Genetic polymorphisms of estrogen metabolizing enzyme and breast cancer risk in Thai women

Abstract

Estrogen and its metabolites are believed to play important roles in breast cancer, and its determinants include both genetic and lifestyle factors. The objective of the study is to investigate the association of breast cancer risk in Thailand with genetic polymorphisms in several genes involved in estrogen synthesis and metabolism. Five hundred and seventy patients with histopathologically confirmed breast cancer and 497 controls were included in the present study. Forty single nucleotide polymorphisms (SNPs) in the CYP1A1, CYP1A2, CYP1B1, CYP17, CYP19, CYP2C9, CYP2C19, AhR, ESR1, PGR, ERRG, COMT, HSD17B1, HSD17B2, EPHX1 and NQO1 genes were genotyped. Association of genotypes with breast cancer risk was evaluated using multivariate logistic regression, which suggested an altered risk for the following SNPs [gene, odds ratio (OR) . In addition, a stratified analysis by menopausal status indicated that the association of the CYP1A2 (rs762551) and CYP17 (rs743572) polymorphisms with breast cancer risk were mainly evident in premenopausal, while ERRG (rs1857407) was significant in postmenopausal women. These findings suggest that CYP1A2, CYP2C19, AhR, ERRG and CYP17 polymorphisms may play an important role in estrogen metabolism and modify individual susceptibility to breast cancer in Thai women. ' UICCKey words: breast cancer; estrogen metabolizing enzyme; single nucleotide polymorphisms Much of the variability in global breast cancer rates has been attributed to country-specific differences in the prevalence of risk factors that determine lifetime exposure to estrogen. Comparatively younger ages at menarche, older ages at first birth and/or menopause and a higher prevalence of postmenopausal obesity have been proposed as explanations for the disparate breast cancer incidence rates among American Caucasian (97/100,000) and Asian women (27/100,000).1,2 Cross cultural differences in height, diet, alcohol consumption and exogenous estrogen use are also believed to contribute to international differences, but to a lesser extent. 3,4 Age-specific breast cancer incidence also varies between high-and low-risk countries: the mean age at diagnosis in developing countries is lower than that for European and American populations.It can be hypothesized that estrogen metabolites contribute to the activation of the estrogen receptor and the generation of DNAdamaging molecular species. 5 The genes involved in the disposition of female sex hormones are well known, and include COMT (catechol-O-methyltransferase), HSD17B1 (17 b-hydroxysteroid dehydrogenase type 1), HSD17B2, ESR a (estrogen receptor a), PGR (progesterone receptor), ERRG (estrogen-related receptor g), NQO1 (NADPH quinine oxoreductase), EPHX1 (epoxide hydrolase), AhR (aryl hydrocarbon receptor a) and members of the cytochrome P450 family including CYP1A1, CYP1A2, CYP1B1, CYP17, CYP19, CYP2C9 and CYP2C19.Because Asian women have, on average, a 20% lower serum estradiol level than Western women, 6 it is possible that the effects of genetic polymorphisms of estrogen-...

Lack of association between the aryl hydrocarbon receptor rs2066853 polymorphism and breast cancer: A meta-analysis on Ahr polymorphism and breast cancer

“…Sangrajrang et al (2009) found that among the women in Thailand, GA heterozygotes of Ahr (rs2066853) increased the risk of breast cancer, while in Chinese women, this polymorph showed the contrary influence on the risk of breast cancer (Sangrajrang et al, 2006). However, neither of such findings was replicated in other studies including those included in this meta-analysis.…”

“…Two studies did not show sufficient information on Ahr (rs2066853) polymorphism (Georgitsi et al, 2007;Tan et al, 2010). Therefore, a total of three individual studies (Le Marchand et al, 2005;Long et al, 2006;Sangrajrang et al, 2009) were included in this meta-analysis. Data from 2999 patients and 3050 controls were obtained from the included.…”

“…Ahr is a key regulator of transcriptional expression for cytochrome P450 (Sangrajrang et al, 2009). Ahr rs2066853 (Arg554Lys) is located in exon 10, a region that encompasses a major portion of the trans-activation domain of this gene (Long et al, 2006).…”

REV1 Genetic Polymorphisms and Breast Cancer Risk in Thai Women

“…Study population: Ascertainment of the cases and controls and their demographic characteristics were described previously (14,15). Brie‰y, cases were all new incident breast cancer patients histologically diagnosed at the National Cancer Institute in Bangkok and at the hospital in Khon Kaen province of North Eastern of ).…”

“…We also reported the genetic polymorphisms in estrogen, alcohol and folate metabolism enzyme (14,15). In this study, we present data on the association between REV1 polymorphisms and breast cancer risk in a case-control study of Thai women.…”