Single-nucleotide polymorphisms in the p53 signaling pathway

Abstract

The p53 tumor suppressor pathway is central both in reducing cancer frequency in vertebrates and in mediating the response of commonly used cancer therapies. This article aims to summarize and discuss a large body of evidence suggesting that the p53 pathway harbors functional inherited single-nucleotide polymorphisms (SNPs) that affect p53 signaling in cells, resulting in differences in cancer risk and clinical outcome in humans. The insights gained through these studies into how the functional p53 pathway SNPs could help in the tailoring of cancer therapies to the individual are discussed. Moreover, recent work is discussed that suggests that many more functional p53 pathway SNPs are yet to be fully characterized and that a thorough analysis of the functional human genetics of this important tumor suppressor pathway is required.

Figure 1.

Incorporating information of both the inherited and somatic genetics of the p53 gene could further define patient populations in their abilities to respond to certain therapies. (A) Some studies suggest that cells from individuals with the proline (Pro) allele of p53 codon72 will undergo less apoptosis in response to DNA-damage-inducing therapies compared with individuals with the arginine (Arg) allele of p53 codon72. This has been suggested to be caused by less transcriptional activation of apoptotic effectors. (B) Other studies suggest that cancer cells with somatic p53 mutations from individuals with the proline (Pro) allele of p53 codon72 will undergo more apoptosis in response to DNA-damage-inducing therapies compared with individuals with the arginine (Arg) allele of p53 codon72. This has been suggested to be potentially because of an enhanced inhibition of the p73 tumor suppressor by mtp53-codon72-Arg.

Figure 2.

Individuals with different genotypes of MDM2 SNP309 could be affected differently by estrogen signaling manipulation. A model has been proposed that the primarily female-specific hormone, estrogen, preferentially stimulated transcription of the MDM2 gene with the G-allele of SNP309, potentially through the direct interaction of the estrogen receptor (ESR) and the transcription factor SP1 on the MDM2 promoter. If true, this predicts that inhibition of estrogen signaling in individuals with the G-allele of MDM2 SNP309 would lead to a reduction of MDM2 levels and a reactivation of p53 activity, allowing for either better tumor suppression or tumor clearance compared with individuals with the T-allele.

Figure 3.

Map of selected p53 pathway-associated genes that harbor known or potential functional SNPs (octagon-shaped boxes) and their closely interacting genes (rectangular boxes). The map depicts genes involved in the core regulation of p53 (light red boxes), the DNA-damage response (yellow), the extrinsic apoptotic response (green), the cell-cycle (turquoise) and oncogenic signaling (dark blue). The arrows (↓) show downstream activation and the inhibitory interactions are delineated by T-shaped (⊥) ends. A network map representing the p53 pathway is illustrated in the distant background.