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Somatic spectrum of cancer‐associated single basepair substitutions in the TP53 gene is determined mainly by endogenous mechanisms of mutation and by selection
Author(s) -
Krawczak Michael,
SmithSorensen Birgitte,
Schmidtke Jörg,
Kakkar Vijay V.,
Cooper David N.,
Hovig Eivind
Publication year - 1995
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.1380050107
Subject(s) - biology , genetics , germline mutation , germline , mutation , somatic cell , gene , cancer , selection (genetic algorithm) , artificial intelligence , computer science
The spectrum of somatic TP53 single basepair substitutions detected in 955 cancers was compared with that of 2,224 different germline mutations in 279 different human genes (other than TP53), reported as the cause of inherited disease. This comparison reveals that, disregarding a relatively small subset (12%) of TP53 mutations that probably result from the action of exogenous mutagens, both the relative rates and the nearest‐neighbor spectra of single basepair substitutions are similar in the two datasets. This spectral resemblance suggests that a substantial proportion of cancer‐associated somatic TP53 mutations result from endogenous cellular mechanisms. The likelihood of clinical observation of a particular mutation type differs, however, between tumors and genetic diseases, when the chemical properties of the resulting amino acid substitutions are considered. Together with a sixfold higher observation likelihood for mutations at evolutionary conserved residues, this finding argues that selection is a critical factor in determining which TP53 mutations are found to be associated with human cancer. © 1995 Wiley‐Liss, Inc.