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亚洲人群中二氢嘧啶脱氢酶（DPYD）基因型与氟嘧啶类药物毒性之间的相关性较差。

Poor association between dihydropyrimidine dehydrogenase (DPYD) genotype and fluoropyrimidine-induced toxicity in an Asian population.

机构信息

Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

出版信息

Cancer Med. 2023 Apr;12(7):7808-7814. doi: 10.1002/cam4.5541. Epub 2022 Dec 16.

DOI:10.1002/cam4.5541
PMID:36524458
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10134304/
Abstract

OBJECTIVE: Dihydropyrimidine dehydrogenase (DPYD) genotype is closely associated with fluoropyrimidine (FP)-induced toxicities in Caucasian population and European Medicines Agency now recommends DPYD genotype-based FP dosing strategy. PATIENTS AND METHODS: The current study aimed to investigate their impact on FP-related toxicities in an Asian population using genome-wide association study (GWAS) data set from 1364 patients with colon cancer. RESULTS: Among 82 variants registered in the Clinical Pharmacogenetics Implementation Consortium, 74 DPYD variants were directly genotyped in GWAS cohort; however, only 7 nonsynonymous DPYD variants (CPIC variants) were identified and none of the four recurrent DPYD variants (DPYD*2A, c.2846A>T, c.1679T>G, c.1236G>A) were included. Seven CPIC variants were investigated for their association with the incidence of FP-related toxicities; however, none of these variants revealed a significant correlation with FP-related toxicities. CONCLUSION: These data suggested that the DPYD genotype registered in CPIC plays a minor role in FP-related toxicities in an Asian population.

摘要

目的：二氢嘧啶脱氢酶（DPYD）基因型与氟嘧啶（FP）在高加索人群中的毒性密切相关，欧洲药品管理局现在推荐基于 DPYD 基因型的 FP 剂量策略。

患者和方法：本研究旨在使用来自 1364 例结肠癌患者的全基因组关联研究（GWAS）数据集，调查其对亚洲人群中 FP 相关毒性的影响。

结果：在临床药物遗传学实施联盟登记的 82 个变异体中，74 个 DPYD 变异体在 GWAS 队列中直接进行了基因分型；然而，只鉴定出 7 个非同义 DPYD 变异体（CPIC 变异体），并且没有包括四个反复出现的 DPYD 变异体（DPYD*2A、c.2846A>T、c.1679T>G、c.1236G>A）。对 7 个 CPIC 变异体与 FP 相关毒性的发生进行了研究；然而，这些变异体均与 FP 相关毒性无显著相关性。

结论：这些数据表明，CPIC 中登记的 DPYD 基因型在亚洲人群中对 FP 相关毒性的作用较小。

相似文献

[1]
Poor association between dihydropyrimidine dehydrogenase (DPYD) genotype and fluoropyrimidine-induced toxicity in an Asian population.

Cancer Med. 2023-4

[2]
DPYD genotype-guided dose individualisation of fluoropyrimidine therapy in patients with cancer: a prospective safety analysis.

Lancet Oncol. 2018-10-19

[3]
Clinical relevance of DPYD variants c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity: a systematic review and meta-analysis of individual patient data.

Lancet Oncol. 2015-10-23

[4]
Impact of pretreatment dihydropyrimidine dehydrogenase genotype-guided fluoropyrimidine dosing on chemotherapy associated adverse events.

Clin Transl Sci. 2021-7

[5]
Discovering novel germline genetic variants linked to severe fluoropyrimidine-related toxicity in- and outside DPYD.

Genome Med. 2024-8-15

[6]
Rs895819 in MIR27A improves the predictive value of DPYD variants to identify patients at risk of severe fluoropyrimidine-associated toxicity.

Int J Cancer. 2016-2-19

[7]
Impact of pharmacogenomic DPYD variant guided dosing on toxicity in patients receiving fluoropyrimidines for gastrointestinal cancers in a high-volume tertiary centre.

BMC Cancer. 2023-4-26

[8]
A cost analysis of upfront DPYD genotype-guided dose individualisation in fluoropyrimidine-based anticancer therapy.

Eur J Cancer. 2018-12-11

[9]
Standard fluoropyrimidine dosages in chemoradiation therapy result in an increased risk of severe toxicity in DPYD variant allele carriers.

Eur J Cancer. 2018-10-23

[10]
Fluoropyrimidine chemotherapy: recommendations for DPYD genotyping and therapeutic drug monitoring of the Swiss Group of Pharmacogenomics and Personalised Therapy.

Swiss Med Wkly. 2020-11-16

引用本文的文献

[1]
Genetic mechanism of β-alanine metabolic pathway affecting colorectal cancer prognosis.

BMC Gastroenterol. 2025-7-1

[2]
Opportunities and Challenges of Population Pharmacogenomics.

Ann Hum Genet. 2025-9

[3]
Gene Polymorphism Modifies the Effect of Common Gene Variants on Severe Toxicity in Patients with Gastrointestinal Tumors Treated with Fluoropyrimidine-Based Anticancer Therapy.

Int J Mol Sci. 2024-8-4

[4]
DPYD genetic polymorphisms in non-European patients with severe fluoropyrimidine-related toxicity: a systematic review.

Br J Cancer. 2024-8

[5]
Assessing the Occurrence and Influence of Cancer Chemotherapy-Related Pharmacogenetic Alleles in the Chilean Population.

Pharmaceutics. 2024-4-19

[6]
Personalizing adjuvant therapy for patients with colorectal cancer.

Nat Rev Clin Oncol. 2024-1

[7]
Implementing pharmacogenetic testing in fluoropyrimidine-treated cancer patients: genotyping to guide chemotherapy dosing in Greece.

Front Pharmacol. 2023-9-14

[8]
Pharmacogenomic-guided dosing of fluoropyrimidines beyond : time for a polygenic algorithm?

Front Pharmacol. 2023-5-15

本文引用的文献

[1]
Importance of Rare Genetic Polymorphisms for 5-Fluorouracil Therapy in the Japanese Population.

Front Pharmacol. 2022-6-15

[2]
Final Analysis of 3 Versus 6 Months of Adjuvant Oxaliplatin and Fluoropyrimidine-Based Therapy in Patients With Stage III Colon Cancer: The Randomized Phase III ACHIEVE Trial.

J Clin Oncol. 2022-10-10

[3]
Large-scale prospective genome-wide association study of oxaliplatin in stage II/III colon cancer and neuropathy.

Ann Oncol. 2021-11

[4]
JOIN trial: treatment outcome and recovery status of peripheral sensory neuropathy during a 3-year follow-up in patients receiving modified FOLFOX6 as adjuvant treatment for stage II/III colon cancer.

Cancer Chemother Pharmacol. 2019-9-23

[5]
Efficacy and Long-term Peripheral Sensory Neuropathy of 3 vs 6 Months of Oxaliplatin-Based Adjuvant Chemotherapy for Colon Cancer: The ACHIEVE Phase 3 Randomized Clinical Trial.

JAMA Oncol. 2019-11-1

[6]
A cost analysis of upfront DPYD genotype-guided dose individualisation in fluoropyrimidine-based anticancer therapy.

Eur J Cancer. 2018-12-11

[7]
DPYD genotype-guided dose individualisation of fluoropyrimidine therapy in patients with cancer: a prospective safety analysis.

Lancet Oncol. 2018-10-19

[8]
Functional Characterization of 21 Allelic Variants of Dihydropyrimidine Dehydrogenase Identified in 1070 Japanese Individuals.

Drug Metab Dispos. 2018-5-16

[9]
Duration of Adjuvant Chemotherapy for Stage III Colon Cancer.

N Engl J Med. 2018-3-29

[10]
Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update.

Clin Pharmacol Ther. 2017-11-20

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