TY - JOUR
T1 - Discovering novel germline genetic variants linked to severe fluoropyrimidine-related toxicity in- and outside DPYD
AU - Knikman, Jonathan E.
AU - Zhai, Qinglian
AU - Lunenburg, Carin A.T.C.
AU - Henricks, Linda M.
AU - Böhringer, Stefan
AU - van der Lee, Maaike
AU - de Man, Femke M.
AU - Offer, Steven M.
AU - Shrestha, Shikshya
AU - Creemers, Geert Jan
AU - Baars, Arnold
AU - Dezentjé, Vincent O.
AU - Imholz, Alexander L.T.
AU - Jeurissen, Frank J.F.
AU - Portielje, Johanna E.A.
AU - Jansen, Rob L.H.
AU - Hamberg, Paul
AU - Droogendijk, Helga J.
AU - Koopman, Miriam
AU - Nieboer, Peter
AU - van de Poel, Marlène H.W.
AU - Mandigers, Caroline M.P.W.
AU - van Schaik, Ron H.N.
AU - Gelderblom, Hans
AU - Mathijssen, Ron H.J.
AU - Schellens, Jan H.M.
AU - Cats, Annemieke
AU - Guchelaar, Henk Jan
AU - Swen, Jesse J.
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/8/15
Y1 - 2024/8/15
N2 - 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 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.
AB - 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 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.
KW - Dihydropyrimidine dehydrogenase
KW - DPYD
KW - Fluoropyrimidines
KW - Personalized medicine
KW - Pharmacogenetics
UR - http://www.scopus.com/inward/record.url?scp=85201434546&partnerID=8YFLogxK
U2 - 10.1186/s13073-024-01354-z
DO - 10.1186/s13073-024-01354-z
M3 - Article
C2 - 39148102
AN - SCOPUS:85201434546
SN - 1756-994x
VL - 16
JO - Genome Medicine
JF - Genome Medicine
IS - 1
M1 - 101
ER -