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

Ivanov, Dobril ORCID: https://orcid.org/0000-0001-6271-6301, Hamby, Stephen E., Stenson, Peter Daniel, Phillips, Andrew David, Kehrer-Sawatzki, Hildegard, Cooper, David Neil ORCID: https://orcid.org/0000-0002-8943-8484 and Chuzhanova, Nadia 2011. Comparative analysis of germline and somatic microlesion mutational spectra in 17 human tumor suppressor genes. Human Mutation 32 (6) , pp. 620-632. 10.1002/humu.21483

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: Q Science > QH Natural history > QH426 Genetics
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Uncontrolled Keywords: Germline and somatic mutational spectra ; Tumor suppressor genes ; Recurrent mutation ; Mutation hotspot ; Non-B DNA ; Driver mutations
Publisher: Wiley Blackwell
ISSN: 1059-7794
Date of Acceptance: 7 February 2011
Last Modified: 19 Oct 2022 09:59
URI: https://orca.cardiff.ac.uk/id/eprint/22844

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