Genetic polymorphisms of cytochrome P450 19 and 1B1, alcohol use, and breast cancer risk in Korean women

Abstract

A case -control study was performed to assess the potential influence of CYP19 Arg 264 Cys and CYP1B1 Leu 432 Val polymorphisms on breast cancer risk in a series of Korean breast cancer patients and controls. The results suggest that the CYP19 Arg 264 Cys polymorphism modifies breast cancer risk (OR ¼ 1.5, 95% CI ¼ 1.1 -2.2), especially in association with alcohol consumption (P for interaction ¼ 0.04), whereas the CYP1B1 Leu 432 Val polymorphism appears to play no role here. Breast cancer is the second most frequent cancer in Korean women and its incidence is increasing (Yoo et al, 1998). Lifetime cumulative exposure to oestrogens is known as the most important risk factor for breast cancer (Yager, 2000). A variety of different enzymes are involved in the synthesis of oestrogen from cholesterol and further metabolism of oestrogen (Thompsen and Ambrosone, 2000). Polymorphisms of genes encoding for these proteins are regarded as the candidates for elevated breast cancer risk.The CYP19 gene encodes aromatase, which catalyses the formation of oestrogens from testosterone and androstenedione. To date, several polymorphisms have been found in the CYP19 gene (i.e. Polymeropulous et al, 1991;Sourdaine et al, 1994;Siegelmann-Danieli and Buetow, 1999;Healey et al, 2000;Miyoshi et al, 2000). One of these, a C-to-T variation in exon 7 resulting in an Arg 264 Cys amino-acid exchange, has been shown to be very common in Asians (Watanabe et al, 1997;Miyoshi et al, 2000) and could thus be an important modifier of breast cancer risk in this ethnic group.The CYP1B1 enzyme is known to be involved in the formation of 4-hydroxyoestradiol, which is a catechol metabolite of oestrogen (Hayes et al, 1996). A C-to-G variation in exon 3 of the CYP1B1 gene results in a Leu 432 Val amino-acid exchange. The Leu/Leu genotype has been associated with increased breast cancer risk in an Asian population (Zheng et al, 2000) but controversial results have been reported as well (Bailey et al, 1998;Watanabe et al, 2000).In this study, we have evaluated the potential influence of CYP19 Arg 264 Cys and CYP1B1 Leu 432 Val polymorphisms on the breast cancer risk among Korean women as an extension of our previous work in this study population (Park et al, 2000;Yim et al, 2001). MATERIALS AND METHODS Study subjectsThe criteria of subject selection and details of data collection on lifestyle have been described elsewhere (Park et al, 2000;Yim et al, 2001). Eligible study population consisted of 389 incident breast cancer cases and 346 controls with no other known cancer or systemic disease, admitted in 1995 -2001 to three teaching hospitals located in Seoul, Korea (Seoul National University Hospital, Borame Hospital, and Asan Medical Center). Each patient was frequency-matched to one control in the following age groups : under 30, 30 -34, 35 -39, 40 -44, 45 -49, 50 -54, 55 -59, 60 -69, and over 70 years; 288 cases and 288 controls were selected and genotyped for CYP19. Informed consents were obtained at the time of blood withdrawal. Information on demogr...

Genetic Polymorphisms of the CYP19A1 Gene and Breast Cancer Survival

“…This SNP results in amino acid changes from Arg to Cys, which may lead to a difference in enzyme activity. Although no reports are available about the relationship between this polymorphism and breast cancer progression, several studies have reported a relationship between the Cys allele and increased breast cancer risk, with odds ratios (95% CIs) of 2.4 (1.0-5.5) in Hawaiians (10), 1.4 (1.1-1.9) in Japanese women (10), and 1.5 (1.1-2.2) in Korean women (27), although no association was observed in Caucasians (28) or another Japanese population (29). We did not find any apparent associations with breast cancer survival through haplotype analyses for the SNPs located in block 4, nor did the Multiethnic Cohort Study for breast cancer risk (10).…”

CYP19 gene polymorphisms and the susceptibility to breast cancer in Xinjiang Uigur women

“…Aromatase, which is encoded by CYP19, is a key enzyme for transforming androgen into estrogen. Specifically, it catalyzes the transformation of androstendion and testosterone into estrone and estradiol, respectively (Miyoshi et al, 2000;Lee et al, 2003;Song et al, 2006a), and thereby influences the synthesis of estrogen (Figure 4). Estrogen levels have a close relationship with breast cancer.…”

Polymorphisms and haplotypes of the gene encoding the estrogen-metabolizing CYP19 gene in Korean women: no association with advanced-stage endometriosis

“…The CYP19 gene has several polymorphisms: a [TTTA]n tetranucleotide repeat polymorphism in intron 4 (Healey et al 2000;Kristensen et al 2000), a 115T>C polymorphism in exon 2 (Trp39Arg) (Miyoshi et al 2000), a silent 240A>G polymorphism at codon 80 in exon 3 (Siegelmann-Danieli and Buetow 1999), a 790C>T polymorphism in exon 8 (Arg264Cys) (Toda et al 1990;Kristensen et al 2000;Lee et al 2003), and a 1531C>T polymorphism in the 3¢ untranslated region of exon 10 (Sourdaine et al 1994). CYP19 gene polymorphisms are reportedly associated with estrogen-dependent diseases, such as uterine myoma, endometriosis, breast cancer, and endometrial cancer (Hirose et al 2004;Bulun et al 2005;Paynter et al 2005).…”