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.

Association Between p53 codon 72 Polymorphism and Cervical Cancer Risk Among Asians: a Huge Review and Meta-analysis

“…There are several single nucleotide polymorphisms (SNPs) in the p53 gene, and codon 72 polymorphism (Arg72Pro, rs1042522 G>C) in exon 4 is the most common candidate (Whibley et al, 2009). This polymorphism changes amino acid residue 72 from arginine to proline (ArggPro), which can be easily detected by polymerase chain reaction (PCR) (Grochola et al, 2010). These two alleles of p53 codon 72 polymorphism exhibit different oncogenic properties, but contradictory outcomes have been reported in various types of cancers (Fan et al, 2000;Koushik et al, 2004).…”

Combined effects of p53 and MDM2 polymorphisms on susceptibility and surgical prognosis in hepatitis B virus-related hepatocellular carcinoma

“…Functional inherited single nucleotide polymorphisms (SNPs) exist in the gene loci of the p53 signaling pathway, affecting the cancer risk and clinical outcome (Grochola et al, 2010). The 215 G > C polymorphisms at codon72 of p53 (Pro72Arg, rs1042522) have been studied in many cancers (Boersma et al, 2006;Han et al, 2008;Horikawa et al, 2008).…”

p53: out of Africa

“…This finding emphasizes the importance of modifier genes in the mechanisms of p53 tumor suppression (Goh et al 2011). Indeed, polymorphic variations in the promoter of Mdm2, a p53 target gene and negative regulator, show effects on tumor incidence in both mouse models and Li-Fraumeni cohorts, thereby defining it as a modifier gene (Pietsch et al 2006;Grochola et al 2010).Further analysis suggests a difference between p53 alleles based on the exact nature of the mutation. For example, some alleles show a dominant-negative phenotype, while others also show a gain of function.…”