Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China; Cancer Genomics Research Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China; Big Data Research Institute, China Pharmaceutical University, Nanjing, 211198, China.
Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China; Cancer Genomics Research Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China; Big Data Research Institute, China Pharmaceutical University, Nanjing, 211198, China.
DNA Repair (Amst). 2020 Apr;88:102785. doi: 10.1016/j.dnarep.2020.102785. Epub 2020 Jan 24.
Many studies have shown that TP53 mutations play a negative role in antitumor immunity. However, a few studies reported that TP53 mutations could promote antitumor immunity. To explain these contradictory findings, we analyzed five cancer cohorts from The Cancer Genome Atlas (TCGA) project. We found that TP53-mutated cancers had significantly higher levels of antitumor immune signatures than TP53-wildtype cancers in breast invasive carcinoma (BRCA) and lung adenocarcinoma (LUAD). In contrast, TP53-mutated cancers had significantly lower antitumor immune signature levels than TP53-wildtype cancers in stomach adenocarcinoma (STAD), colon adenocarcinoma (COAD), and head and neck squamous cell carcinoma (HNSC). Moreover, TP53-mutated cancers were more likely to have a higher tumor mutation burden (TMB) and tumor aneuploidy level (TAL) than TP53-wildtype cancers. However, the TMB differences were more marked between TP53-mutated and TP53-wildtype cancers than the TAL differences in BRCA and LUAD, and the TAL differences were more significant in STAD and COAD. Furthermore, we showed that TMB and TAL had a positive and a negative correlation with antitumor immunity and that TMB affected antitumor immunity more than TAL did in BRCA and LUAD while TAL affected antitumor immunity more strongly than TMB in STAD and HNSC. These findings indicate that the distinct correlations between TP53 mutations and antitumor immunity in different cancer types are a consequence of the joint effect of the altered TMB and TAL caused by TP53 mutations on tumor immunity. In addition, the deregulation of p53-mediated pathways, including cell cycle and apoptosis, may also contribute to the different correlations of TP53 mutations with antitumor immunity between different cancer cohorts. Furthermore, we demonstrated the different correlations of TP53 mutations with the response to immune checkpoint inhibitors between different cancer cohorts, suggesting that the TP53 mutation status could be a useful biomarker for predicting the response to cancer immunotherapy in different cancer types.
许多研究表明，TP53 突变在抗肿瘤免疫中起负向作用。然而，也有少数研究报道称，TP53 突变可促进抗肿瘤免疫。为了解释这些相互矛盾的发现，我们分析了来自癌症基因组图谱（TCGA）项目的五个癌症队列。我们发现，在乳腺浸润性癌（BRCA）和肺腺癌（LUAD）中，TP53 突变型癌症的抗肿瘤免疫特征水平明显高于 TP53 野生型癌症。相反，在胃腺癌（STAD）、结肠腺癌（COAD）和头颈部鳞状细胞癌（HNSC）中，TP53 突变型癌症的抗肿瘤免疫特征水平明显低于 TP53 野生型癌症。此外，TP53 突变型癌症比 TP53 野生型癌症具有更高的肿瘤突变负担（TMB）和肿瘤非整倍体水平（TAL）。然而，在 BRCA 和 LUAD 中，TP53 突变型和 TP53 野生型癌症之间的 TMB 差异比 TAL 差异更为显著，而在 STAD 和 COAD 中，TAL 差异更为显著。此外，我们表明 TMB 和 TAL 与抗肿瘤免疫呈正相关和负相关，并且在 BRCA 和 LUAD 中，TMB 对抗肿瘤免疫的影响大于 TAL，而在 STAD 和 HNSC 中，TAL 对抗肿瘤免疫的影响大于 TMB。这些发现表明，不同癌症类型中 TP53 突变与抗肿瘤免疫之间的不同相关性是由 TP53 突变引起的 TMB 和 TAL 改变对肿瘤免疫的共同作用所致。此外，p53 介导的途径失调，包括细胞周期和凋亡，也可能导致不同癌症队列中 TP53 突变与抗肿瘤免疫之间的不同相关性。此外，我们还证明了不同癌症队列中 TP53 突变与免疫检查点抑制剂反应之间的不同相关性，提示 TP53 突变状态可能是预测不同癌症类型癌症免疫治疗反应的有用生物标志物。
