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DNA damage response proteins and its role in tumor progression of uveal melanoma with patient outcome

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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 significance.

Methods

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.

Results

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.

Conclusion

Our data suggest that ATR might serve as a potential prognostic marker in UM patients and could serve as a potential therapeutic target.

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Acknowledgements

Jayanti Jha is thankful to the Indian Council of Medical Research for providing Research Assistant (RA). We are supported by Mr. Pankaj Kumar for providing technical support in IHC.

Funding

This work was supported by the Indian Council of Medical Research (ICMR), New Delhi (ICMR File No. 5/13/17/2014-NCD-III).

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Authors and Affiliations

  1. Department of Ocular Pathology, Dr. R. P. Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India

    S. Kashyap, J. Jha, M. K. Singh & S. Sen

  2. Department of Ophthalmology, Dr. R. P. Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India

    M. S. Bajaj & N. Pushker

  3. Department of Biosciences, JMI, New Delhi, India

    L. Singh

  4. Department of Ocular Biochemistry, Dr. R. P. Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India

    J. Kaur

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  1. S. Kashyap
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  2. J. Jha
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  4. L. Singh
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  5. S. Sen
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  6. J. Kaur
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Contributions

SK executed the study, data analysis and in association with JJ; MKS contributed to the design and draft of the manuscript. LS helped in the experiments and coordination of the manuscript. NP and MSB provide the enucleated specimens. SS and SK were responsible for histopathological examination. All authors read and approved the final manuscript.

Corresponding author

Correspondence to N. Pushker.

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Conflict of interest

All authors declare that they have no conflict of interest.

Ethical approval

The study was performed after the approval from the Institutional Ethics Committee (IEC), All India Institute of Medical Sciences (IEC/NP-177/05.06.2014). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional ethical committee of AIIMS and with the Helsinki declaration and comparable with ethical standards.

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Informed consent was obtained from all participants included in the study.

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Kashyap, S., Jha, J., Singh, M.K. et al. DNA damage response proteins and its role in tumor progression of uveal melanoma with patient outcome. Clin Transl Oncol 22, 1472–1480 (2020). https://doi.org/10.1007/s12094-019-02281-x

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  • DOI: https://doi.org/10.1007/s12094-019-02281-x

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