The interaction of p53 and DNA repair gene mutations and their impact on tumor mutation burden and immune response in human malignancies

P53 suppresses tumorigenesis through multiple cellular functions/mechanisms, including genomic stability surveillance. Recently, it has also be reported for its role in cancer immune response modulation. Deficiency in DNA repair pathways lead to the accumulation of genomic alterations and tumor mutation burden and in consequence resulting in the activation of immune response. We investigated the interaction of p53 and DNA repair gene mutations and their impact on tumor mutation burden and immune response in human malignancies by mining cBioPortal data of a range of human cancers. We found that in the majority of human cancers, p53 mutations are equally distributed between DNA repair gene mutation positive and negative cases and in a number of human cancers, p53 and DNA repair gene mutations have a tendency of co-occurrence. Only in colorectal cancer, there is a tendency of 'mutual exclusivity' of mutations in p53 and DNA repair genes. In most tumors, p53 and DNA repair gene mutations have synergistic/additive effect in increasing tumor mutation burden, but not in colorectal cancer where they are mutually exclusive. The impact of p53 and DNA repair gene mutations and their interaction on tumor microenvironment immune cells are complex and tumor type specific and not always correlated with tumor mutation burden. In colorectal cancers, these two types of mutations resulted in similar immune cell subpopulation changes and in tumors where the mutations have a tendency of co-occurrence, p53 showed dominant roles on immune response, although they can also counter-act each other for their effect on certain immune cell subtypes.

Automated summary

P53 suppresses tumorigenesis through various mechanisms, including genomic stability surveillance and modulation of cancer immune response. The interaction between p53 and DNA repair gene mutations and their impact on tumor mutation burden and immune response in human malignancies were investigated. It was found that p53 mutations are equally distributed between DNA repair gene mutation positive and negative cases in most human cancers. Co-occurrence of p53 and DNA repair gene mutations was observed in some cancers. However, in colorectal cancer, mutations in p53 and DNA repair genes were mutually exclusive. The complex impact of these mutations and their interaction on tumor microenvironment immune cells varied among different tumor types and was not always correlated with tumor mutation burden.