. 2024 Aug 15;16(1):101.

doi: 10.1186/s13073-024-01354-z.

Discovering novel germline genetic variants linked to severe fluoropyrimidine-related toxicity in- and outside DPYD

Jonathan E Knikman^#¹, Qinglian Zhai^#², Carin A T C Lunenburg³, Linda M Henricks⁴, Stefan Böhringer^{2

5}, Maaike van der Lee², Femke M de Man⁶, Steven M Offer^{7

8

9}, Shikshya Shrestha¹⁰, Geert-Jan Creemers¹¹, Arnold Baars¹², Vincent O Dezentjé^{13

14}, Alexander L T Imholz¹⁵, Frank J F Jeurissen¹⁶, Johanna E A Portielje³, Rob L H Jansen¹⁷, Paul Hamberg¹⁸, Helga J Droogendijk¹⁹, Miriam Koopman²⁰, Peter Nieboer²¹, Marlène H W van de Poel²², Caroline M P W Mandigers²³, Ron H N van Schaik²⁴, Hans Gelderblom³, Ron H J Mathijssen⁶, Jan H M Schellens²⁵, Annemieke Cats²⁶, Henk-Jan Guchelaar²⁷, Jesse J Swen²

Affiliations

¹ Division of Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
² Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
³ Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands.
⁴ Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, Leiden, The Netherlands.
⁵ Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands.
⁶ Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
⁷ Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
⁸ Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA.
⁹ Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN, USA.
¹⁰ Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
¹¹ Department of Medical Oncology, Catharina Hospital, Eindhoven, The Netherlands.
¹² Department of Internal Medicine, Hospital Gelderse Vallei, Ede, The Netherlands.
¹³ Department of Internal Medicine, Reinier de Graaf Hospital, Delft, The Netherlands.
¹⁴ Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
¹⁵ Department of Internal Medicine, Deventer Hospital, Deventer, The Netherlands.
¹⁶ Department of Internal Medicine, Haaglanden Medical Center, The Hague, The Netherlands.
¹⁷ Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands.
¹⁸ Department of Internal Medicine, Franciscus Gasthuis en Vlietland, Rotterdam, The Netherlands.
¹⁹ Department of Internal Medicine, Bravis Hospital, Roosendaal, The Netherlands.
²⁰ Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands.
²¹ Department of Internal Medicine, Wilhelmina Hospital Assen, Assen, The Netherlands.
²² Department of Internal Medicine, Laurentius Hospital, Roermond, The Netherlands.
²³ Department of Internal Medicine, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands.
²⁴ Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, Netherlands.
²⁵ Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
²⁶ Department of Gastroenterology and Hepatology, Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
²⁷ Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands. h.j.guchelaar@lumc.nl.

^# Contributed equally.

PMID: 39148102
PMCID: PMC11325793
DOI: 10.1186/s13073-024-01354-z

Discovering novel germline genetic variants linked to severe fluoropyrimidine-related toxicity in- and outside DPYD

Jonathan E Knikman et al. Genome Med. 2024.

. 2024 Aug 15;16(1):101.

doi: 10.1186/s13073-024-01354-z.

Authors

Affiliations

¹ Division of Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
² Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
³ Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands.
⁴ Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, Leiden, The Netherlands.
⁵ Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands.
⁶ Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
⁷ Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
⁸ Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA.
⁹ Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN, USA.
¹⁰ Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
¹¹ Department of Medical Oncology, Catharina Hospital, Eindhoven, The Netherlands.
¹² Department of Internal Medicine, Hospital Gelderse Vallei, Ede, The Netherlands.
¹³ Department of Internal Medicine, Reinier de Graaf Hospital, Delft, The Netherlands.
¹⁴ Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
¹⁵ Department of Internal Medicine, Deventer Hospital, Deventer, The Netherlands.
¹⁶ Department of Internal Medicine, Haaglanden Medical Center, The Hague, The Netherlands.
¹⁷ Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands.
¹⁸ Department of Internal Medicine, Franciscus Gasthuis en Vlietland, Rotterdam, The Netherlands.
¹⁹ Department of Internal Medicine, Bravis Hospital, Roosendaal, The Netherlands.
²⁰ Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands.
²¹ Department of Internal Medicine, Wilhelmina Hospital Assen, Assen, The Netherlands.
²² Department of Internal Medicine, Laurentius Hospital, Roermond, The Netherlands.
²³ Department of Internal Medicine, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands.
²⁴ Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, Netherlands.
²⁵ Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
²⁶ Department of Gastroenterology and Hepatology, Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
²⁷ Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands. h.j.guchelaar@lumc.nl.

^# Contributed equally.

PMID: 39148102
PMCID: PMC11325793
DOI: 10.1186/s13073-024-01354-z

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.

Keywords: DPYD; Dihydropyrimidine dehydrogenase; Fluoropyrimidines; Personalized medicine; Pharmacogenetics.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest in relationship with this work. Carin Lunenburg is currently employed by Bristol-Myers Squibb, not related to the contents of this manuscript. She was supported by an unrestricted grant from Roche Pharmaceuticals. Jan Schellens is an (part time) employee, stock- and patent holder of Modra Pharmaceuticals, a spin out company developing oral taxane formulations; Jan Schellens is also a part time employee of Byondis bv and received consultancy fees from Debiopharm, all not related to the contents of the manuscript. Steven Offer has received consultancy fees from Processa Pharmaceuticals, Inc. for activities not related to the contents of this manuscript. The remaining authors declare that they have no competing interests.

Figures

**Fig. 1**
Study design. Severe fluoropyrimidine-related toxicity was defined as CTC-AE grade ≥ 3. *The four known DPYD variants are DPYD*2A, c.1236G > A, c.2846A > T, and c.1679 T > G

**Fig. 2**
Flowchart of patient inclusion. Patients who experienced grade 2 toxicity were excluded from the GWAS analyses to maximize the contrast between severe and non-severe toxicity. Abbreviations: QC, quality control; DPYD, gene encoding dihydropyrimidine dehydrogenase; NT, not tested, NA, prediction not available

See this image and copyright information in PMC

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Discovering novel germline genetic variants linked to severe fluoropyrimidine-related toxicity in- and outside DPYD

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Discovering novel germline genetic variants linked to severe fluoropyrimidine-related toxicity in- and outside DPYD

Authors

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Abstract

Conflict of interest statement

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