title: Comparison of induced and cancer-associated mutational spectra using multivariate data analysis.
abstract: One of the most useful tools for investigating the aetiopathology of cancer is the mutation spectrum, which comprises the type and distribution of mutations within a gene sequence. Many studies have generated mutagen-induced spectra using in vitro or in vivo model systems in an attempt to find correlations with those observed in cancer-associated genes such as the TP53 tumour suppressor gene. Consequently, meaningful similarities in the types of mutation found in induced and human spectra have been demonstrated. However, it is more difficult to draw such conclusions about the distribution or sequence context of mutations when they arise in different target sequences. We have developed an analytical approach for base substitution spectra that capture information for both sequence context and mutation type simultaneously. The resulting mutation signature is a fixed set of data points that allows comparison of multiple mutation spectra regardless of sequence. We have applied this method to a mixed set of mutation spectra observed in exons 5, 7 and 8 of TP53 from cancers of brain, breast, skin, colon, oesophagus, liver, head and neck, stomach and lung (smokers and non-smokers) and spectra induced by benzo[a]pyrene diol epoxide, ultraviolet (UV) B, UVC, simulated sunlight and hydroxyl radicals in the cII, supF and yeast p53 model systems. We demonstrate that this approach allows human cancer and mutagen-induced signatures to be grouped together according to similarity. Specifically, the analysis reveals key differences between smoking- and non-smoking-related lung cancer for TP53 mutations and the mutability of CpG sites between exons in skin cancer.
authors.affiliation: Cancer Informatics Group, Institute of Life Science, Swansea Medical School, Swansea University, Singleton Park, Swansea SA2 8PP, UK. p.d.lewis@swansea.ac.uk
authors.forename: P D
authors.initials: PD
authors.lastname: Lewis
authors.forename: B
authors.initials: B
authors.lastname: Manshian
authors.forename: M N
authors.initials: MN
authors.lastname: Routledge
authors.forename: G B
authors.initials: GB
authors.lastname: Scott
authors.forename: P A
authors.initials: PA
authors.lastname: Burns
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002273:Carcinogens; D004252:DNA Mutational Analysis; D006801:Humans; D008175:Lung Neoplasms / Q000209:etiology; D051379:Mice; D015999:Multivariate Analysis; D009153:Mutagens; D009154:Mutation; D009369:Neoplasms / Q000209:etiology* / Q000235:genetics* / Q000473:pathology; D012907:Smoking / Q000009:adverse effects
chemical_list: D002273:Carcinogens; D009153:Mutagens