title: Comparative analysis of germline and somatic microlesion mutational spectra in 17 human tumor suppressor genes.
abstract: 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 tumor suppressor genes, which focused upon missense single base-pair substitutions and microdeletions/microinsertions. 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 characterized 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 microdeletions/microinsertions. Both germline and somatic microdeletions/microinsertions 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.
authors: Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors: Dobril
authors: D
authors: Ivanov
authors: Stephen E
authors: SE
authors: Hamby
authors: Peter D
authors: PD
authors: Stenson
authors: Andrew D
authors: AD
authors: Phillips
authors: Hildegard
authors: H
authors: Kehrer-Sawatzki
authors: David N
authors: DN
authors: Cooper
authors: Nadia
authors: N
authors: Chuzhanova
mesh_terms: D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D019295:Computational Biology; D004252:DNA Mutational Analysis; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D054643:INDEL Mutation; D009154:Mutation / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D025521:Tumor Suppressor Proteins