CEBP Translational Cancer Medicine 2008: Cancer Clinical Trials and Personalized Medicine
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Cancer Epidemiology Biomarkers & Prevention Vol. 11, 215-216, February 2002
© 2002 American Association for Cancer Research

Null Results in Brief

No Association between a Single Nucleotide Polymorphism in CYP19 and Breast Cancer Risk1

Christopher A. Haiman, Susan E. Hankinson, Donna Spiegelman, Myles Brown and David J. Hunter2

Department of Epidemiology, Harvard School of Public Health [C. A. H., S. E. H., D. S., D. J. H.], Department of Medicine, Brigham and Women’s Hospital [S. E. H., M. B., D. J. H.], and the Department of Adult Oncology, Dana-Farber Cancer Institute [M. B.], Boston, Massachusetts 02115


   Introduction
Top
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
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.


   Materials and Methods
Top
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
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.


   Results
Top
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
No association was observed between CYP19 genotype and breast cancer risk (Table 1)Citation , 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)Citation . 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.


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  		Table 1 The relationship between CYP19 genotype, breast cancer risk, and steroid hormone levels

 

   Discussion
Top
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
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.


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


   Footnotes
 
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. Back

2 To whom requests for reprints should be addressed, at Channing Laboratory, 181 Longwood Avenue, Boston, Massachusetts 02115. Back

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). Back

Received 8/24/01; revised 11/14/01; accepted 12/ 3/01.


   References
Top
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Kristensen V. N., Anderson T. I., Lindblom L., Erikstein B., Magnus P., Börrensen-Dale A. L. A rare CYP19 (aromatase) variant may increase the risk of breast cancer. Pharmacogenetics, 8: 43-48, 1998.[Medline]
  2. Haiman C. A., Hankinson S. E., Spiegelman D., De Vivo I., Colditz G. A., Willett W. C., Speizer F. E., Hunter D. J. A tetranucleotide repeat polymorphism in CYP19 and breast cancer risk. Int. J. Cancer, 87: 204-210, 2000.[Medline]
  3. Siegelmann-Danielli N., Buetow K. H. Constitutional genetic variation at the human aromatase gene (CYP19) and breast cancer risk. Br. J. Cancer, 79: 456-463, 1999.[Medline]
  4. Kristensen V. N., Harada N., Haraldsen E., Yoshimura N., Lönning P. E., Erikstein B., Käresen R., Kristensen T., Börresen-Dale A. L. Genetic variants of CYP19 (aromatase) and breast cancer risk. Oncogene, 19: 1329-1333, 2000.[Medline]



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HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Cell Growth & Differentiation