Figure 3.

Scheme illustrating the paradox of detecting multiple p53 mutations of Rd origin in the same tumor. (A) In application to the p53 gene, the classic scheme of clonal Rd evolution in neoplasia (29, 36, 37) implies that the second p53 mutation confers some additional proliferative advantage over that of the first p53 mutation within the same clone; only in this case, because of intensifying selection, the daughter clone bearing the p53 doublet would eventually prevail over those clones bearing singlets and therefore would be detectable in tumor samples. However, this scheme is inconsistent with the fact that one of the mutations in p53 doublets is a hitchhiker (14). (B) The paradox in clonal Rd evolution is that the final frequency of neutral hitchhikers would be rather small (reflecting only the rate of Rd mutations). As a consequence, there is a minimal chance to detect (by routine survey) the p53 doublet clone compared with its singlet precursor in the same tumor. There is no such problem for the Td unicellular origin of p53 doublets (Fig. 1B).