Single Nucleotide Polymorphism of Pi-Class Glutathione S-Transferase and Susceptibility to Endometrial Carcinoma

Abstract

Purpose: Endometrial carcinoma is the most common gynecologic cancer in developed countries. Prolonged unopposed estrogen exposure has been identified as the major risk factor. The pi-class glutathione S-transferase (GSTP1) is a phase II metabolic enzyme that is important in the detoxification of a wide range of electrophiles including carcinogenic steroid-hormone intermediates generated through oxidative metabolism. In this study, we aimed at determining the association between the GSTP1 polymorphism and the risk of endometrial carcinoma in a Chinese population. Experimental Design: Genotyping of 180 cases and 200 age-matched controls were assessed by PCR-RFLP approach and confirmed by direct sequencing. Results: Statistical analysis showed that patients of valine allele carriers had 2.03-fold of increased risk of developing endometrial carcinoma (P < 0.01). The allele frequencies for the Ile and Val variants between the cancer cases and controls were also significantly different (P < 0.01; odds ratio, 1.59; 95% confidence interval, 1.13-2.23). Such association was shown in endometrial cancers as a group and in type I endometrioid adenocarcinoma but not the type II nonendometrioid adenocarcinoma. In addition, the Val allele was found significantly associated with high-grade endometrial cancer and/or endometrial cancer of deep myometrial invasion (P < 0.01). Interestingly, the relatively low frequency of Val/Val genotype in both the cancer cases and controls, in parallel with the lower incidence of endometrial cancer in Chinese, was observed when compared with those in Caucasians. Conclusions: Our findings suggested that the GSTP1 Ile 105 Val polymorphism was associated with an increased risk of endometrial cancer. Further studies may be required to explore the possible significance of these polymorphisms on GSTP1-related metabolism that may affect the susceptibility of Asians to endometrial carcinoma.

Exposure to pesticides and heterozygote genotype of GSTP1-Alw26I are associated to Parkinson's disease

“…In this study, with mixed ethnic Brazilian casuistics, the GSTP1-Alw26I polymorphism genotypic distribution is similar to that in the general population, considering distinct racial groups 8,13,14 . Heterozygote genotype (I/V) prevailed among familial or sporadic PD patients, and also in the control group.…”

“…GSTP1 polymorphisms have been first described by Board et al 11 Following studies demonstrated important allelic differences in substrate selectivity, which usually reduces GSTP1 activity 7,12 . GSTP1-Alw26I distribution in population varies among different racial groups, with emphasis on Ile/ Ile genotype around 45 and 65%, followed by Ile/Val from 30 to 45% and Val/Val from 5 to 10%, in Caucasian, Chinese and Korean populations 13 . Transitions of nucleotides 313 (AàG), exon 5, and 341 in exon 6 (GàT) were found, involving 2 substitutions of amino acids in the active site of the enzyme (Ile àVal and Val à Ala).…”

Detection and relevance of germline genetic polymorphisms in glutathione S-transferases (GSTs) in breast cancer patients from northern Indian population

“…Such amino acid substitution may limit free access of the substrate to H-site of the enzyme required for conjugating with glutathione as well as its thermostability [29,30]. However, the exact underlying biological mechanism is not completely understood [31]. As GSTP1 enzyme is effective in detoxifying some epoxides including highly carcinogenic diol-epoxide intermediate from benzo(a)pyrene [32], its absence can be considered a risk factor for slight increased risk for breast cancer as demonstrated in this study.…”

Haplotype-Environment Interactions That Regulate the Human Glutathione S-Transferase P1 Promoter

“…Ten single nucleotide polymorphisms (SNP) have been published in the GSTP1 coding region but only one in the promoter (8,9). Thus far, genetic studies of the human GSTP1 promoter have been largely limited to the identification of essential responsive elements involved in basal gene expression.…”