Dihydropyrimidine dehydrogenase (DPD) single nucleotide polymorphisms (SNP) in Thai patients treated with 5-FU based regimens

Abstract

14537 Background: DPD deficiency is a genetic disease caused by molecular defects in the DPD gene (DPYD). Cancer patients with DPD deficiency developed severe toxicity after receiving 5-FU based chemotherapy. The objective of this study is to determine the extent of DPYD gene polymorphisms of Thai cancer patients who received 5-FU based chemotherapy regimens. Methods: We conducted a molecular analysis to determine the polymorphisms of DPYD gene in 116 Thai cancer patients. 76 patients developed severe (grade 3–4) toxicities after receiving the first or second cycle of 5-FU based chemotherapy. The other subject group consisted of 40 patients without severe toxicity. The clinical characteristics (sex, age, diagnosis, regimen and dosage) of both groups were recorded. We isolated genomic DNA from buffy coat of their peripheral blood samples then performed PCR. The DNA sequencing of every amplicon was done to identify 11 mutations as reported in Asian population. The actual change of absolute neutrophil count (ANC), hematocrit, platelet and percentage of neutrophil were compared in each SNP using Mann Whitney U test. Results: We detected 13 SNPs which 6 SNPs were found in exons; 967G>A, 1011A>T, 1236G>A, 1774C>T, 1896T>C and 1627A>G. The other 7 SNPs were found in introns but only IVS14+1G>A is the intron splice site. There have never been report in 10 SNPs; 967G>A, 1011A>T, 1236G>A, 1774C>T, IVS8–118A>G, IVS8–17A>C, IVS11–15T>C, IVS14–68T>G, IVS14+19C>A and IVS14+134G>T. We found homozygous GG of 1627A>G in 4 patients who had severe toxicities. Statistic significant in actual ANC change and percentage of neutrophil change in homozygous GG (p=.011 and .009) were found. The median nadir ANC of homozygous GG is 399.6 cells/mm3. This SNP cause the amino acid change from isoleucine to valine. Novel heterozygous SNPs (967G>A, 1774C>T) that cause the amino acid change were found in two patients with severe toxicities. Conclusions: 1627A>G, 967G>A, 1774C>T and IVS14+G>A may be the cause of DPD deficiency in Thai patients. The further study needs to establish the functional DPD protein in this population. Ten novel SNPs were discovered in our study. No significant financial relationships to disclose.