Carcinogenesis, Vol 18, 1445-1452, Copyright © 1997 by Oxford University Press
BS Strauss
Published data on TP53 mutations can be used to examine the question of
whether generalized hypermutability is a necessary condition for
tumorigenesis. Although individual mutations do play an etiologic role in
tumor formation, the evidence so far does not make it necessary to assume a
general mutability. Silent and multiple mutations in the TP53 data set
indicate that a special hypermutability process operates on this gene
during the generation of tumors. The percentage of silent p53 mutations
observed (3%) is at least 20 times greater than would be expected and
indicates hypermutability for this gene. The greater proportion of silent
mutations among multiple p53 mutations (10%) indicates that the mutations
occur nonselectively. The presence of silent mutations implies that not all
mutations observed in tumors have an etiologic role. Analysis of the
distribution of tumors with two, three, four and more p53 mutations
suggests that mutations in some tumors occur in clusters possibly as a
result of 'stuttering' in DNA synthesis. It is argued that the most likely
alternative explanations of the data, polymorphism and/or a selective role
for silent mutations, are not correct. It remains possible that the
hypermutability process is restricted to particular genes or to regions of
the genome as, for example, in antibody production. There is a surprising
paucity of data on human polymorphism and nucleotide diversity which makes
the analysis difficult.
ARTICLES
Silent and multiple mutations in p53 and the question of the hypermutability of tumors [published erratum appears in Carcinogenesis 1998 Jan;19(1):237]
Department of Molecular Genetics and Cell Biology, The University of Chicago, IL 60637, USA.
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