Department of Ocular Pathology, Dr. R. P. Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India.
Department of Biosciences, JMI, New Delhi, India.
Clin Transl Oncol. 2020 Sep;22(9):1472-1480. doi: 10.1007/s12094-019-02281-x. Epub 2020 Mar 2.
The role of DNA damage response (DDR) proteins is poorly understood in uveal melanoma. ATR belongs to one of those proteins that induce DDR by arresting the cell cycle which leads to DNA repair. ATR is localized at position 23 on the same chromosome 3 where BAP1 is located at position 21.1 which is a known poor prognostic marker of UM. The aim of our study is to detect the expression of ATR at the protein and RNA levels and determine its prognostic significance.
Expression of nuclear ATR was investigated on sixty-nine UM patients. Formalin-fixed paraffin-embedded choroidal melanoma samples were taken to evaluate the expression of ATR. Fifty samples were also validated by real-time PCR. Results of both protein and mRNA were then correlated with clinicopathological parameters. To determine the prognostic significance, Kaplan-Meier and multivariate analyses were performed.
Loss of ATR protein was seen in 72% cases which was statistically significant with epithelioid cell type (p = 0.005), tumor thickness (p = 0.016), mitotic figures (p = 0.001) and BAP1 loss (p < 0.001). At the transcriptional level loss of ATR was seen in 76% cases which were statistically significant with metastasis (p = 0.046), staging (0.044) and loss of BAP1 (p = 0.022). On multivariate analysis loss of ATR and tumor staging came out to be independent prognostic parameters.
Our data suggest that ATR might serve as a potential prognostic marker in UM patients and could serve as a potential therapeutic target.
DNA 损伤反应（DDR）蛋白在葡萄膜黑色素瘤中的作用尚不清楚。ATR 属于通过使细胞周期停滞从而导致 DNA 修复来诱导 DDR 的蛋白之一。ATR 位于与 BAP1 相同的染色体 3 上的 23 号位置，BAP1 位于已知的 UM 不良预后标志物 21.1 号位置。我们研究的目的是检测 ATR 在蛋白质和 RNA 水平的表达，并确定其预后意义。
对 69 例 UM 患者进行核 ATR 表达研究。采集福尔马林固定石蜡包埋脉络膜黑色素瘤样本，以评估 ATR 的表达。50 例样本也通过实时 PCR 进行验证。然后将蛋白质和 mRNA 的结果与临床病理参数相关联。为了确定预后意义，进行了 Kaplan-Meier 和多变量分析。
ATR 蛋白丢失见于 72%的病例，与上皮样细胞类型（p=0.005）、肿瘤厚度（p=0.016）、有丝分裂象（p=0.001）和 BAP1 丢失（p<0.001）具有统计学意义。在转录水平，ATR 丢失见于 76%的病例，与转移（p=0.046）、分期（p=0.044）和 BAP1 丢失（p=0.022）具有统计学意义。多变量分析显示 ATR 丢失和肿瘤分期是独立的预后参数。
我们的数据表明，ATR 可能是 UM 患者潜在的预后标志物，并可能成为潜在的治疗靶点。
