Sequence Variability and Candidate Gene Analysis in Two Cancer Patients with Complex Clinical Outcomes During Morphine Therapy

Abstract

This article is available online at http://dmd.aspetjournals.org ABSTRACT:In this case report, we present genetic differences in two morphine-related gene sequences, UDP-glucuronosyltransferase 2B7 (UGT2B7) and opioid receptors (MOR1), in two cancer patients whose clinical responses to morphine were very different [i.e., sensitive (patient 1) and low responder (patient 2)]. In addition, allelic variants in the UGT2B7 gene were analyzed in 46 Japanese individuals. Amplified DNA fragments for the two genes of interest were screened using single strand conformation polymorphism and then sequenced. In the UGT2B7 gene, 12 single nucleotide polymorphisms (SNPs) were newly identified with an allelic frequency ranging from 0.022 to 0.978. Six SNPs in the promoter region (A-1302G, T-1295C, T-1111C, G-899A, A-327G, and T-125C) and two coding SNPs (UGT2B7*2 in exon 2 and C1059G in exon 4) appeared to be consistently linked. Remarkable differences in the nucleotide sequence of UGT2B7 were observed between the two patients; in contrast to patient 1 who had "reference" alleles at almost SNP positions, but a rare ATTGAT*2(AT)C haplotype as homozygosity, patient 2 was a homozygous carrier for the predominant GCCAGC*1(TC)G sequence. Serum morphine and two glucuronide concentrations in patient 2 suggest that the predominant GCCAGC*1G sequence was not associated with a "poor metabolizer" phenotype. In the MOR1 gene, patient 1 had no SNPs, whereas patient 2 was a heterozygous carrier for both the G-1784A and A118G alleles. The present study describes substantial differences in genotype patterns of two genes of interest between the two patients. The results necessitate larger trials to confirm these observations in larger case control studies.

Prevalence of UGT1A9 and UGT2B7 nonsynonymous single nucleotide polymorphisms in West African, Papua New Guinean, and North American populations

“…Finally, we did not observe the variant allele 1192A in any study sample, suggesting that 1192A is a rare allele. Overall, our results are in accordance with the results of previous studies that 802T is the most common UGT2B7 nonsynonymous SNP in various populations [18][19][20][21][22].…”

“…Our data regarding 802C>T frequency in Caucasian-Americans are concordant with previous findings [21,22]. However, the frequency was higher (41%) in our Asian-Americans compared with Japanese (24.4-29.3%) [18][19][20][21] and another Asian population from North America (26.6%) [22], suggesting ethnic and spatial differences, respectively. The allele 211T was observed only in two North American ethnic groups, 9% in Asian-American [n=13/83 (all heterozygous), n=1/83 (homozygous)] and 2% in Hispanic-American (n=4/87, heterozygous).…”

“…The frequency of 211G>T in Asian-Americans was significantly higher (P=0.05, Fisher'sexact test) than the frequency in Hispanic-Americans. However, the frequency was lower (9%) in our AsianAmericans compared with Japanese populations (14.8-18.5%) [18][19][20], suggesting ethnic differences. Finally, we did not observe the variant allele 1192A in any study sample, suggesting that 1192A is a rare allele.…”

“…These are: 211G>T (A71S, exon-1), 802C>T (H268Y, exon-2), and 1192G>A (D398N, exon-5) (http://galien.pha.ulaval.ca/labocg/alleles/UGT2B/UGT2B7.htm). The reported frequencies of these polymorphisms are: 211G>T (14.8-18.5%, Japanese) [18][19][20], 802C>T (24.4-29.3%, Japanese; 48.9-53.7%, Caucasians) [18][19][20][21][22], and 1192G>A (<1%, Japanese) [19].…”

“…Recently, pharmaco-vigilance of artemisinin-based combination therapy in Africa has been suggested in order to assess the safety of these drugs when used widely [23]. Unfortunately, only limited information is available regarding UGT1A9 and UGT2B7 pharmacogenetic variations in various populations; the information pertains mainly to Caucasian and Japanese populations [14,15,[18][19][20][21][22]. Here, for the first time, we present a comprehensive account of UGT1A9 and UGT2B7 nonsynonymous SNPs in populations from two different malaria-endemic regions, West Africa (Ghana, Guinea, Ivory Coast, Sierra Leone, and Senegal) and PNG, and in four major North American ethnic groups (Caucasian, African, Asian, and Hispanic).…”