Comparative analysis of germline and somatic microlesion mutational spectra in 17 human tumor suppressor genes

✍ Scribed by Dobril Ivanov; Stephen E. Hamby; Peter D. Stenson; Andrew D. Phillips; Hildegard Kehrer-Sawatzki; David N. Cooper; Nadia Chuzhanova

• Publisher: John Wiley and Sons
• Year: 2011
• Tongue: English
• Weight: 260 KB
• Volume: 32
• Category: Article
• ISSN: 1059-7794
• DOI: 10.1002/humu.21483

✦ Synopsis

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.