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

Abstract

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.

Keywords: DNA repair gene; Gene mutation; P53; tumor infiltrating immune cell population; tumor mutation burden.

Figure 1

Boxplot of global mutations among four groups of samples based on p53 and the 10 DRG (p53 target) mutation status in each type of cancer with wilcoxon test. A. TMB (Silent and non-silent mutations/MB). B. Non-silent mutations/MB. MB: megabase; None: without any mutation in both type of genes; Both: with mutations in both type of genes; TP53: with p53 mutation but not DRG mutation; DRGs: with any of the 10 DRG mutations but not p53 mutation.

Figure 2

Boxplot of immune cells (CIBERSORT) among four groups of cancers based on p53 and the 10 DRG (p53 target) mutation status with wilcoxon test in colorectal cancer. None: without any mutation in both type of genes; Both: with mutations in both type of genes; TP53: with p53 mutation but not DRG mutation; DRGs: with any of the 10 DRG mutations but not p53 mutation.

Figure 3

Boxplot of leucocyte fraction among four groups of samples based on p53 and the 19 DRG (MMRs and p53 target) mutation status in each type of cancer with wilcoxon test. None: without any mutation in both type of genes; Both: with mutations in both type of genes; TP53: with p53 mutation but not DRG mutation; DRGs: with any of the 19 DRG mutations but not p53 mutation.

Figure 4

Boxplot of TIL regional fraction among four groups of samples based on p53 and the 19 DRG (MMRs and p53 target) mutation status in each type of cancer with wilcoxon test. None: without any mutation in both type of genes; Both: with mutations in both type of genes; TP53: with p53 mutation but not DRG mutation; DRGs: with any of the 19 DRG mutations but not p53 mutation.