Editors' ChoiceCancer

When the Guardian Looks Away

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Science Translational Medicine  29 Sep 2010:
Vol. 2, Issue 51, pp. 51ec152
DOI: 10.1126/scitranslmed.3001732

p53, the “guardian of the genome,” is one of the best-studied genes, probably because it is mutated in more than half of human tumors. We can identify mutations in p53 by comparing tumor DNA with normal (germline) DNA from the same person; the differences, which must have occurred during development of the tumor, are known as somatic mutations. We can also identify germline mutations in p53 by comparing the normal DNA sequence of the individual with a canonical p53 sequence found in most of the population. Such germline mutations are extremely rare and cause a cancer predisposition syndrome named Li-Fraumeni after its codiscoverers. In contrast, some sequences in the genome are highly variable in the population. These are referred to as polymorphisms or, if the variable sequence is one nucleotide long, single-nucleotide polymorphisms, or SNPs. One such SNP exists in the promoter of the MDM2 gene, which encodes an enzyme that marks p53 for degradation. The canonical sequence at this position is T/T, but 40% of the population carries T/G and 15% G/G. Prior studies suggest that G/G is associated with higher levels of MDM2, which leads to less p53 and increased risk of a variety of cancers, including breast cancer.

Post and colleagues generated transgenic mice in which a portion of the mouse MDM2 gene is replaced with the corresponding human sequence containing either the T/T or the G/G genotype. As predicted from prior work, MDM2 levels were increased, and p53 function attenuated, in the G/G mice. Consistent with the guardian function of p53, spontaneous tumors appeared more often in these mice, specifically breast adenocarcinomas, which are otherwise extremely rare in mice.

One cancer in which the role of the MDM2 promotor SNP has not been previously explored is prostate cancer. Sun and colleagues examined a large collection of prostate cancer specimens from over 4000 Caucasian patients for the same SNP in MDM2 at position 309 (as well as several other SNPs). They found that the cancers with the T/T genotype were more histologically aggressive and more likely to metastasize than those with the G/G genotype. This result is in contrast to data in other cancers such as breast cancer, in which the G/G genotype is more cancer-prone both in humans and, as now demonstrated by Post et al., in mice.

These studies illustrate the growing importance of polymorphisms in determining cancer predisposition. Perhaps one day this information will enable us to customize screening procedures on the basis of genetic information obtained at birth. As the contrasting results of these two studies demonstrate, this will be no easy task because it appears that the same SNP in such seemingly universal regulators as p53 and MDM2 play distinct roles in breast adenocarcinoma and in prostate cancer.

S. M. Post et al., A high-frequency regulatory polymorphism in the p53 pathway accelerates tumor development. Cancer Cell 18, 220–230 (2010). [Abstract]

T. Sun et al., Single-nucleotide polymorphisms in p53 pathway and aggressiveness of prostate cancer in a Caucasian population. Clin. Cancer Res. 20 September 2010 (10.1158/1078-0432.CCR-10-1261). [Abstract]

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