Laboratory of Environmental Carcinogenesis and Mutagenesis National Institute of Environmental Health Science PO Box 12233 Research Triangle Park NC 27709, USA
Dear Editor
I am writing to you with regard to the paper entitled: `Chromosome 11 allelotypes reflect a mechanism of chemical carcinogenesis in heterozygous p53-deficient mice.' This paper was published in Carcinogenesis volume 22 pages 8998. The authors are J.E.Hulla, J.E.French and J.K.Dunnick. The paper states: `If breeding protocols were carried out as described, the unexpected allelotype patterns observed in histologically normal tissues might be due to mitotic homologous recombination during embryogenesis.' This letter is written to report that the study mice were not bred as we reported. The breeding protocol that appears as Figure 1 of the paper is correct. However, the TSG-p53TM mice were N4 generation and not N5 as stated in the paper.
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Evidence for recombination related to p53 haploinsufficiency is reported in two other papers:
Misidentification of N4 mice as N5 mice impacts the results reported in Hulla et al. (2). The impact is similar to what is discussed in the previous paragraph. The investigation reported by Boley et al. (1) attributed patterns of loss of heterozygosity (LOH) in lymphomas from p53(+/) mice to mitotic recombination and p53 haploinsufficiency. These findings are brought to your attention for two reasons. First, the study mice were reported to be p53(+/) N5 mice and it now seems possible that the mice were in fact N4. Second, there are methodological weaknesses. For example, examination of normal liver tissue from the tumor-bearing mice revealed C57BL/6 homozygosity at many loci. These loci should have been considered uninformative for LOH. However, the authors made the assumption that both a 129Sv allele and a C57BL/6 allele should reside at each locus and attributed the absence of a 129Sv allele in normal liver to common instability of repeat sequences. Thus, they reported the C57BL/6 homozygosity found in the animal's induced tumor as LOH in the face of evidence that the locus was uninformative for LOH. The loci that define the tumor LOH patterns purported to be evidence of mitotic recombination were those same loci found in the normal liver to be uninformative for LOH. The authors also assumed that a 129Sv allele and a C57BL/6 allele were present at each polymorphic locus in mice bearing spontaneous tumors. Spontaneous tumor loci at which only one allele was detected were reported as LOH without a determination from mouse-matched normal tissue that those loci were informative for LOH. The paper also reports duplication of the null p53 allele. This finding is unfounded because the determination was based on the false assumption that the p53 pseudogene is a single copy gene.
In summary, there is little or no evidence from the three investigations to support the contention that p53(+/) mice are haploinsufficient for suppression of mitotic recombination.