Prevalence of PRKDC mutations and association with response to immune checkpoint inhibitors in solid tumors
Prevalence of PRKDC mutations and association with response to immune checkpoint inhibitors in solid tumors
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DOI：
10.1002/1878-0261.12739
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发表时间：
2020-06-30
影响因子：
6.6
通讯作者：
Chen, Chuanben
中科院分区：
文献类型：
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作者：
Chen, Yu;Li, Yi;Chen, Chuanben
对免疫检查点抑制剂（ICI）反应的预测性生物标志物有助于识别将从免疫治疗中受益的癌症患者。蛋白激酶，DNA激活的催化亚基（PRKDC）是DNA双链断裂（DSB）修复和中枢T细胞耐受的重要基因。我们的目的是研究PRKDC突变与肿瘤突变负荷（TMB）、肿瘤微环境（TME）和ICI反应之间的关系。使用来自癌症基因组图谱（TCGA）的4023个实体瘤样品的全外显子组测序数据和来自中国北京的Geneplus-Beijing的3877个实体瘤样品的基于组的测序数据来分析TMB。利用来自TCGA的3541个实体瘤样本的mRNA表达数据来探讨PRKDC突变对TME的影响。分析了4个ICI治疗的队列，以验证PRKDC突变与ICI应答之间的相关性。在TCGA和Geneplus数据集中，我们发现PRKDC突变样本的TMB显著高于PRKDC野生型样本（分别为P < 0.0001）。此外，TCGA数据集显示，与PRKDC野生型样本相比，PRKDC突变样本与CD 8（+）T细胞、NK细胞、免疫检查点、趋化因子等的表达显著增加相关（P < 0.05）。在ICI治疗的队列中，我们还发现PRKDC突变与生存率增加有关（中位PFS，未达到vs. 6.8个月，HR，0.2893; 95% CI，0.1255-0.6672;P = 0.0650，Hellmann队列;中位OS，1184天vs. 250天，HR，0.5126; 95% CI，0.2715-0.9679; P = 0.1020，艾伦队列），多变量分析显示增加显著（HR，0.361; 95% CI，0.155-0.841;P = 0.018，艾伦队列; HR，0.240 95% CI，0.058-0.998;P = 0.050，赫尔曼队列）。综上所述，我们发现PRKDC突变通常与其他一些DNA损伤修复机制的缺陷共存，并且仍然是与TMB增加，炎症TME和对ICI的更好反应相关的重要因素之一。
Predictive biomarkers of response to immune checkpoint inhibitors (ICI) help to identify cancer patients who will benefit from immunotherapy. Protein kinase, DNA-activated, catalytic subunit (PRKDC) is an important gene for DNA double-strand break (DSB) repair and central T-cell tolerance. We aimed to investigate the association betweenPRKDCmutations and tumor mutation burden (TMB), tumor microenvironment (TME), and response to ICI. Whole-exome sequencing data of 4023 solid tumor samples from the Cancer Genome Atlas (TCGA) and panel-based sequencing data of 3877 solid tumor samples from Geneplus-Beijing, China, were used to analyze the TMB. The mRNA expression data of 3541 solid tumor samples from TCGA were used to explore the effect ofPRKDCmutations on the TME. Four ICI-treated cohorts were analyzed for verifying the correlation betweenPRKDCmutations and the response to ICI. In both the TCGA and Geneplus datasets, we found that the TMB inPRKDCmutation samples was significantly higher than inPRKDCwild-type samples (P P < 0.0001, respectively). Further, TCGA datasets showed thatPRKDCmutation samples were associated with a significantly increased expression of CD8(+)T cells, NK cells, immune checkpoint, chemokines, etc. compared toPRKDCwild-type samples (P < 0.05). In ICI-treated cohorts, we also found thePRKDCmutations were associated with increased survival (median PFS, not reached vs. 6.8 months, HR, 0.2893; 95% CI, 0.1255-0.6672;P = 0.0650, Hellmann cohort; median OS, 1184 days vs. 250 days, HR, 0.5126; 95% CI, 0.2715-0.9679;P = 0.1020, Allen cohort), and the increase was significant in multivariate analysis (HR, 0.361; 95% CI, 0.155-0.841;P = 0.018, Allen cohort; HR, 0.240 95% CI, 0.058-0.998;P = 0.050, Hellmann cohort). In summary, we found thatPRKDCmutation often appeared to co-exist with deficiency in some other DNA damage repair mechanism and is nonetheless one of the important factors associated with increased TMB, inflamed TME, and better response to ICI.