Genetic polymorphisms in CYP19 have been hypothesized to alter aromatase activity and have been examined in relationship with breast cancer risk (1, 2, 3, 4). A greater frequency of tetranucleotide (TTTA)n repeat alleles in intron 4 have been reported among affected women (1,2). In a Scandinavian case-control study (cases/controls, 481/236) Kristensen et al. (4) observed a positive association between a SNP3 (C → T) in the untranslated region of exon 10 and risk of breast cancer (TT versus CC genotypes; OR, 2.00; 95% CI, 1.28–3.11), and a greater frequency of the TT genotype among women with larger and more advanced tumors. We assessed the association between CYP19 genotype, breast cancer risk, and endogenous steroid hormone levels in the prospective Nurses’ Health Study.

Detailed information regarding the design of this nested case-control study (cases, n = 461; controls, n = 619) has been published previously (2). CYP19 genotyping analysis was performed by the Taqman Allelic Discrimination method (Applied Biosystems, Foster City, CA). ORs and 95% CIs were calculated using conditional and unconditional logistic regression and were adjusted for established breast cancer risk factors (2). Linear regression models were used to evaluate associations between genotype and circulating hormone levels among controls, controlling for age, body mass index, and laboratory batch.

No association was observed between CYP19 genotype and breast cancer risk (Table 1), or between genotype and established breast cancer risk factors. We did not observe the TT genotype to be overrepresented among cases with more advanced disease (4+ involved nodes: CT: OR, 0.7; 95% CI, 0.3–1.8; TT: OR, 1.0; 95% CI; 0.4–2.5). In addition, the TT genotype was not significantly overrepresented among larger tumors (>2 versus ≤2 cm, 32 versus 25%; P = 0.2) or tumors positive for the estrogen or progesterone receptor (data not shown). Linkage disequilibrium was observed between the T nucleotide and (TTTA)n repeats 8–13 (P < 0.001). We observed no significant interactions between the T allele and established breast cancer risk factors. Among postmenopausal controls, estrogen levels were not elevated among T allele carriers (Table 1). However, compared to noncarriers, women with the T allele had significantly lower levels of testosterone, androstenedione, DHEA, and DHEAS, and a significantly greater E1:A ratio.

We did not observe an association between the C → T SNP in exon 10 of CYP19 and breast cancer risk among Caucasian women. We had 86% power to detect a significant relative risk as low as 1.75 for homozygous carriers of the T allele compared with women with the CC genotype. In addition, our results do not provide support for the previous observation that the T allele is associated with larger, more advanced tumors. We were unable to demonstrate that the positive associations reported between rare tetranucleotide repeat alleles and breast cancer risk previously described by us (2) and Kristensen et al. (1) can be accounted for by this SNP in exon 10. However, the decrease in androgen levels and greater E1:A ratio support the hypothesis that the T allele may have elevated aromatase activity.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

        
1

Supported by NIH Grants CA40356, CA49449, and CA65725. M. B. is supported by NIH Grant CA57374.

                
3

The abbreviations used are: SNP, single nucleotide polymorphism; DHEA, dehydroepiandrosterone; DHEAS, DHEA sulfate; OR, odds ratio; CI, confidence interval; E1:A, estrone:androstenedione (ratio).

Table 1

The relationship between CYP19 genotype, breast cancer risk, and steroid hormone levels

CYP19 genotype, n (%)P trend
CCCTTT
Cases 103 (22) 240 (52) 118 (26)  
Controls 134 (22) 310 (51) 167 (27)  
OR (95% CI)a 1.0 0.96 0.87  
  (0.69–1.34) (0.60–1.27)  
Hormone (n = 51–60) (n = 140–154) (n = 77–85)  
 Estrone sulfate (pg/ml) 208.8 173.9b 199.9 0.88 
 Estrone (pg/ml) 29.0 27.1 28.4 0.91 
 Estradiol (pg/ml) 7.2 7.1 7.6 0.38 
 Testosterone (ng/dl) 23.5 20.1c 19.2b 0.04 
 Androstenedione (ng/dl) 63.7 53.6b 51.1b 0.02 
 DHEA (ng/dl) 226.2 182.3b 162.8d 0.004 
 DHEAS (μg/dl) 89.3 73.1c 64.2d 0.008 
 E1:A × 10 4.6 5.0 5.3b 0.04 
CYP19 genotype, n (%)P trend
CCCTTT
Cases 103 (22) 240 (52) 118 (26)  
Controls 134 (22) 310 (51) 167 (27)  
OR (95% CI)a 1.0 0.96 0.87  
  (0.69–1.34) (0.60–1.27)  
Hormone (n = 51–60) (n = 140–154) (n = 77–85)  
 Estrone sulfate (pg/ml) 208.8 173.9b 199.9 0.88 
 Estrone (pg/ml) 29.0 27.1 28.4 0.91 
 Estradiol (pg/ml) 7.2 7.1 7.6 0.38 
 Testosterone (ng/dl) 23.5 20.1c 19.2b 0.04 
 Androstenedione (ng/dl) 63.7 53.6b 51.1b 0.02 
 DHEA (ng/dl) 226.2 182.3b 162.8d 0.004 
 DHEAS (μg/dl) 89.3 73.1c 64.2d 0.008 
 E1:A × 10 4.6 5.0 5.3b 0.04 
a

Estimated by conditional logistic regression and adjusted for established breast cancer risk factors.

b

P ≤ 0.05.

c

P ≤ 0.10.

d

P ≤ 0.01.

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We are indebted to the participants of the Nurses’ Health Study for their dedication and commitment.

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