Vol.:(0123456789) 1 3 Clinical and Translational Oncology https://doi.org/10.1007/s12094-019-02281-x RESEARCH ARTICLE DNA damage response proteins and its role in tumor progression of uveal melanoma with patient outcome S. Kashyap 1  · J. Jha 1  · M. K. Singh 1  · L. Singh 3  · S. Sen 1  · J. Kaur 4  · M. S. Bajaj 2  · N. Pushker 2 Received: 21 October 2019 / Accepted: 26 December 2019 © Federación de Sociedades Españolas de Oncología (FESEO) 2020 Abstract Background 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 signifcance. Methods Expression of nuclear ATR was investigated on sixty-nine UM patients. Formalin-fxed parafn-embedded choroi- dal 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 signifcance, Kaplan–Meier and multivariate analyses were performed. Results Loss of ATR protein was seen in 72% cases which was statistically signifcant with epithelioid cell type (p = 0.005), tumor thickness (p = 0.016), mitotic fgures (p = 0.001) and BAP1 loss (p < 0.001). At the transcriptional level loss of ATR was seen in 76% cases which were statistically signifcant 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. Conclusion Our data suggest that ATR might serve as a potential prognostic marker in UM patients and could serve as a potential therapeutic target. Keywords Uveal melanoma · ATR  · Immunohistochemistry · Metastasis Introduction Uveal melanoma (UM) is an intraocular malignant tumor which arises from the melanocytes of the uveal layer. The uveal layer comprises the choroid with a strong propensity for metastasis, followed by the iris and the ciliary body. UM has a high tendency to metastasize to the liver with the median survival of 4–5 months [1]. The poor prognosis of uveal melanoma is dependent on several clinicopathological parameters such as advanced tumor staging, large tumor height and diameter, extraocular spread, epithelioid cell type, presence of tumor infltrating lymphocytes, etc. Aggressive or metastatic UM also includes some genetic factors such as monosmoy 3 and BAP1 loss. Because of the lack of efective therapy in UM patients, there is a need for better understanding and new approaches that can infuence the early detection of metastasis and treat- ment in UM. The primary objective of a cell to function normally is to detect DNA damage and its repair mechanism. This repair mechanism is coordinated by DNA damage response which includes many signalling and repairing factors or proteins. Alteration in those repairing factors leads to failure in DNA damage response which is a hallmark of every cancer- ous cell [2]. One of those proteins or repairing factors is BAP1 (BRCA1-associated protein 1) which is frequently * N. Pushker pushkern@hotmail.com 1 Department of Ocular Pathology, Dr. R. P. Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India 2 Department of Ophthalmology, Dr. R. P. Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India 3 Department of Biosciences, JMI, New Delhi, India 4 Department of Ocular Biochemistry, Dr. R. P. Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India