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Fluoropyrimidine-associated toxicity and DPYD variants c.85T>C, c.496A>G, and c.1236G>A: impact of haplotype

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Abstract

Dihydropyrimidine dehydrogenase (DPYD) is the rate-limiting step in fluoropyrimidines metabolism. Currently, genotype-guided fluoropyrimidine dosing is recommended for four DPYD single nucleotide variants (SNVs). However, the clinical impact of additional DPYD SNVs on fluoropyrimidine-related toxicity remains controversial. We assessed common DPYD SNVs c.85T>C, and c.496A>G which are often in linkage disequilibrium with c.1236G>A, a variant currently recommended for DPYD genotyping, in a retrospective cohort of cancer patients who had received fluoropyrimidines (N = 1371). When assessing individual SNVs, during the total chemotherapy treatment period, a significant increased risk of severe grade ≥ 3 toxicity was seen in carriers of c.496A>G (OR = 1.38, 95% CI 1.01–1.88, p = 0.0405) after adjusting for age, sex and treatment drug (capecitabine or 5-Fluorouracil). No association with fluoropyrimidine-related toxicity was seen in patients given standard dosing among those carrying one allele of DPYD c.1236G>A (OR = 1.19, 95% CI 0.59–2.27, p = 0.6147) or c.85T>C (OR = 1.04, 95% CI 0.80–1.62, p = 0.7536). Haplotype analysis confirmed a high linkage disequilibrium of these three variants. Toxicity was not significantly increased in haplotypes containing only one of c.85T>C or c.496A>G or c.1236G>A alleles. However, the haplotype containing both c.85T>C and c.496A>G alleles, which had a predicted frequency of 7.1%, was associated with an increased risk of fluoropyrimidine toxicity (OR = 1.57, 95% CI 1.15–2.13, p = 0.0041). This study suggests DPYD haplotype structure may help explain previous conflicting studies concerning the impact of these variants. Our findings suggest patients with both DPYD c.85T>C and c.496A>G variants have a significant increased risk for toxicity and may potentially benefit from genotype-guided fluoropyrimidine dosing.

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Funding

Ontario Institute of Cancer Research Pre-CATA (P.CTP.725), Ministry of Research, Innovation and Science—Ontario Research Excellence Fund Round 8 (RE08-063), Canadian Institutes of Health Research Team Grant: Personalized Health (PHT-178435) and Wolfe Medical Research Chair in Pharmacogenomics to R.B.K.

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Authors and Affiliations

  1. London Health Sciences Centre, London, ON, Canada

    Samantha Medwid, Theodore J. Wigle & Richard B. Kim

  2. Department of Medicine, University of Western Ontario, London, ON, Canada

    Samantha Medwid, Theodore J. Wigle & Richard B. Kim

  3. Lawson Health Research Institute, London, ON, Canada

    Richard B. Kim

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  1. Samantha Medwid
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  2. Theodore J. Wigle
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  3. Richard B. Kim
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Correspondence to Richard B. Kim.

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RBK has received a patient education grant from Pfizer Canada.

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Medwid, S., Wigle, T.J. & Kim, R.B. Fluoropyrimidine-associated toxicity and DPYD variants c.85T>C, c.496A>G, and c.1236G>A: impact of haplotype. Cancer Chemother Pharmacol 91, 97–102 (2023). https://doi.org/10.1007/s00280-022-04491-7

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  • DOI: https://doi.org/10.1007/s00280-022-04491-7

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