The role of p53 dysfunction in colorectal cancer and its implication for therapy

Abstract

Colorectal cancer (CRC) is one of the most common and fatal cancers worldwide. The carcinogenesis of CRC is based on a stepwise accumulation of mutations, leading either to an activation of oncogenes or a deactivation of suppressor genes. The loss of genetic stability triggers activation of proto-oncogenes (e.g., KRAS) and inactivation of tumor suppression genes, namely TP53 and APC, which together drive the transition from adenoma to adenocarcinoma. On the one hand, p53 mutations confer resistance to classical chemotherapy but, on the other hand, they open the door for immunotherapy, as p53-mutated tumors are rich in neoantigens. Aberrant function of the TP53 gene product, p53, also affects stromal and non-stromal cells in the tumor microenvironment. Cancer-associated fibroblasts together with other immunosuppressive cells become valuable assets for the tumor by p53-mediated tumor signaling. In this review, we address the manifold implications of p53 mutations in CRC regarding therapy, treatment response and personalized medicine.