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Genetic and epigenetic alterations in MGMT gene and correlation with concomitant chemoradiotherapy (CRT) in cervical cancer

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Abstract

Purpose

The MGMT (O6-methylguanine-DNA methyltransferase) gene plays a crucial role in repairing DNA damage caused by alkylating agents, including those used in chemotherapy. Genetic and epigenetic alterations can influence the regulation of MGMT gene, which in turn may impact the response to concomitant chemoradiotherapy (CRT) in cervical cancer. The present study was undertaken to evaluate the correlation of such variations in MGMT gene with the treatment outcome of concomitant chemoradiotherapy (CRT) in cervical cancer.

Methods

A total of 460 study subjects (240 controls and 220 patients) were subjected to genotypic analysis of MGMT gene variants rs12917(T/C) and rs2308327(A/G) by Amplification Refractory Mutation System-Polymerase Chain Reaction (ARMS-PCR). Out of them, 48 each of controls and patients were analyzed for promoter methylation and expression by methylation-specific PCR and real-time PCR, respectively. Patients (n = 48) were followed up and evaluated for treatment (CRT) outcome. Statistical analyses were done using GraphPad (9.0) and SPSS version 18.0.

Results

Individuals with GG genotype, G allele of rs2308327, and haplotype ‘TA’ of both variants showed a significant increase in the development of cervical cancer (P ≤ 0.05). In epigenetic regulation, there was a significant hypermethylation of MGMT gene and down-regulation of their expression in patients compared to control individuals. In treatment outcome of CRT, GG genotype of rs2308327(A/G) gene variant showed better response and GG + AG was significantly associated with vital status (alive). Unmethylated MGMT gene showed better median overall survival up to 25 months significant in comparison to methylated MGMT promoter.

Conclusion

Gene variant rs2308327(A/G) and promoter hypermethylation regulated MGMT gene can be a good prognostic for treatment response in cervical cancer patients.

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All data generated or analyzed during this study are included within the article.

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Acknowledgements

The authors extend their gratitude to Indian Council of Medical Research (ICMR), New Delhi, University Grant Commission (UGC), New Delhi, India, Centre of Excellence and Research and Development Schemes, Higher Education, Government of Uttar Pradesh, Lucknow, India for financial support. MKG and ASK are thankful to Indian Council of Medical Research (ICMR), New Delhi, India for providing senior research fellowship.

Funding

This work was supported by DST, DBT, UGC, ICMR, New Delhi; Centre of Excellence, Govt of Uttar Pradesh, Lucknow, India.

Author information

Author notes

  1. Atar Singh Kushwah

    Present address: Icahn School of Medicine at Mount Sinai, New York, 10029, USA

  2. Maneesh Kumar Gupta and Atar Singh Kushwah have contributed equally to this work.

Authors and Affiliations

  1. Molecular and Human Genetics Laboratory, Department of Zoology, University of Lucknow, Lucknow, 226007, India

    Maneesh Kumar Gupta, Atar Singh Kushwah & Monisha Banerjee

  2. Department of Obstetrics and Gynecology, King George’s Medical University, Lucknow, 226003, India

    Renu Singh

  3. Department of Radiotherapy, King George’s Medical University, Lucknow, 226003, India

    Kirti Srivastava

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  1. Maneesh Kumar Gupta
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Contributions

MKG and ASK designed, performed the experiments, analyzed the data, and wrote the manuscript. RS diagnosed the cervical cancer patients, provided clinical data, and arranged for sample collection. KS provided the CRT and treatment outcome data. MB conceived the work, provided financial support, supervised the entire research, and critically edited the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Monisha Banerjee.

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Conflict of interest

The authors declare that they have no competing interests.

Ethical approval and consent to participate

The study was approved by the institutional ethics committee of King George’s Medical University (4135/R.Cell-13, dated 15/4/2013). Our study conforms to provisions of the Declaration of Helsinki. Informed written consent to participate in this study was provided by all participants (or their parent or legal guardian) before the starting of data collection.

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Informed written consent for publication was obtained from all participants (or their parent or legal guardian) before the starting this study.

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Gupta, M.K., Kushwah, A.S., Singh, R. et al. Genetic and epigenetic alterations in MGMT gene and correlation with concomitant chemoradiotherapy (CRT) in cervical cancer. J Cancer Res Clin Oncol 149, 15159–15170 (2023). https://doi.org/10.1007/s00432-023-05305-w

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  • DOI: https://doi.org/10.1007/s00432-023-05305-w

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