Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID: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. 2618 37

We report the first clinical description of a patient with cancer with a heterozygous germline codon-stop mutation in the TYMS gene. The mutation g.657795_657826del, c.53_84del (NM_001071.2), p.Gln18Argfs*42 causes loss of function of one of the TYMS alleles, resulting in a truncated protein. This gene codifies for the target enzyme of 5-fluorouracil (5-FU), the basic treatment in colorectal cancer. The patient, diagnosed with metastatic colorectal cancer, had diarrhea and neutropenia grade 4 and mucositis and neurological toxicity grade 3 under 5-FU-based therapy and exceeded by more than 50% the average survival after metastasectomy. On the basis of the patient's characteristics and the key role of TYMS in 5-FU activity, we hypothesize that this mutation may contribute to the drug response and toxicities suffered by the patient.
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PMID:Long Survival and Severe Toxicity Under 5-Fluorouracil-Based Therapy in a Patient With Colorectal Cancer Who Harbors a Germline Codon-Stop Mutation in TYMS. 2621 Jul 4

Combination chemotherapy using docetaxel, cisplatin and 5-fluorouracil (DCF) is a promising treatment option for patients with advanced esophageal squamous cell carcinoma (ESCC), although its clinical application is limited by severe systemic toxicities. There are no validated markers for predicting the adverse effects caused by this regimen. This pharmacogenetic study enrolled 57 patients with chemotherapy-naive advanced ESCC between July 2012 and March 2016 (UMIN000008462). All patients received at least one course of DCF chemotherapy (docetaxel, 60 mg/m2 on day 1; cisplatin, 70 mg/m2 on day 1; 5-fluorouracil, 600 mg/m2 on days 1-5). The associations between four gene polymorphisms (ERCC1 rs11615, GSTP1 rs1695, TYMS rs151264360 and XPD rs13181) and the development of grade 3/4 adverse events during the first course of chemotherapy were prospectively investigated. The patients had a median age of 66 years (range, 45-77 years) and the majority were male (51 males vs. 6 females). The treatment settings were neoadjuvant (47 patients), adjuvant (1 patient) and salvage (9 patients), with dose intensities of 100% (51 patients) or 80% (6 patients). The severe adverse events were leukopenia (70.2%), neutropenia (86.0%), febrile neutropenia (36.8%), acute kidney injury (29.1%) and hyponatremia (43.9%). Two polymorphisms were independently associated with the development of severe hyponatremia among patients carrying the minor allele (vs. patients with major homozygote genotype): TYMS 3'-UTR rs151264360 (odds ratio, 3.64; 95% confidence interval, 1.11-11.9) and XPD Lys751Gln rs13181 (odds ratio, 10.1; 95% confidence interval, 1.10-93.3). Therefore, the presence of the TYMS and XPD polymorphisms may aid in identifying patients with a high risk of developing severe hyponatremia during DCF chemotherapy.
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PMID:Effects of gene polymorphisms on the risk of severe hyponatremia during DCF chemotherapy for patients with esophageal squamous cell carcinoma. 3021 18