Epigenetic Alterations Upstream and Downstream of p53 Signaling in Colorectal Carcinoma.

Colorectal cancer (CRC) belongs to the most common tumor types, and half of all CRC harbor missense mutations in the tumor suppressor gene. In addition to genetically caused loss of function of p53, epigenetic alterations (DNA methylation, histone modifications, micro-RNAs) contribute to CRC development. In this review, we focused on epigenetic alterations related to the entire p53 signaling pathway upstream and downstream of p53. Methylation of genes which activate p53 function has been reported, and methylation of and was associated with increased mutation rates of . The micro-RNA 34a activates and was methylated in CRC. Proteins that regulate TP53 DNA methylation, mutations, and acetylation of TP53-related histones were methylated in CRC. P53 regulates the activity of numerous downstream proteins. Even if is not mutated, the function of wildtype p53 may be compromised if corresponding downstream genes are epigenetically inactivated. Thus, the role of p53 for CRC development, therapy response, and survival prognosis of patients may be much more eminent than previously estimated. Therefore, we propose that novel diagnostic devices measuring the entirety of genetic and epigenetic changes in the "p53 signalome" have the potential to improve the predictive and prognostic power in CRC diagnostics and management.