Extended Data Figure 9: Mutation enrichment around TFBS across cancer types.
From: Nucleotide excision repair is impaired by binding of transcription factors to DNA
Overrepresentation of mutations at TFBS as compared to their immediate flanking regions for different cancer types and mutational signatures. The mutational process/signatures specific to each cancer type are defined as in ref. 36: UV-light associated signature (C>T) in melanoma (SKCM), tobacco smoking associated signature (C>A) in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), mutated POL-E associated signatures (T(C>A)T, T(C>T)G) in colorectal samples, and APOBEC associated mutational signature (T(C>G)T, T(C>G)A, T(C>T)T, T(C>T)A) in breast (BRCA), bladder (BLCA) and head and neck squamous cell carcinomas (HNSC). Mutations in each sample that don’t follow the aforementioned mutational signatures are grouped into one class (referred to as ‘others’) for each cancer type. The log2 fold change in the x axis represents how much higher (positive fold change) or lower (negative fold change) than the expected the observed mutation rate in TFBS is; the corresponding significance value (derived from a chi-square test) is shown on the y axis for each cancer type-signature combination. These results show that the only tumour samples with mutations clearly overrepresented at TFBS are lung carcinomas and melanomas. In both cases it is the predominant mutational signature, induced by the external mutagenic agent (UV-caused C > T mutations in melanomas, and tobacco-caused C > A mutations in lung carcinomas) which causes originally bulky lesions in the DNA that are repaired by NER. In contrast, no increment of the mutation rate in TFBS is observed in colon adenocarcinomas, where NER activity is not expected to play a major role in the mutational process, and only a modest increment is detected in other tumour types. Note that given the small number of whole-genome samples available and the lower mutational burden of breast, bladder and head and neck tumours compared to melanomas, lung carcinomas and colorectal tumours (Extended Data Table 1), the results for these tumour types should be taken with caution. Future analyses with larger cohorts of whole genomes, which would also allow a more accurate and specific separation of mutations by mutational processes should shed clearer light on this question.
