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
|
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: | 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: | 06 Jan 2024 05:58 |
| URI: | https://orca.cardiff.ac.uk/id/eprint/22844 |
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