Deleterious Impact of Mutational Processes on Transcription Factor Binding Sites in Human Cancer

MutViz 2.0: visual analysis of somatic mutations and the impact of mutational signatures on selected genomic regions

“…At the same time, the low counts of A[C→T]G, C[C→T]G and G[C→T]G, and the only moderate count of T[C→T]G evidence that only a small fraction of these mutations fall on CpGs and can hence be caused by the spontaneous deamination of 5-methylcytosine already mentioned above. This is consistent with the hypothesis that the majority of somatic CTCF binding site mutations in melamona are caused by ultraviolet light ( 8 ).…”

“…Figure 2 , for example, clearly shows that in melamona CTCF binding sites are significantly more often mutated than their flanking sequences ( P < 10 −4 ) and that the vast majority are C→T base changes (including the reverse complement G→A), with the two highest peaks corresponding to mutations (on the forward and the reverse strand) of positions 13 and 14 of the CTCF motif shown in Figure 1 . This enrichment can partly be explained by the C→T and CC→TT mutations associated with ultraviolet light ( 8 , 24 ) and has been observed also in other skin cancers ( 25 ).…”

“…Since the trinucleotide frequencies in potentially small genomic regions of interest can differ greatly from the genome-wide frequencies ( 8 ), it is not appropriate to directly apply (genome-wide) mutational signatures to the limited set of mutations located within these regions.…”

“…In this context, it is important to understand that the various mutational processes can have largely different effects on different subsets of the genome—like coding regions, promoter regions, regulatory elements and so on—depending on both their functional constraints and their different sequence content ( 8–10 ). While, for instance, the cytosine to thymine (C→T) or cytosine–cytosine to thymine–thymine (CC→TT) changes associated with ultraviolet light ( 11 , 12 ) can mutate several positions in consensus CTCF binding sites ( 8 ) (see Figure 1 ; in particular positions 4–5, 7, 10, 13–15 and 17), the age-related spontaneous deamination of 5-methylcytosines (also C→T) actually requires the presence of CpGs (hence, CpG→TpG), which are usually much less abundant than cytosines in these binding sites (mostly at position 15/16; see Figure 1 ).…”

“…In our own previous work, we have investigated the enrichment of somatic mutations, abnormal methylation and copy number alterations in the proximity of active CTCF binding sites at the boundaries of topologically associated domains (TADs) in 26 cancer types ( 14 ), and developed a theoretical, mathematical framework to predict the impact of different mutational processes on binding sites of specific transcription factors ( 8 ).…”