Carcinogenesis Advance Access originally published online on February 22, 2008
Carcinogenesis 2008 29(4):772-778; doi:10.1093/carcin/bgn053
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Comparison of induced and cancer-associated mutational spectra using multivariate data analysis
Cancer Informatics Group
1 Developmental Medicine Group, Institute of Life Science, Swansea Medical School, Swansea University, Singleton Park, Swansea SA2 8PP, UK
2 Molecular Epidemiology Unit, Leeds Institute for Genetics, Health and Therapeutics, The Light Laboratories, University of Leeds, Leeds LS2 9JT, UK
3 Pathology and Tumour Biology, Leeds Institute of Molecular Medicine, Wellcome Trust Brenner Building, St James's University Hospital, Leeds LS9 7TF, UK
* To whom correspondence should be addressed. Tel: +44 1792 295222; Fax: +44 1792 13430;Email: p.d.lewis{at}swansea.ac.uk
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.
Abbreviations: BPDE, benzo[a]pyrene diol epoxide; CPD, cyclobutane pyrimidine dimmer; FA, fuzzy cluster analysis; PCA, principal components analysis; rdm, relative dinucleotide mutabilities; SC, silhouette coefficient; SCC, squamous cell carcinoma; UV, ultraviolet
Received November 12, 2007; revised January 18, 2008; accepted February 12, 2008.
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