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.
摘要:
P53通过多种细胞功能/机制抑制肿瘤发生,包括基因组稳定性监测。最近,它在癌症免疫反应调节中的作用也有报道。DNA修复途径的缺陷导致基因组改变和肿瘤突变负担的积累,并因此导致免疫应答的激活。我们通过挖掘一系列人类癌症的cBioPortal数据,研究了p53和DNA修复基因突变的相互作用及其对人类恶性肿瘤中肿瘤突变负荷和免疫应答的影响。我们发现在大多数人类癌症中,p53突变在DNA修复基因突变阳性和阴性病例之间以及许多人类癌症中分布相等。p53和DNA修复基因突变有共同发生的趋势。只有在大肠癌中,p53和DNA修复基因突变存在“相互排斥”的趋势。在大多数肿瘤中,p53和DNA修复基因突变在增加肿瘤突变负荷方面具有协同/累加效应,但在结直肠癌中却没有,因为它们是相互排斥的。p53和DNA修复基因突变及其相互作用对肿瘤微环境免疫细胞的影响是复杂且肿瘤类型特异性的,并不总是与肿瘤突变负荷相关。在结直肠癌中,这两种类型的突变导致相似的免疫细胞亚群变化和突变有共同发生趋势的肿瘤,p53在免疫反应中显示出主导作用,尽管它们对某些免疫细胞亚型的影响也可以相互抵消。