Naslov
DPYD polymorphisms and fluoropyrimidine toxicity- a single institution case control study

Autori
Božina, Nada ; Bilić, Ivan ; Pleština, Stjepko ; Vrbanec, Damir ; Kralik, Marko ; Ganoci, Lana

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
Abstract Book of the 15th International Congress of Therapeutic Drug Monitoring & Clinical Toxicology / - : IATDMCT, 2017 / - , 2017

Skup
15th International Congress of Therapeutic Drug Monitoring and Clinical Toxicology

Mjesto i datum
Kyoto, Japan, 24.09.2017. - 27.09.2017

Vrsta sudjelovanja
Predavanje

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
DPYD Gene Polymorphism Fluoropyrimidines Irinotecan ; Toxicity

Sažetak
Background Fluoropyrimidines (FP) are frequently used in oncology. Dihydropyrimidine- dehydrogenase (DPD) is the rate-limiting enzyme of FP metabolism, degrading 80% of FP. Patients with partial or complete enzyme-deficiency have increased toxicity risk, possibly detectable by genotyping. Here we present preliminary results of a single-institution case-control cohort genotyped for DPYD-polymorphisms and monitored for toxicity during FP therapy. Methods Fluoropyrimidine-treated patients (N=305) were genotyped for five DPYD- polymorphisms (*2A, *13, c.2846A>T, c.1236G>A and c.496A>G). Those receiving irinotecan were also genotyped for UGT1A1*28. Side-effects were followed-up for three months. The observed patient group included grade III and IV toxicity (N=138), whereas controls comprised grade I and II (N=167). DNA was isolated from whole blood (3ml) and genotyped according to manufacturer’s propositions using Real-time PCR (TaqMan® for DPYD, LightCycler® for UGT1A1). Polymorphism frequency distribution was analyzed by non-parametric tests and binary logistic regression. Results During the study, we recorded a total of 705 adverse events (273 of high- and 432 low grade). Subjects in the observed group developed adverse effects more rapidly (2nd vs. 3rd cycle of chemotherapy) and accumulated greater total number of events per capita (3 vs 1.7). Aggregated DPYD polymorphisms (N=93 ; 30.5%) were distributed unevenly with higher frequency of carriers in the observed group (49.3% vs. 15%), thus creating a statistically significant increase of risk for severe toxicity among carriers of mutated DPYD variant (OR=4.91 ; P<0.001). All DPYD*2A carriers (N=11 ; 3.6%) developed high-grade toxicity with one lethal event in a homozygote. c.496A>G carriers (N=69 ; 22.6%) had increased risk for toxicity (OR=4.64 ; P<0.001) with three of them being compound heterozygotes for DPYD*2A. Detected frequencies of c.2846A>T and c.1236G>A were too low to draw any statistically significant conclusion on their particular impact. We did not detect any DPYD*13 polymorphism. UGT1A1*28 variant had stronger influence on toxicity risk than DPYD polymorphisms when irinotecan was given in combination with FP (OR=8.1 ; P<0.001), as expected. Conclusions Significant association and predictive value of DPYD- mutation status considering FP-toxicity is shown, while UGT1A1*28 remained important for irinotecan toxicity. The detected frequencies of polymorphisms were slightly inconsistent with published data, thus emphasizing the importance of genetic background for selection of variants to be genotyped in particular ethnic groups.

Izvorni jezik
Engleski

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