Affiliations of authors: H. Jernström, Centre for Research in Women's Health, Toronto, ON, Canada, and The Jubileum Institute, Department of Oncology, University Hospital, Lund, Sweden; D. Vesprini, S. A. Narod, Centre for Research in Women's Health, Toronto; H. L. Bradlow, Strang Cancer Research Laboratory, New York, NY.
Correspondence to: Steven A. Narod, M.D., FRCPC, Centre for Research in Women's Health, 790 Bay St., 7th floor, Toronto, ON, M5G 1N8 Canada (e-mail: steven.narod{at}swchsc.on.ca).
Spurdle et al. (1) reported a positive association between the CC genotype of the CYP17 gene and the risk of breast cancer in young Australian women. This polymorphism is the result of a T to C transition in the 5` untranslated region of the gene. Among women with breast cancer and a first- or second-degree relative with breast cancer, 23% had a CC variant compared with 11% in control subjects (two-sided P = .006). CYP17 encodes for the cytochrome P450c17 enzyme, which catalyzes reactions at several key points in estradiol synthesis. The 5` promoter polymorphism may influence promoter activity and, thereby, influence CYP17 expression and estradiol biosynthesis.
Premenopausal nulliparous women with the CC genotype have higher mean levels of serum estradiol than women with the TT genotype [reviewed in (2)]. The CC genotype has been associated with early-onset breast cancer in two studies (1,3). However, larger studies of predominantly postmenopausal women with breast cancer [reviewed in (2)] have failed to find an association.
The relative abundance of different types of estrogen may be more relevant to carcinogenesis than the specific levels of individual hormones. In particular, 2-hydroxyestrone (2OHE) is less potent than the 16-hydroxyestrone (16
OHE) form. Two prospective studies (4,5) have reported that a low urinary ratio of 2OHE to 16
OHE increased the subsequent risk of both premenopausal and postmenopausal breast cancers.
To evaluate a possible relationship between the CYP17 genotype and the urinary ratio of 2OHE to 16OHE, we determined the genotype of 494 nulliparous women, aged 1735 years, in Toronto, ON, Canada. The protocol was approved by the University of Toronto Ethics Committee. Written informed consent was obtained from all of the women. Three hundred thirty-eight women were white, 76 women were Asian, 26 women were IndianPakistani, 13 women were black, and 41 women were of other or mixed ethnicity. Two hundred fifteen women used combined oral contraceptives. CYP17 genotyping and measuring of the 2OHE and 16
OHE in urine were carried out according to previously described methods (6,7). The values of the ratio were not distributed normally; therefore, a nonparametric test (MannWhitney U test) was used for univariate analyses.
The 2OHE-to-16OHE urinary ratio was highest in women with the TT genotype (median = 1.47), was intermediate in women with the TC genotype (1.38; P = .36 compared with TT), and was lowest in women with the CC genotype (1.21; P = .01 compared with TT). After adjustment for current oral contraceptive use, age, body mass index, current smoking, and ethnic group, the ratio was lower in women with the CC genotype than in women with either the TT or the TC genotype (P = .02). The difference in the median ratio between the TT and CC genotypes was greater for women who were not using the oral contraceptive pills (1.64 versus 1.35; P = .01) than for women who were using the pills (1.26 versus 1.08; P = .14) (Fig. 1
). A family history of breast cancer in a first- or second-degree relative was not more common among women with the CC genotype (19%) than among women with other (TC and TT combined) genotypes (22%; P = .62).
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NOTES
Editor's note: Spurdle et al. declined to respond to the correspondence of Jernström et al.
Supported by Svenska Läkeresällskapet (Swedish Society for Medicine), the Murray and Isabella Rayburn fund, and the Canadian Breast Cancer Research Initiative Streams of Excellence.
REFERENCES
1
Spurdle AB, Hopper JL, Dite GS, Chen X, Cui J, McCredie MR, et al. CYP17 promoter polymorphism and breast cancer in Australian women under age forty years. J Natl Cancer Inst 2000;92:167481.
2 Thompson PA, Ambrosone C. Molecular epidemiology of genetic polymorphisms in estrogen metabolizing enzymes in human breast cancer. J Natl Cancer Inst Monogr 2000;27:12534.[Medline]
3 Bergman-Jungestrom M, Gentile M, Lundin AC, Wingren S. Association between CYP17 gene polymorphism and risk of breast cancer in young women. Int J Cancer 1999;84:3503.[Medline]
4 Meilahn EN, De Stavola B, Allen DS, Fentiman I, Bradlow HL, Sepkovic DW, et al. Do urinary oestrogen metabolites predict breast cancer? Guernsey III cohort follow-up. Br J Cancer 1998;78:12505.[Medline]
5 Muti P, Bradlow HL, Micheli A, Krogh V, Freudenheim JL, Schunemann HJ, et al. Estrogen metabolism and risk of breast cancer: a prospective study of the 2 : 16alpha-hydroxyestrone ratio in premenopausal and postmenopausal women. Epidemiology 2000;11:63540.[Medline]
6 Carey AH, Waterworth D, Patel K, White D, Little J, Novelli P, et al. Polycystic ovaries and premature male pattern baldness are associated with one allele of the steroid metabolism gene CYP17. Hum Mol Genet 1994;3:18736.[Abstract]
7 Klug TL, Bradlow HL, Sepkovic DW. Monoclonal antibody-based enzyme immunoassay for simultaneous quantitation of 2- and 16 alpha-hydroxyestrone in urine. Steroids 1994;59:64855.[Medline]
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