© 2005 Oxford University Press
CORRESPONDENCE |
RESPONSE: Re: Polymorphisms Associated With Circulating Sex Hormone Levels in Postmenopausal Women
Affiliations of authors: Cancer Research–UK Department of Oncology (AMD, CSH, PDPP, BEJP) and European Prospective Investigation of Cancer (RNL, NED), and Cancer Research–UK Genetic Epidemiology Group University of Cambridge (DFE), Strangeways Research Laboratory, Cambridge, UK; Academic Department of Biochemistry, Royal Marsden Hospital, London, UK (MD, EF)
Correspondence to: Alison Dunning, PhD, Cancer Research–UK Department of Oncology, Strangeway’s Research Laboratory, Wort's Causeway, Cambridge, CB1 8RN UK (e–mail: alisond{at}srl.cam.ac.uk)
De Castro et al. have studied the response of 213 premenopausal women to gonadotrophin releasing hormone agonist (GnRHa) in relation to genotype at several single nucleotide polymorphisms (SNPs) in hormone signaling and metabolism genes. For the CYP19 3'untranslated region (UTR) t–c SNP (rs10046), they report an association between the c allele and circulating estradiol levels opposite to the one we recently reported in 1975 postmenopausal women (1), although they do not present the mean values observed in each genotype class for comparison. They argue that the opposing results may be due to SNP rs10046 acting as a marker for functional alleles in the multiple CYP19 gene promoters and that these promoters may be activated differently in pre- and postmenopausal women.
From our data we calculated that we would expect a 5–10% relative increase in the risk of breast cancer due to an increase in mean circulating estradiol level from 15.0 pmol/L (cc genotype) to 17.1 pmol/L (tt genotype). In our breast cancer case–control study (N = 2635 case patients and 3630 control subjects), we observed an odds ratio of 1.07 (95% confidence interval = 0.96 to 1.19) (1) for risk of breast cancer in women with the cc genotype versus those with the tt genotype. To investigate the suggestion of De Castro et al. that there should be different odds ratios in pre- and postmenopausal women, we determined the menopausal status for 2309 case patients and 3614 control subjects (Table 1). The genotype distribution between pre- and postmenopausal case patients (
2 = 1.6, P = .45, 2 degrees of freedom) is similar. The estimated odds ratios for the two groups are also similar and are both consistent with the predicted 5–10% relative increase from the effect of circulating hormone levels (1) (although they are also consistent with no association between genotypes and breast cancer risk).
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Thus, we do not have any evidence for a differential effect of SNP rs10046 in risk of pre- versus postmenopausal breast cancer. Moreover, Haiman et al. (2) demonstrate that multiple promoter exons of CYP19 fall into four different linkage disequilibrium blocks, with recombination occurring rarely between each block. Hence, rs10046, which is in block 4, is unlikely to be a good marker for promoter variants in blocks 1, 2, and 3, as proposed by De Castro et al. In addition, Kristensen et al. (3) reported that the c allele of rs10046 is associated with reduced CYP19 RNA levels, which would lead in turn to low CYP19 levels and activity. Therefore, the 3'UTR SNP c allele appears to be a likely cause of the differences observed in circulating estradiol levels in postmenopausal women in our study. The association of the rs10046 SNP allele with circulating estradiol levels reported by De Castro et al. may reflect a response to GnRHa treatment, rather than natural variation in estradiol levels.
REFERENCES
1 Dunning AM, Dowsett M, Healey CS, Tee L, Luben RN, Folkerd K, et al. polymorphisms associated with circulating sex hormone levels in postmenopausal women. J Natl Cancer Inst 2004;96:936–45.
2 Haiman CA, Stram DO, Pike MC, Kolonel LN, Burtt NP, Altshuler D et al. A comprehensive haplotype analysis of CYP19 and breast cancer risk: the Multiethnic cohort. Hum Mol Genet 2003;12:2679–92.
3 Kristensen VN, Harada N, Yoshimura N, Haraldsen E, Lonning PE, Erikstein B et al.Genetic variants of CYP19 (aromatase) and breast cancer risk. Oncogene 2000;19:1329–33.[CrossRef][Web of Science][Medline]
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J Natl Cancer Inst 2005 97: 152-153.
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