Discovering novel germline genetic variants linked to severe fluoropyrimidine-related toxicity in- and outside DPYD
Knikman, Jonathan E.; Zhai, Qinglian; Lunenburg, Carin A.T.C.; Henricks, Linda M.; Böhringer, Stefan; van der Lee, Maaike; de Man, Femke M.; Offer, Steven M.; Shrestha, Shikshya; Creemers, Geert Jan; Baars, Arnold; Dezentjé, Vincent O.; Imholz, Alexander L.T.; Jeurissen, Frank J.F.; Portielje, Johanna E.A.; Jansen, Rob L.H.; Hamberg, Paul; Droogendijk, Helga J.; Koopman, Miriam; Nieboer, Peter; van de Poel, Marlène H.W.; Mandigers, Caroline M.P.W.; van Schaik, Ron H.N.; Gelderblom, Hans; Mathijssen, Ron H.J.; Schellens, Jan H.M.; Cats, Annemieke; Guchelaar, Henk Jan; Swen, Jesse J.
(2024) Genome Medicine, volume 16, issue 1
(Article)
Abstract
Background: The Alpe-DPD study (NCT02324452) demonstrated that prospective genotyping and dose-individualization using four alleles in DPYD (DPYD*2A/rs3918290, c.1236G > A/rs75017182, c.2846A > T/rs67376798 and c.1679 T > G/rs56038477) can mitigate the risk of severe fluoropyrimidine toxicity. However, this could not prevent all toxicities. The goal of this study was to identify
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additional genetic variants, both inside and outside DPYD, that may contribute to fluoropyrimidine toxicity. Methods: Biospecimens and data from the Alpe-DPD study were used. Exon sequencing was performed to identify risk variants inside DPYD. In silico and in vitro analyses were used to classify DPYD variants. A genome-wide association study (GWAS) with severe fluoropyrimidine-related toxicity was performed to identify variants outside DPYD. Association with severe toxicity was assessed using matched-pair analyses for the exon sequencing and logistic, Cox, and ordinal regression analyses for GWAS. Results: Twenty-four non-synonymous, frameshift, and splice site DPYD variants were detected in ten of 986 patients. Seven of these variants (c.1670C > T, c.1913 T > C, c.1925 T > C, c.506delC, c.731A > C, c.1740 + 1G > T, c.763 − 2A > G) were predicted to be deleterious. The carriers of either of these variants showed a trend towards a 2.14-fold (95% CI, 0.41–11.3, P = 0.388) increased risk of severe toxicity compared to matched controls (N = 30). After GWAS of 942 patients, no individual single nucleotide polymorphisms achieved genome-wide significance (P ≤ 5 × 10−8), however, five variants were suggestive of association (P < 5 × 10−6) with severe toxicity. Conclusions: Results from DPYD exon sequencing and GWAS analysis did not identify additional genetic variants associated with severe toxicity, which suggests that testing for single markers at a population level currently has limited clinical value. Identifying additional variants on an individual level is still promising to explain fluoropyrimidine-related severe toxicity. In addition, studies with larger samples sizes, in more diverse cohorts are needed to identify potential clinically relevant genetic variants related to severe fluoropyrimidine toxicity.
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Keywords: Dihydropyrimidine dehydrogenase, DPYD, Fluoropyrimidines, Personalized medicine, Pharmacogenetics, Molecular Medicine, Molecular Biology, Genetics, Genetics(clinical)
ISSN: 1756-994x
Publisher: BioMed Central
Note: Publisher Copyright: © The Author(s) 2024.
(Peer reviewed)