Genetic Modifiers of the p53 Pathway

The tumor suppressor gene TP53 is the most frequently mutated gene in human cancer; this gene is subject to inactivation by mutation or deletion in >50% of sporadic cancers. Genes that encode proteins that regulate p53 function, such as MDM2, MDM4, and CDKN2A (p14(ARF)) are also frequently altered in tumors, and it is generally believed that the p53 pathway is likely to be inactivated by mutation in close to 100% of human tumors. Unlike most other cancer-relevant signaling pathways, some of the genes in the p53 pathway contain functionally significant single nucleotide polymorphisms (SNPs) that alter the amplitude of signaling by this protein. These variants, thus, have the potential to impact cancer risk, progression, and the efficacy of radiation and chemotherapy. In addition, the p53 pathway plays a role in other biological processes, including metabolism and reproductive fitness, so these variants have the potential to modify other diseases as well. Here we have chosen five polymorphisms in three genes in the p53 pathway for review, two in TP53, two in MDM2, and one in MDM4. These five variants were selected based on the quality and reproducibility of functional data associated with them, as well as the convincingness of epidemiological data in support of their association with disease. We also highlight two other polymorphisms that may affect p53 signaling, but for which functional or association data are still forthcoming (KITLG and ANRIL). Finally, we touch on three questions regarding genetic modifiers of the p53 pathway: Why did these variants arise? Were they under selection pressure? And, is there compelling evidence to support genotyping these variants to better predict disease risk and prognosis?