TP53 Mutation as Potential Negative Predictor for Response of Anti-CTLA-4 Therapy in Metastatic Melanoma.
TP53 Mutation as Potential Negative Predictor for Response of Anti-CTLA-4 Therapy in Metastatic Melanoma.
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TP53 突变作为转移性黑色素瘤抗 CTLA-4 治疗反应的潜在阴性预测因子
DOI：
10.1016/j.ebiom.2018.05.019
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发表时间：
2018-06
期刊：
影响因子：
11.1
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Xiao W;Du N;Huang T;Guo J;Mo X;Yuan T;Chen Y;Ye T;Xu C;Wang W;Wang G;Cai S;Chen J
TP53 已被证明与细胞毒性 T 细胞诱导的细胞凋亡相关，然而，TP53 与黑色素瘤免疫治疗益处之间的关联尚未研究。在本研究中，我们通过分析由 110 名转移性黑色素瘤患者组成的公共队列的数据，研究了转移性黑色素瘤中 TP53 突变与 CTLA-4 阻断反应之间的关系。使用癌症基因组图谱 (TCGA) 中 368 名皮肤黑色素瘤患者的测序、mRNA 和生存数据来探索其潜在机制。 TP53突变与显着较差的无进展生存期（HR，2.25；95% CI，1.15-4.37；P=0.014）、较差的总生存期（HR，2.05；95% CI，1.02-4.13；P=0.040）和较差的反应趋势（OR，0.20；95% CI， 0.02–1.62；P=0.131)。在乳酸脱氢酶、肿瘤突变负荷和肿瘤分期等多变量分析中，相关性显着（P<0.05）。在 TCGA 中，未观察到 TP53 突变与生存之间存在关联（P=0.55）。 TP53突变患者的FAS mRNA表达量低于TP53野生型患者。我们的研究结果表明，TP53 突变是 CTLA-4 阻断治疗转移性黑色素瘤的潜在阴性预测因子。 TP53 突变与接受抗 CTLA-4 治疗的转移性黑色素瘤患者的较差预后相关。 TP53突变患者的FAS mRNA表达量低于TP53野生型患者。 TP53 是 CTLA-4 阻断治疗的转移性黑色素瘤的潜在阴性预测因子。通过增强免疫系统的抗肿瘤活性来阻断免疫检查点已成为多种晚期肿瘤的标准治疗方法，然而，只有一小部分患者可以从中受益。在这项研究中，我们发现携带 TP53 突变的黑色素瘤患者的生存结果和抗 CTLA-4 治疗的反应较差。 TP53突变患者中FAS的mRNA表达较低，表明TP53下调FAS的表达并阻止细胞毒性T细胞诱导的黑色素瘤细胞凋亡。这些结果表明 TP53 突变可能作为黑色素瘤抗 CTLA-4 治疗的阴性预测因子。
TP53 has been proved to be associated with cytotoxic T-cell induced apoptosis, however, the association between TP53 and the benefit of immunotherapy in melanoma has not been studied. In the present study, we examined the relationship between TP53 mutation and response to CTLA-4 blockade in metastatic melanoma by analyzing the data from one public cohort consisting of 110 patients with metastatic melanoma. The sequencing, mRNA and survival data of 368 patients with skin melanoma from The Cancer Genome Atlas (TCGA) was used to explore the underlying mechanism. TP53 mutation was associated with significant poorer progression-free survival (HR, 2.25; 95% CI, 1.15–4.37; P = 0.014), poorer overall survival (HR, 2.05; 95% CI, 1.02–4.13; P = 0.040) and trend of poorer response (OR, 0.20; 95% CI, 0.02–1.62; P = 0.131). The correlations were significant in multivariate analysis including lactate dehydrogenase, tumor mutational burden and tumor stage (P < 0.05). In TCGA, no association was observed between TP53 mutation and survival (P = 0.55). The mRNA expression of FAS was lower in patients with TP53 mutation than TP53 wild-type. Our findings suggest that TP53 mutation is a potential negative predictor of metastatic melanoma treated with CTLA-4 blockade. TP53 mutation is associated with poorer outcomes in patients with metastatic melanoma receiving anti-CTLA-4 treatment. The mRNA expression of FAS was lower in patients with TP53 mutation than TP53 wild-type. TP53 is a potential negative predictor of metastatic melanoma treated with CTLA-4 blockade. Immune checkpoint blockades by enhancing the anti-tumor activity of immune system have been standard treatment for several advanced tumors, however, only a subset of patients can benefit from them. In this study, we find patients with melanoma harboring TP53 mutation show poorer survival outcome and response of anti-CTLA-4 treatment. The mRNA expression of FAS is lower in patients with TP53 mutation, suggesting that TP53 down-regulates the expression of FAS and impede cytotoxic T-cell induced apoptosis in melanoma. These results suggest that TP53 mutation may serve as a negative predictor of anti-CTLA-4 treatment in melanoma.
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DOI：
10.1056/nejmoa1003466
发表时间：
2010-08-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hodi FS;O'Day SJ;McDermott DF;Weber RW;Sosman JA;Haanen JB;Gonzalez R;Robert C;Schadendorf D;Hassel JC;Akerley W;van den Eertwegh AJ;Lutzky J;Lorigan P;Vaubel JM;Linette GP;Hogg D;Ottensmeier CH;Lebbé C;Peschel C;Quirt I;Clark JI;Wolchok JD;Weber JS;Tian J;Yellin MJ;Nichol GM;Hoos A;Urba WJ
通讯作者：
Urba WJ
影响因子：
158.5
作者：
Robert, Caroline;Schachter, Jacob;Ribas, Antoni
通讯作者：
Ribas, Antoni
影响因子：
28.4
作者：
Mezquita, Laura;Auclin, Edouard;Besse, Benjamin
通讯作者：
Besse, Benjamin
影响因子：
0.9
作者：
Braun MW;Iwakuma T
通讯作者：
Iwakuma T
影响因子：
12.3
作者：
Li B;Severson E;Pignon JC;Zhao H;Li T;Novak J;Jiang P;Shen H;Aster JC;Rodig S;Signoretti S;Liu JS;Liu XS
通讯作者：
Liu XS