Research Article

MIR27A rs895819 TC genotype increases risk of fluoropyrimidine-induced severe toxicity independently of DPYD variations

Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Alexandroupolis, 68100, Greece

Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), Alexandroupolis, Greece

Department of Medical Oncology, University General Hospital of Alexandroupolis, Medical School, Democritus University of Thrace, Alexandroupolis, 68100, Greece

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Triantafyllia Koukaki

Department of Medical Oncology, University General Hospital of Alexandroupolis, Medical School, Democritus University of Thrace, Alexandroupolis, 68100, Greece

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Kyriakos Amarantidis

Department of Medical Oncology, University General Hospital of Alexandroupolis, Medical School, Democritus University of Thrace, Alexandroupolis, 68100, Greece

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Vangelis G Manolopoulos

*Author for correspondence: Tel.: +30 255 103 0523;

E-mail Address: emanolop@med.duth.gr

https://orcid.org/0000-0003-0849-5469

Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Alexandroupolis, 68100, Greece

Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), Alexandroupolis, Greece

Clinical Pharmacology Unit, Academic General Hospital of Alexandroupolis, Alexandroupolis, Greece

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Published Online:14 Feb 2024https://doi.org/10.2217/pgs-2023-0223

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Abstract

Aim: MicroRNA 27a (miR-27a) regulates post-transcriptionally DPD activity. We have analyzed the association of MIR27A rs895819T>C variation, that modulates miR-27a expression, with fluropyrimidine-induced toxicity. Materials & methods:MIR27A rs895819T>C genotyping was conducted by TaqMan® allelic discrimination assay in 313 FP-treated cancer patients. Results: In overdominance (TC vs TT + CC), TC genotype was associated with grade 3–4 toxicity (p = 0.002), any grade toxicity (p = 0.052), and delayed drug administration or therapy discontinuation (p = 0.038). Odds of grade 3–4 toxicity were increased by both DPYD deficiency (OR: 8.923; p = 0.006) and MIR27A rs895819 TC genotype (OR: 3.865; p = 0.002). Conclusion:MIR27A rs895819 TC genotype is an independent risk factor for fluoropyrimidine-associated toxicity in the Greek population. Thus, MIR27A rs895819TC patients can be closely monitored for fluoropyrimidine-induced severe toxicity.

Plain language summary

What is this summary about?

To date, for cancer patients treated with fluoropyrimidines (capecitabine and 5-fluorouracil), analyzing DPYD gene can be used to guide the optimal dose of treatment in order to reduce the incidence of severe, even life threatening toxicity and thus, increase drug safety. However, the frequency of clinically significant DPYD variants is rare, below 5%, and there is therefore an urgent medical need to identify additional genes that can help in predicting response to fluoropyrimidines. Apart from changes in DPYD gene, noncoding RNAs modulate DPD enzymatic activity. MiR-27a is such a modulator. MIR27A rs895819 polymorphism affects miR-27a expression and is a potential candidate of fluoropyrimidine response. In this study, we have analyzed the association of MIR27A rs895819T>C polymorphism with fluoropyrimidine-induced toxicity in cancer patients.

What were the results?

MIR27A rs895819 TC genotype is associated with fluoropyrimidine-induced grade 3–4 toxicity, any grade toxicity and delayed drug administration or therapy discontinuation. Carrying MIR27A rs895819 TC genotype leads to over of threefold increased risk for grade 3–4 toxicity and can improve sensitivity of DPYD genotyping alone.

What do the results mean?

MIR27A rs895819 TC carriers should be closely monitored for fluoropyrimidine-induced severe toxicity. Fluoropyrimidine pharmacogenomics can help in improving drug safety and patient response.

Tweetable abstract

Beyond DPYD, MIR27A rs895819 TC genotype is an independent risk factor for fluoropyrimidine induced severe toxicity. MIR27A rs895819TC genotype can be used to closely monitor patients for adverse event incidence.

Keywords:

Papers of special note have been highlighted as: • of interest; •• of considerable interest

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Vol. 25, No. 2

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History

Received 27 November 2023

Accepted 23 January 2024

Published online 14 February 2024

Published in print January 2024

Information

Keywords

Author contributions

G Ragia and VG Manolopoulos wrote the manuscript; G Ragia and VG Manolopoulos designed the research; E Biziota, T Koukaki and K Amarantidis performed the sample acquisition; E Biziota, T Koukaki and K Amarantidis collected the data; G Ragia performed the experimental procedures; G Ragia analyzed the data; VG Manolopoulos obtained research funding.

Financial disclosure

Financial support for project IMPReS (MIS 5047189) was provided to VG Manolopoulos by the Program “Competitiveness, Entrepreneurship and Innovation” (NSRF 2014-2020) co-financed by Greece and the European Union (European Regional Development Fund). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Conflict of interests

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval and have followed the principles outlined in the Declaration of Helsinki for their investigation. In addition, informed consent has been obtained from the participants involved.

Data sharing statement

Data can be made available upon reasonable request.

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