Recently, further evidence was provided for the involvement of APOBEC3B in human cancers, as its expression was elevated in tumours compared to their matched normal samples [ 88 and 89]. By comparing the substitution patterns

of all signatures with experimental data, one of the mutational signatures was associated with exposure to ultraviolet light while another with benzo[a]pyrene, a known tobacco carcinogen. The signature associated with UV-light exhibited a higher presence of CC > TT dinucleotide substitutions as well as a strand bias indicative of the formation of photodimers, which further confirmed the association. In contrast, a mutational signature associated in lung cancer exhibited predominantly C > A selleck chemical mutations with a transcriptional strand bias suggesting the formation of bulky adducts on guanine. Interestingly, this mutational signature was also associated with CC > AA dinucleotide substitutions with a strong strand

bias. Statistical tests comparing smokers with non-smokers in two cancer types (viz. lung adenocarcinoma and tumours of the head and neck) confirmed a highly significant elevation of this ‘tobacco smoking signature’ in smokers indicating that it was due to tobacco mutagens. Further statistical analysis was performed to associate mutations in genes with the presence of mutational signatures. Distinct mutational signatures Navitoclax in vitro were associated with: mutations in BRCA1/2 in breast and pancreatic cancers; failure of the DNA mismatch repair pathway (e.g. due to methylation of the MLH1 promoter) in colorectal cancers; hypermutation of the immunoglobulin gene in CLL; recurring polymerase ɛ mutations in uterine and colorectal cancers. Interestingly, the mutational signature associated with failure of DNA mismatch repair was observed in nine different cancer types. While this process was operative in ∼20% of colorectal cancers and ∼15% of uterine cancers, it was also found in at least 1% of cancer samples in another seven cancer types. Another interesting

observation was that while almost all BRCA1/2 mutants exhibit a specific mutational signature, there were also BRCA1/2 wild-type samples with high number of mutations due to this mutational process. Thus, it is possible that some BRCA1/2 wild-type samples might harbour somatic mutations or other abnormalities Urease that result in a failure of homologous repair and activation of this mutational process. Chemotherapy treatment could cause its own set of somatic mutations [24]. Examining the pre-treatment history of all 7 042 cancer samples revealed that melanomas and glioblastomas pre-treated with an alkylating agent exhibit a distinct mutational signature. The performed global analysis was able to propose an association for 11 of the 22 validated mutation signatures, while the origins and aetiology of the other 11 mutational signatures remains unknown.