Fig 1.
Models for regulatory element involvement in cancer.
In the trans-model of cancer enhancers, somatic mutation to a chromatin modifier gene, here MLL3/4 (red pentagon), results in that chromatin modifier binding more tightly to a DNA-bound transcription factor (yellow oval) and aberrantly creates a persistently open chromatin state, up-regulating the target gene. In the cis-model of cancer enhancers, a somatic mutation to a noncoding regulatory element (orange bar) creates the same open chromatin state, perhaps by creating a binding site for a transcription factor that is recruited to the locus and facilitates opening local chromatin.
Fig 2.
PLC NCVs occur more often than expected in heterologous cell type-specific regulatory elements.
(a) Filtering strategy for SNVs from whole genome resequenced samples in COSMIC. (b) Annotation of filtered SNVs by UCSC known genes. (c) SNVs in cell type restricted or shared DNaseI promoters or enhancers. Y-axis is fold observed over expected, based on background distribution of cell type restricted or shared DHSs. (d) Observed versus expected SNVs in each ChromHMM-18 state in each of the 78 Roadmap cells and tissues with available data. Orange dot is primary liver sample (Roadmap E066); gray dots are the other 77 Roadmap samples; black line is 1. (e) Browser view of C1orf61 locus and three regulatory elements mutated in three unique samples. The top track is the Epilogos track (http://compbio.mit.edu/epilogos/), which provides a visualization of the chromatin state models for several cell types at once. The presented track depicts the ChromHMM-18 state model 127 Roadmap cell types (primary and cell lines) at a 200bp resolution. Red and orange colors represent active promoter annotations; light green and yellow colors represent genic enhancers and enhancers, respectively; pink and beige are bivalent states; grays are repressed Polycomb states. Middle track: Positions of PLC WGS SNVs (red lines) on a yellow background. Bottom track: RefSeq genes track. (f) Expression from TCGA PLC tumor and matched normal samples for C1orf61. Red line = median expression for normal samples. (g) Browser view for ESRP1 and three regulatory elements mutated in three unique samples. Tracks are as in (e). (h) Expression as in (f) for ESRP1.
Table 1.
Number of SNVs per regulatory element.
Table 2.
Number of genes with SNV-containing putative regulatory elements.
Fig 3.
Systematic motif detection identifies oncogenic TFBS gain-of-binding events.
(a) Analysis pipeline for detecting motifs from wildtype and mutant allele sequences. (b) Histogram of delta values for WGS SNV allele pairs after filtering to keep only allele pairs with at least one motif score of absolute value ≥ 2.
Fig 4.
Gain-of-binding site events at known oncogenes.
(a) ZFAS1 locus. SNV occurs in the last intron creating a JUND binding site. (b) FGF5 locus. SNV in the promoter creates a MYC binding site.
Fig 5.
Liver cancer SNV pathway enrichment.
Right: Heat map of 25 pathways tested. Color intensity represents the significance of enrichment (–log10(P-value)) for PLC SNVs in promoters that are found in genes for each pathway. WGS = whole genome resequencing-derived PLC SNVs; ExomeSeq = ExomeSeq-derived PLC SNVs. Left: Colored boxes depict a sample of top hits from significantly enriched pathways. Genes listed have the most recurrently hit promoters for the given pathway. Green box = ERBB signaling pathway; blue box = transcriptional misregulation in cancer; purple box = MAPK signaling pathway; gold box = MTOR signaling pathway.