Discovery of novel mutations in the dihydropyrimidine dehydrogenase gene associated with toxicity of fluoropyrimidines and viewpoint on preemptive pharmacogenetic screening in patients

The EPMA Journal
Marzia Del ReRomano Danesi

Abstract

Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme of the metabolic pathway of 5-fluorouracil (5-FU) and other fluoropyrimidines to inactive compounds. For this reason, severe, life-threatening toxicities may occur in patients with deficient DPD activity when administered standard doses of 5-FU and its prodrugs. We selected three patients with colorectal adenocarcinoma who displayed unexpected severe adverse reactions after treatment with 5-FU and capecitabine. To investigate the possible involvement of deficient variants of the DPD gene (DPYD), a denaturing HPLC (dHPLC) approach followed by target exon sequencing of DPYD was performed on DNA extracted from peripheral blood. Three novel non-synonymous mutations of DPYD, c.2509-2510insC, c.1801G>C, and c.680G>A, were detected in these subjects. Due to the absence of other deficient variants of DPYD and the compatibility of adverse reactions with fluoropyrimidine treatment, the novel variants were associated with a poor-metabolizer phenotype. Stratification of patients on the basis of their genotype may help prevent toxicity, and the large body of evidence about the pathogenesis of fluoropyrimidine-induced adverse reactions strongly encourages the adopt...Continue Reading

References

May 10, 2000·Pharmacogenetics·E S Collie-DuguidH L McLeod
Jul 27, 2001·Current Pharmaceutical Biotechnology·F TanakaM Fukushima
Dec 14, 2001·Laboratory Investigation; a Journal of Technical Methods and Pathology·G KellerH Höfler
Jan 11, 2002·Advances in Experimental Medicine and Biology·A B van KuilenburgA H van Gennip
Jan 25, 2003·Annals of Clinical Biochemistry·André B P van KuilenburgAlbert H van Gennip
Mar 15, 2005·Clinical Therapeutics·Christine M Walko, Celeste Lindley
Nov 14, 2006·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·André B P van KuilenburgHenk-Jan Guchelaar
Dec 14, 2006·Cancer Chemotherapy and Pharmacology·M W SaifRobert B Diasio
Mar 14, 2007·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·Jane L Yen, Howard L McLeod
Oct 2, 2007·Comptes rendus biologies·Radhia Ben FredjSaâd Saguem
Nov 16, 2007·Trends in Pharmacological Sciences·Cédric Mercier, Joseph Ciccolini
May 3, 2008·Journal of Clinical Pharmacy and Therapeutics·Y-F HeW-Q Jiang
Sep 17, 2011·Pharmacogenomics·Ursula AmstutzCarlo R Largiadèr
Nov 9, 2014·Journal of the National Cancer Institute·Federico Innocenti
Feb 19, 2015·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Daniel A GoldsteinChristopher R Flowers

❮ Previous
Next ❯

Methods Mentioned

BETA
PCR
genotyping

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.