Abstract
Background
Numerous studies point to a positive relationship between elevated levels of estrogens and increased risk of breast. Androgens are converted to estrogens by the aromatase enzyme, which is encoded by the CYP19 gene. We recently published resequencing data on 88 polymorphisms identified in that gene. The hypothesis tested in this study was that polymorphisms, or haplotypes, in CYP19 are related to risk of breast cancer.
Methods
Incident cases of breast cancer were identified through the Division of Medical Oncology at the Mayo Clinic in Rochester, MN. Controls were patients visiting Mayo for an annual medical examination. Controls were frequency matched to cases based on age and region of residence. Tag-polymorphisms were selected using 2 methods: (1) 12 variants using the tag-selection method of Carlson et al. (Am J Hum Genet 74:106–120, 2004); and (2) 12 variants using the haplotype method of Stram (Genet Epidemiol 27:365–374, 2004). Six SNPs were selected by both methods. Genotyping was conducted using SNPStream, TaqMan and RFLP analyses. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI). Analyses were conducted among all cases and controls, or stratified by estrogen receptor alpha (ER) status and/or menopausal status.
Results
A total of 750 cases (60% postmenopausal) and 732 controls (75% postmenopausal) were included. No association with breast cancer risk was detected for individual variants, selected tagSNPs or hap-tag SNPs despite 80% power to detect OR as low as 1.49 for minor allele frequency (MAF) of 0.10. Similarly, stratified analyses based on ER status or menopausal status failed to detect any association with breast cancer risk.
Conclusion
These analyses suggest that variants of CYP19 are not associated with risk of breast cancer.
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Yager JD, Davidson NE (2006) Estrogen carcinogenesis in breast cancer. N Engl J Med 354:270–282
Clemons M, Goss P (2001) Estrogen and the risk of breast cancer. N Engl J Med 344:276–285
Key TJ, Appleby PN et al (2003) Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. J Natl Cancer Inst 95:1218–1226
Rosner B, Colditz GA (1996) Nurses’ health study: log-incidence mathematical model of breast cancer incidence. J Natl Cancer Inst 88:359–364
Paffenbarger RS Jr, Kampert JB et al (1980) Characteristics that predict risk of breast cancer before and after the menopause. Am J Epidemiol 112:258–268
Ingle JN, Suman VJ (2005) Aromatase inhibitors for therapy of advanced breast cancer. J Steroid Biochem Mol Biol 95:113–119
Ingle JN (2006) Adjuvant endocrine therapy for postmenopausal women with early breast cancer. Clin Cancer Res 12:1031s–1036s
Cavalieri E, Frenkel K et al (2000) Estrogens as endogenous genotoxic agents—DNA adducts and mutations. J Natl Cancer Inst Monogr 75–93
Santen RJ, Yue W et al.(2004) Estradiol-induced carcinogenesis via formation of genotoxic metabolites. Advances in endocrine therapy of breast cancer. Proceedings of the 2003 Gleneagles conference. New York, NY, Marcel Dekker, pp 13–177
Kristensen VN, Andersen TI et al (1998) A rare CYP19 (aromatase) variant may increase the risk of breast cancer. Pharmacogenetics 8:43–48
Haiman CA, Hankinson SE et al (2000) A tetranucleotide repeat polymorphism in CYP19 and breast cancer risk. Int J Cancer 87:204–210
Siegelmann-Danieli N, Buetow KH (1999) Constitutional genetic variation at the human aromatase gene (Cyp19) and breast cancer risk. Br J Cancer 79:456–463
Baxter SW, Choong DY et al (2001) Polymorphic variation in CYP19 and the risk of breast cancer. Carcinogenesis 22:347–349
Miyoshi Y, Ando A et al (2003) Association of genetic polymorphisms in CYP19 and CYP1A1 with the oestrogen receptor-positive breast cancer risk. Eur J Cancer 39:2531–2537
Probst-Hensch NM, Ingles SA et al (1999) Aromatase and breast cancer susceptibility. Endocr Relat Cancer 6:165–173
Thyagarajan B, Brott M et al (2004) CYP1B1 and CYP19 gene polymorphisms and breast cancer incidence: no association in the ARIC study. Cancer Lett 207:183–189
Kristensen VN, Harada N et al (2000) Genetic variants of CYP19 (aromatase) and breast cancer risk. Oncogene 19:1329–1333
Haiman CA, Hankinson SE et al (2002) No association between a single nucleotide polymorphism in CYP19 and breast cancer risk. Cancer Epidemiol Biomarkers Prev 11:215–216
Ma CX, Adjei AA et al (2005) Human aromatase: gene resequencing and functional genomics. Cancer Res 65:11071–11082
Carlson CS, Eberle MA et al (2004) Selecting a maximally informative set of single-nucleotide polymorphisms for association analyses using linkage disequilibrium. Am J Hum Genet 74:106–120
Stram DO (2004) Tag SNP selection for association studies. Genet Epidemiol 27:365–374
Bell PA, Chaturvedi S et al (2002) SNPstream UHT: ultra-high throughput SNP genotyping for pharmacogenomics and drug discovery. Biotechniques Suppl: 70–72, 74, 76–77
Denomme GA, Van Oene M (2005) High-throughput multiplex single-nucleotide polymorphism analysis for red cell and platelet antigen genotypes. Transfusion 45:660–666
Schaid DJ, Rowland CM et al (2002) Score tests for association between traits and haplotypes when linkage phase is ambiguous. Am J Hum Genet 70:425–434
Armitage P (1955) Tests for linear trends in proportions and frequencies. Biometrics 11:375–386
Acknowledgements
This work was supported by grants from the National Cancer Institute P01 CA 82267, P50 CA116201 and the National Institute of General Medical Sciences R01 GM28157, R01 GM35720, and U01 GM 61388 (The Pharmacogenetics Research Network)
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Olson, J.E., Ingle, J.N., Ma, C.X. et al. A comprehensive examination of CYP19 variation and risk of breast cancer using two haplotype-tagging approaches. Breast Cancer Res Treat 102, 237–247 (2007). https://doi.org/10.1007/s10549-006-9324-7
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DOI: https://doi.org/10.1007/s10549-006-9324-7