Mutational hotspots in the TP53 gene and, possibly, other tumor suppressors evolve by positive selection

Abstract

Background: The mutation spectra of the TP53 gene and other tumor suppressors contain multiple hotspots, i.e., sites of non-random, frequent mutation in tumors and/or the germline. The origin of the hotspots remains unclear, the general view being that they represent highly mutable nucleotide contexts which likely reflect effects of different endogenous and exogenous factors shaping the mutation process in specific tissues. The origin of hotspots is of major importance because it has been suggested that mutable contexts could be used to infer mechanisms of mutagenesis contributing to tumorigenesis.

Results: Here we apply three independent tests, accounting for non-uniform base compositions in synonymous and non-synonymous sites, to test whether the hotspots emerge via selection or due to mutational bias. All three tests consistently indicate that the hotspots in the TP53 gene evolve, primarily, via positive selection. The results were robust to the elimination of the highly mutable CpG dinucleotides. By contrast, only one, the least conservative test reveals the signature of positive selection in BRCA1, BRCA2, and p16. Elucidation of the origin of the hotspots in these genes requires more data on somatic mutations in tumors.

Conclusion: The results of this analysis seem to indicate that positive selection for gain-of-function in tumor suppressor genes is an important aspect of tumorigenesis, blurring the distinction between tumor suppressors and oncogenes.

Reviewers: This article was reviewed by Sandor Pongor, Christopher Lee and Mikhail Blagosklonny.

Figure 1

The procedure used for random sampling of mutations at non-synonymous sites in the NSMC test. Step 1 includes the selection of a sample of non-synonymous sites such that the number of sites and their base composition were the same as in the entire set of synonymous substitutions in the given gene; sampling was performed without replacement. The comparison of the number of hotspots, i.e., sites with at least two substitutions, between the samples of synonymous and non-synonymous sites gives a measure of the skewness of the distribution of mutations (Step 2). Synonymous sites and sampled non-synonymous sites are shown by inverse shading, synonymous hotspots are shown in yellow, and simulated non-synonymous hotspots are shown in green.