Computer program for the analysis of mutational spectra: application to p53 mutations

Abstract

Mutations in the p53 oncogene are extremely common in human cancers, and environmental exposure to mutagenic agents may play a role in the frequency and nature of the mutations. Differences in the patterns of p53 mutations have been observed for different tumor types. It is not trivial to determine if the differences observed in two mutational spectra are statistically significant. To this end, we present a computer program for comparison of two mutational spectra. The program runs on IBM-compatible personal computers and is freely available. The input for the program is a text file containing the number and nature of mutations observed in the two spectra. The output of the program is a P value, which indicates the probability that the two spectra are drawn from the same population. To demonstrate the program, the mutational spectra of single base substitutions in the p53 gene are compared in (i) bladder cancers from smokers and non-smokers, (ii) small-cell lung cancers, non-small-cell lung cancers and colon cancers and (iii) hepatocellular carcinomas from high- and low-aflatoxin exposure groups. p53 mutations differ in several important aspects from a typical mutational spectra experiment, where a homogeneous population of cells is treated with a specific mutagen and mutations at a specific locus are recovered by phenotypic selection. The means by which p53 mutations are recognized is by the appearance of a cancer, and this phenotype is very complex and varied.

Genotoxic effects of acrylamide and glycidamide in mouse lymphoma cells

“…Positive responses are defined as those where the induced MF in one or more treated cultures exceeds the global evaluation factor (GEF) of 126 mutants per 10 6 cells and there is also a dose related increase with MF. LOH patterns of mutants were compared using the computer program (Cariello et al, 1994) for Monte Carlo analysis developed by Adams and Skopek (1987).…”

A human cancer-associated truncation of MBD4 causes dominant negative impairment of DNA repair in colon cancer cells

“…Statistical comparisons of mutation spectra were carried out using the Monte Carlo approximation to Fisher's exact test of Adams and Skopek (1987), with 1700 iterations in a programme available on the web (Cariello et al, 1994) and the significance level set at 0.05. The test conducts pairwise comparisons using the 11 mutational classes shown in Figure 4B and Supplementary Table 2), including the subset of G:C to A:T mutations that occurred at CpG sites.…”

Elevated mutant frequencies and predominance of G:C to A:T transition mutations in Msh6−/− small intestinal epithelium

“…pfu=plaque forming unit; AVG=average; SD=standard deviation; ND=not determined without correction for clonality, with the result being that the total number of mutants rose from 81 to 131, the transitions went up to 90% (most of which are G:C?A:T transitions) and the percentage in the other categories went down (since all the clonal mutations are transitions). A Monte Carlo simulation of the hypergeometric test (Cariello et al, 1994) was performed on the two spectra, using the number of mutants of each category as input, and there was no significant difference between them (P=0.97). MSH6 (through MutSa) supports the repair of base mismatches, single nucleotide (nt) insertions/deletions and to a lesser extent larger IDLs in vitro, thus one would not expect to see larger IDLs reflected in the in vivo mutation spectrum of MSH6-deficient mice since MutSb is still present and is primarily involved in the repair of IDLs and, to a lesser degree, single base loops (Genschel et al, 1998).…”