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Temozolomide-induced myelotoxicity and single nucleotide polymorphisms in the MGMT gene in patients with adult diffuse glioma: a single-institutional pharmacogenetic study

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Abstract

Purpose

Nearly 10% of patients with adult diffuse glioma develop clinically significant myelotoxicity while on temozolomide (TMZ) leading to treatment interruptions. This study aimed to assess single nucleotide polymorphisms (SNPs) in the O6-methylguanine-DNA methyltransferase (MGMT) gene in adults with biopsy-proven diffuse glioma who develop TMZ-induced myelotoxicity and correlate their presence with severity and duration of such toxicity.

Methods

This study assessed 33 adults treated with TMZ for diffuse glioma who developed ≥ grade 2 thrombocytopenia and/or ≥ grade 3 neutropenia. Genomic DNA was extracted from peripheral blood cells for MGMT SNP analysis after written informed consent. TMZ-induced severe myelotoxicity (≥ grade 3) was correlated with three specified SNPs commonly seen in the MGMT gene (L84F, I143V/K178R) using chi-square test or Fischer’s exact test as appropriate.

Results

Of the 33 adults, 24 (72.7%) experienced ≥ grade 3 thrombocytopenia and/or neutropenia, while 9 (27.3%) developed grade 2 thrombocytopenia only. The variant T allele of L84F was expressed in 28.7% (19/66) of analyzed alleles, which was substantially higher than previously reported for South Asian ancestry. The variant G allele of I143V/K178R was expressed in 9.3% (6/64) of analyzed alleles. Of which 3 patients showed statistically significant association with prolonged myelosuppression for > 2 months (p = 0.03). No significant correlation was established between the mentioned SNPs and severe myelotoxicity.

Conclusions

There is substantially higher frequency of variant T allele (L84F) in Indian patients than previously reported for South Asians. The presence of specific SNPs in the MGMT gene correlates with prolonged duration but not severity of TMZ-induced myelotoxicity.

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Data availability

The datasets analysed during the current study can be made available from the corresponding author on reasonable request.

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Funding

All SNP analysis in the study was done through financial support by Sarin Lab, ACTREC,TMC.

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Authors and Affiliations

  1. Departments of Radiation Oncology, Tata Memorial Hospital (TMH)/Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, 410210, India

    Prithwijit Moitra, Abhishek Chatterjee, Archya Dasgupta, Rajiv Sarin & Tejpal Gupta

  2. Sarin Lab, Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India

    Priti Khatri Kota, Pradnya Kowtal & Rajiv Sarin

  3. Department of Pathology, Tata Memorial Hospital (TMH)/Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India

    Sridhar Epari

  4. Department of Medical Oncology, Tata Memorial Hospital (TMH)/Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India

    Vijay Patil

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  1. Prithwijit Moitra
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  9. Tejpal Gupta
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Contributions

Study concept and design: TG. Study conduct (clinical): PM, AC, SE, VP, TG. Study conduct (genotyping): PK, PK, RS. Data extraction and analysis: PM, AC, PK, TG. Manuscript—initial draft: PM. Editing and revision of manuscript: AC, AD, TG. Final approval: All authors.

Corresponding author

Correspondence to Tejpal Gupta.

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Conflict of interest

None of the authors have any conflicts of interest to declare.

Ethical approval

The study is registered with Clinical Trials Registry of India (CTRI-2020/07/026317) and was duly approved by the Institutional Ethics Committee that functions in accordance with the Declaration of Helsinki. All SNP analysis in the study was done through financial support from the Department of Atomic Energy, Government of India, to Sarin Lab, Advanced Centre for Treatment Research & Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, India.

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Moitra, P., Chatterjee, A., Kota, P.K. et al. Temozolomide-induced myelotoxicity and single nucleotide polymorphisms in the MGMT gene in patients with adult diffuse glioma: a single-institutional pharmacogenetic study. J Neurooncol 156, 625–634 (2022). https://doi.org/10.1007/s11060-022-03944-6

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