nicholas A.
A1 French, Juliet D.
A1 Kron, Ken J.
A1 Ho, Jason
A1 Moore, Jason H.
A1 Stambolic, Vuk
A1 Edwards, Stacey L.
A1 Lupien, Mathieu
A1 Kellis, Manolis
YR 2017
UL http://biorxiv.org/content/early/2017/08/26/097451.abstract
AB Cancer sequencing predicts driver genes using recurrent protein-altering mutations, but detecting recurrence for non-coding mutations remains unsolved. Here, we present a convergence framework for recurrence analysis of non-coding mutations using three-dimensional co-localization of epigenomically-identified regions. We define the regulatory plexus of each gene as its cell-type-specific three-dimensional gene-regulatory neighborhood, inferred using Hi-C chromosomal interactions and chromatin state annotations. Using 16 matched tumor-normal prostate transcriptomes, we predict tumor-upregulated genes, and find enriched plexus mutations in distal regulatory regions normally repressed in prostate, suggesting out-of-context de-repression. Using 55 matched tumor-normal prostate genomes, we predict 15 driver genes by convergence of dispersed, low-frequency mutations into high-frequency dysregulation events along prostate-specific plexi, while controlling for mutational heterogeneity across regions, chromatin states, and patients. These putative drivers play roles in growth signaling, immune evasion, mitochondrial function, and vascularization, suggesting higher-order pathway-level convergence. We experimentally validate the PLCB4 plexus and its ability to affect the canonical PI3K cancer pathway.