title: Increased risk of severe fluoropyrimidine-associated toxicity in patients carrying a G to C substitution in the first 28-bp tandem repeat of the thymidylate synthase 2R allele.
abstract: The fluoropyrimidines act by inhibiting thymidylate synthase (TS). Recent studies have shown that patients' risk of severe fluoropyrimidine-associated toxicity is affected by polymorphisms in the 5'-untranslated region of TYMS, the gene encoding TS. A G>C substitution in the promoter enhancer region of TYMS, rs183205964 (known as the 2RC allele), markedly reduces TS activity in vitro, but its clinical relevance is unknown. We determined rs183205964 in 1605 patients previously enrolled in a prospective multicenter study. Associations between putative low TS expression genotypes (3RC/2RC, 2RG/2RC, and 2RC/2RC) and severe toxicity were investigated using univariable and multivariable logistic regression. Activity of TS and TYMS gene expression were determined in peripheral blood mononuclear cells (PBMCs) of a patient carrying genotype 2RC/2RC and of a control group of healthy individuals. Among 1,605 patients, 28 patients (1.7%) carried the 2RC allele. Twenty patients (1.2%) carried a risk-associated genotype (2RG/2RC, n=13; 3RC/2RC, n=6; and 2RC/2RC, n=1), the eight remaining patients had genotype 3RG/2RC. Early severe toxicity and toxicity-related hospitalization were significantly more frequent in risk-associated genotype carriers (OR 3.0, 95%CI 1.04-8.93, p=0.043 and OR 3.8, 95%CI 1.19-11.9, p=0.024, respectively, in multivariable analysis). The patient with genotype 2RC/2RC was hospitalized twice and had severe febrile neutropenia, diarrhea, and hand-foot syndrome. Baseline TS activity and gene expression in PBMCs of this patient, and a healthy individual with the 2RC allele, were found to be within the normal range. Our study suggests that patients carrying rs183205964 are at strongly increased risk of severe, potentially life-threatening, toxicity when treated with fluoropyrimidines.
authors.affiliation: Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.|Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Didier
authors.initials: D
authors.lastname: Meulendijks
authors.affiliation: Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.|Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Bart A W
authors.initials: BA
authors.lastname: Jacobs
authors.affiliation: Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Abidin
authors.initials: A
authors.lastname: Aliev
authors.affiliation: Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Dick
authors.initials: D
authors.lastname: Pluim
authors.affiliation: Department of Biometrics, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Erik
authors.initials: E
authors.lastname: van Werkhoven
authors.affiliation: Department of Clinical Pharmacy, Catharina Hospital, Eindhoven, The Netherlands.
authors.forename: Maarten J
authors.initials: MJ
authors.lastname: Deenen
authors.affiliation: Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.|Division of Pharmacoepidemiology and Clinical Pharmacology, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands.
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Annemieke
authors.initials: A
authors.lastname: Cats
authors.affiliation: Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.|Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.|Division of Pharmacoepidemiology and Clinical Pharmacology, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands.
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
mesh_terms: D020121:5' Untranslated Regions; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects* / Q000627:therapeutic use; D016022:Case-Control Studies; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000627:therapeutic use; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011743:Pyrimidines / Q000009:adverse effects* / Q000627:therapeutic use; D020080:Tandem Repeat Sequences; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors / Q000235:genetics*; D055815:Young Adult
chemical_list: D020121:5' Untranslated Regions; D000964:Antimetabolites, Antineoplastic; D011743:Pyrimidines; D013940:Thymidylate Synthase; C030986:pyrimidine; D005472:Fluorouracil
keywords: 5-fluorouracil; capecitabine; fluoropyrimidines; thymidylate synthase; toxicity