Journal article
Discovering novel germline genetic variants linked to severe fluoropyrimidine-related toxicity in- and outside DPYD
Genome medicine, Vol.16(1), 101
08/15/2024
DOI: 10.1186/s13073-024-01354-z
PMCID: PMC11325793
PMID: 39148102
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 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.
Details
- Title: Subtitle
- Discovering novel germline genetic variants linked to severe fluoropyrimidine-related toxicity in- and outside DPYD
- Creators
- Jonathan E. Knikman - Oncode InstituteQinglian Zhai - Leiden University Medical CenterCarin A. T. C. Lunenburg - Leiden University Medical CenterLinda M. Henricks - Leiden University Medical CenterStefan Böhringer - Leiden University Medical CenterMaaike van der Lee - Leiden University Medical CenterFemke M. de Man - Erasmus MCSteven M. Offer - University of IowaShikshya Shrestha - Harvard UniversityGeert-Jan Creemers - Radboud University NijmegenArnold Baars - Ziekenhuis Gelderse ValleiVincent O. Dezentjé - The Netherlands Cancer InstituteAlexander L. T. Imholz - Deventer ZiekenhuisFrank J. F. Jeurissen - Medisch Centrum HaaglandenJohanna E. A. Portielje - Leiden University Medical CenterRob L. H. Jansen - Maastricht UniversityPaul Hamberg - Sint Franciscus GasthuisHelga J. Droogendijk - Bravis ZiekenhuisMiriam Koopman - University Medical Center UtrechtPeter Nieboer - Wilhelmina Children's HospitalMarlène H. W. van de Poel - Laurentius ZiekenhuisCaroline M. P. W. Mandigers - Canisius-Wilhelmina ZiekenhuisRon H. N. van Schaik - Erasmus MCHans Gelderblom - Leiden University Medical CenterRon H. J. Mathijssen - Erasmus MCJan H. M. Schellens - Utrecht UniversityAnnemieke Cats - The Netherlands Cancer InstituteHenk-Jan Guchelaar - Leiden University Medical CenterJesse J. Swen - Leiden University Medical Center
- Resource Type
- Journal article
- Publication Details
- Genome medicine, Vol.16(1), 101
- Publisher
- BioMed Central
- DOI
- 10.1186/s13073-024-01354-z
- PMID
- 39148102
- PMCID
- PMC11325793
- ISSN
- 1756-994X
- eISSN
- 1756-994X
- Grant note
The authors thank the Human Genotyping Facility of the Erasmus Medical Center for the execution of the genotyping and all participating centres of the NCT02324452 study for their help in including patients in the study.DAS:Sequence and GWAS data that support the findings of this study are available in our European Genome and Phenotype Archive (EGA) account EGA-box-1314 accession code EGAS00001007855.
- Language
- English
- Date published
- 08/15/2024
- Academic Unit
- Pathology
- Record Identifier
- 9984697059502771
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