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.