Comparative Analysis of Germline and Somatic Micro-lesion Mutational Spectra in 17 Human Tumour Suppressor Genes
Résumé
Mutations associated with tumorigenesis may either arise somatically or can be inherited through the germline. We performed a comparison of somatic, germline, shared (found in both soma and germline) and somatic recurrent mutational spectra for 17 human tumour suppressor genes which included missense single base-pair substitutions and micro-deletions/micro-insertions. Somatic and germline mutational spectra were similar in relation to C.G>T.A transitions but differed with respect to the frequency of A.T>G.C, A.T>T.A and C.G>A.T substitutions. Shared missense mutations were characterised by higher mutability rates, greater physicochemical differences between wild-type and mutant residues, and a tendency to occur in evolutionarily conserved residues and within CpG/CpHpG oligonucleotides. Mononucleotide runs (≥ 4 bp) were identified as hotspots for shared micro-deletions/micro-insertions. Both germline and somatic micro-deletions/micro-insertions were found to be significantly overrepresented within the 'indel-hotspot' motif, GTAAGT. Using a naïve Bayes' classifier trained to discriminate between five missense mutation groups, 63% of mutations in our dataset were on average correctly recognized. Applying this classifier to an independent dataset of probable driver mutations, we concluded that ~50% of these somatic missense mutations possess features consistent with their being either shared or recurrent, suggesting that a disproportionate number of such lesions are likely to be drivers of tumorigenesis.
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