[ 11••, 12 and 13]). The TP53 somatic mutations were aggregated, their spectrum was reported as specific for the given cancer type, and this spectrum

was then compared to mutations generated experimentally in in vitro or in vivo systems [ 11•• and 13]. It should Selleck MDV3100 be noted that the mutational spectra of other genes, albeit rarely, were also used for such analysis [ 14]. These early studies revealed a significant heterogeneity of the TP53 spectra across different cancer types, which allowed associating some patterns of mutation to known carcinogens. Here, we provide a brief summary of some of the more important findings while details could be found in Refs. [ 11••, 12 and 13]. The TP53 spectrum of skin carcinomas exhibited C > T and CC > TT mutations at dipyrimidines (all substitutions and dinucleotide substitutions are referred to by the pyrimidine(s) of the mutated Watson-Crick base pair). This was consistent with the in vitro described

mutational signature of UV light. The TP53 mutational spectrum derived from lung cancers CSF-1R inhibitor in tobacco smokers was overwhelmed by C > A substitutions, which coincided with the class of mutation produced experimentally as a result of bulky adduct formation by tobacco carcinogens on guanine [ 15]. In other tobacco associated cancers, such as oesophageal and head and neck tumours, C > A mutations (while still ubiquitous) were less common while there was a significant increase of T > C mutations. Interestingly, in both smokers and non-smokers, C > T and C > G mutations at non-CpG sites were elevated when these compared to all other cancer types, with bladder tumours harbouring the most

C > G mutations [ 11••]. Additionally, it was demonstrated that C > A transversions were common in hepatocellular cancers and these mutations were believed to be associated with aflatoxin, a known carcinogen commonly found in food from southern Africa and Asia [ 16]. Lastly, all cancer types harboured at least some C > T mutations at CpG dinucleotides (mutated base underlined), a process attributed to the normal cellular event of deamination of 5-methylcytosine [ 11••]. The analyses of TP53 spectra were the first attempts to bridge the gap between molecular cancer genetics and epidemiology [ 17]. The large number of studies examining TP53 spectra required a computational resource to facilitate and retrieve the already identified somatic mutations. At first these data were managed by the researchers that were generating it but in 1994 the International Agency for Research on Cancer (IARC) started to maintain a database while providing a free access to it [ 17]. The first release of the IARC TP53 database contained ∼3 000 somatic mutations [ 18] while the most recent version (R16) released in November of 2012, which can be found at http://p53.iarc.fr/, contains almost 30 000 somatic mutations in TP53. Though extremely informative, the data gathered from single gene studies have significant limitations.