DNA Damage Response Pathway Alteration in Locally Advanced Clear-Cell Renal-Cell Carcinoma Is Associated With a Poor Outcome
DNA Damage Response Pathway Alteration in Locally Advanced Clear-Cell Renal-Cell Carcinoma Is Associated With a Poor Outcome
复制标题
DOI：
10.1016/j.clgc.2019.05.004
复制
发表时间：
2019-08-01
影响因子：
3.2
通讯作者：
Kim, Isaac Yi
中科院分区：
文献类型：
--
作者：
Na, Joon Chae;Nagaya, Naoya;Kim, Isaac Yi
我们为晚期透明细胞肾细胞癌（ccRCC）（最常见的肾癌）寻找新的治疗靶点。在来自癌症基因组图谱数据库的312例局部ccRCC病例中研究了DNA损伤反应（DDR）途径。DDR通路的改变与局部晚期肾透明细胞癌的复发率增加相关，可能是一个潜在的治疗靶点。背景：晚期肾透明细胞癌（ccRCC）是肾癌最常见的亚型，尽管治疗药物最近取得了进展，但仍被认为是致命的。目前可用药物的辅助或新辅助治疗的益处仍存在争议。我们研究了DNA损伤反应（DDR）通路对局部晚期ccRCC的临床意义。患者和方法：从临时TCGA（癌症基因组图谱）数据库中选择局部ccRCC病例。评估DDR通路相关基因的突变或拷贝数改变的存在。根据疾病进展评估无病生存期和总生存期。结果：从TCGA数据库中，确定了312例具有完整突变和拷贝数改变数据的局部ccRCC。25.0%的病例存在DDR通路的改变。女性受试者更有可能在DDR通路中发生改变（34.6% vs. 48.7%，P = 0.026）。在局部晚期T3-4疾病病例中，DDR通路改变与无病生存率降低相关（T3和T4疾病的中位数分别为123.7和23.0个月，P = 0.031）。这种关联在T3 a疾病病例中更为突出（正常组中位数未达到，改变组中位数为17.7个月，P <0.001）。在考克斯回归分析中，DDR通路改变是预测无病生存期较短的独立因素（比值比= 4.41; 95%置信区间，1.47与13.28相似; P = 0.008）。结论：DDR通路的改变与局部晚期ccRCC的复发增加相关，应考虑针对该人群的DDR通路治疗药物的研究。(C)2019爱思唯尔公司All rights reserved.
We searched for a new therapeutic target for advanced clear-cell renal-cell carcinoma (ccRCC), the most common kidney cancer. The DNA damage response (DDR) pathway was investigated in 312 cases of localized ccRCC from The Cancer Genome Atlas database. Alterations in the DDR pathway are associated with increased recurrence in locally advanced ccRCC and may be a potential therapeutic target.Background: Advanced clear-cell renal-cell carcinoma (ccRCC), which is the most common subtype of kidney cancer, is considered to be lethal despite recent advancements in therapeutic agents. The benefit of adjuvant or neoadjuvant therapy with currently available agents remains controversial. We investigated the clinical implications of DNA damage response (DDR) pathway for locally advanced ccRCC. Patients and Methods: Localized ccRCC cases were selected from the Provisional TCGA (The Cancer Genome Atlas) database. Presence of mutation or copy-number alteration of DDR pathway-related genes were evaluated. Disease-free survival and overall survival according to disease progression were evaluated. Results: From TCGA database, 312 cases were identified of a localized ccRCC with full data on mutation and copy-number alteration. Alteration in the DDR pathway was present in 25.0% of cases. Female subjects were more likely to have alterations in the DDR pathway (34.6% vs. 48.7%, P = .026). DDR pathway alteration was associated with decreased disease-free survival in cases of locally advanced T3-4 disease (median, 123.7 vs. 23.0 months, T3 and T4 disease, P = .031). The association was more prominent in cases of T3a disease (normal group median not reached, altered group median 17.7 months, P < .001). DDR pathway alteration was an independent factor predicting a shorter disease-free survival on Cox regression analysis (odds ratio = 4.41; 95% confidence interval, 1.47 similar to 13.28; P = .008). Conclusion: Alteration in the DDR pathway was associated with increased recurrence in locally advanced ccRCC, and investigation of therapeutic agents targeting the DDR pathway for this population should be considered. (C) 2019 Elsevier Inc. All rights reserved.