Skip to main content

Advertisement

SpringerLink
Log in

Associations between CYP19A1 polymorphisms, Native American ancestry, and breast cancer risk and mortality: the Breast Cancer Health Disparities Study

  • Original paper
  • Published:
Cancer Causes & Control Aims and scope Submit manuscript

Abstract

The cytochrome p450 family 19 gene (CYP19A1) encodes for aromatase, which catalyzes the final step in estrogen biosynthesis and conversion of androgens to estrogens. Genetic variation in CYP19A1 is linked to higher circulating estrogen levels and increased aromatase expression. Using data from the Breast Cancer Health Disparities Study, a consortium of three population-based case–control studies in the United States (n = 3,030 non-Hispanic Whites; n = 2,893 Hispanic/Native Americans (H/NA) and Mexico (n = 1,810), we examined influence of 25 CYP19A1 tagging single-nucleotide polymorphisms (SNPs) on breast cancer risk and mortality, considering NA ancestry. Odds ratios (ORs) and 95 % confidence intervals (CIs) and hazard ratios estimated breast cancer risk and mortality. After multiple comparison adjustment, none of the SNPs were significantly associated with breast cancer risk or mortality. Two SNPs remained significantly associated with increased breast cancer risk in women of moderate to high NA ancestry (≥29 %): rs700518, ORGG 1.36, 95 % CI 1.11–1.67 and rs11856927, ORGG 1.35, 95 % CI 1.05–1.72. A significant interaction was observed for rs2470144 and menopausal status (p adj = 0.03); risk was increased in postmenopausal (ORAA 1.22, 95 % CI 1.05–1.14), but not premenopausal (ORAA 0.78, 95 % CI 0.64–0.95) women. The absence of an overall association with CYP19A1 and breast cancer risk is similar to previous literature. However, this analysis provides support that variation in CYP19A1 may influence breast cancer risk differently in women with moderate to high NA ancestry. Additional research is warranted to investigate the how variation in an estrogen-regulating gene contributes to racial/ethnic disparities in breast cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Simpson ER et al (1994) Aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis. Endocr Rev 15(3):342–355

    PubMed  CAS  Google Scholar 

  2. Mahendroo MS et al (1991) Tissue-specific expression of human P-450AROM. The promoter responsible for expression in adipose tissue is different from that utilized in placenta. J Biol Chem 266(17):11276–11281

    PubMed  CAS  Google Scholar 

  3. Hulka BS, Liu ET, Lininger RA (1994) Steroid hormones and risk of breast cancer. Cancer 74(3 Suppl):1111–1124

    Article  PubMed  CAS  Google Scholar 

  4. Eliassen AH et al (2012) Urinary estrogens and estrogen metabolites and subsequent risk of breast cancer among premenopausal women. Cancer Res 72(3):696–706

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  5. Key T et al (2002) Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J Natl Cancer Inst 94(8):606–616

    Article  PubMed  CAS  Google Scholar 

  6. Henderson BE, Ponder B, Ross R (2003) Hormones, genes, and cancer. Oxford University Press, New York 450

    Google Scholar 

  7. Bulun SE et al (1993) A link between breast cancer and local estrogen biosynthesis suggested by quantification of breast adipose tissue aromatase cytochrome P450 transcripts using competitive polymerase chain reaction after reverse transcription. J Clin Endocrinol Metab 77(6):1622–1628

    PubMed  CAS  Google Scholar 

  8. Platet N et al (2004) Estrogens and their receptors in breast cancer progression: a dual role in cancer proliferation and invasion. Crit Rev Oncol Hematol 51(1):55–67

    Article  PubMed  Google Scholar 

  9. Saha Roy S, Vadlamudi RK (2012) Role of estrogen receptor signaling in breast cancer metastasis. Int J Breast Cancer 2012:654698

    Article  PubMed  PubMed Central  Google Scholar 

  10. Dunning AM et al (2004) Polymorphisms associated with circulating sex hormone levels in postmenopausal women. J Natl Cancer Inst 96(12):936–945

    Article  PubMed  CAS  Google Scholar 

  11. Beckmann L et al (2011) Comprehensive analysis of hormone and genetic variation in 36 genes related to steroid hormone metabolism in pre- and postmenopausal women from the breast and prostate cancer cohort consortium (BPC3). J Clin Endocrinol Metab 96(2):E360–E367

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  12. Lundin E et al (2012) Selected polymorphisms in sex hormone-related genes, circulating sex hormones and risk of endometrial cancer. Cancer Epidemiol 36(5):445–452

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  13. Haiman CA et al (2007) Genetic variation at the CYP19A1 locus predicts circulating estrogen levels but not breast cancer risk in postmenopausal women. Cancer Res 67(5):1893–1897

    Article  PubMed  CAS  Google Scholar 

  14. Riancho JA et al (2007) Identification of an aromatase haplotype that is associated with gene expression and postmenopausal osteoporosis. J Clin Endocrinol Metab 92(2):660–665

    Article  PubMed  CAS  Google Scholar 

  15. Clendenen T et al (2013) Genetic variants in hormone-related genes and risk of breast cancer. PLoS ONE 8(7):e69367

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  16. Zhang B et al (2011) Genetic variants associated with breast-cancer risk: comprehensive research synopsis, meta-analysis, and epidemiological evidence. Lancet Oncol 12(5):477–488

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  17. Canzian F et al (2010) Comprehensive analysis of common genetic variation in 61 genes related to steroid hormone and insulin-like growth factor-I metabolism and breast cancer risk in the NCI breast and prostate cancer cohort consortium. Hum Mol Genet 19(19):3873–3884

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  18. Chen C et al (2008) Genetic variation in CYP19A1 and risk of breast cancer and fibrocystic breast conditions among women in Shanghai China. Cancer Epidemiol Biomarkers Prev 17(12):3457–3466

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  19. Kristensen VN et al (2000) Genetic variants of CYP19 (aromatase) and breast cancer risk. Oncogene 19(10):1329–1333

    Article  PubMed  CAS  Google Scholar 

  20. Olson JE et al (2007) A comprehensive examination of CYP19 variation and risk of breast cancer using two haplotype-tagging approaches. Breast Cancer Res Treat 102(2):237–247

    Article  PubMed  PubMed Central  Google Scholar 

  21. Fasching PA et al (2008) Single nucleotide polymorphisms of the aromatase gene (CYP19A1), HER2/neu status, and prognosis in breast cancer patients. Breast Cancer Res Treat 112(1):89–98

    Article  PubMed  CAS  Google Scholar 

  22. Long JR et al (2006) Genetic polymorphisms of the CYP19A1 gene and breast cancer survival. Cancer Epidemiol Biomarkers Prev 15(11):2115–2122

    Article  PubMed  CAS  Google Scholar 

  23. Udler MS et al (2009) Common germline polymorphisms in COMT, CYP19A1, ESR1, PGR, SULT1E1 and STS and survival after a diagnosis of breast cancer. Int J Cancer 125(11):2687–2696

    Article  PubMed  CAS  Google Scholar 

  24. Goode EL et al (2002) Effect of germ-line genetic variation on breast cancer survival in a population-based study. Cancer Res 62(11):3052–3057

    PubMed  CAS  Google Scholar 

  25. Huang CS et al (2008) The CYP19 TTTA repeat polymorphism is related to the prognosis of premenopausal stage I–II and operable stage III breast cancers. Oncologist 13(7):751–760

    Article  PubMed  CAS  Google Scholar 

  26. Kuo SH et al (2013) CYP19 genetic polymorphism haplotype AASA is associated with a poor prognosis in premenopausal women with lymph node-negative, hormone receptor-positive breast cancer. Biomed Res Int 2013:562197

    PubMed  PubMed Central  Google Scholar 

  27. Price AL et al (2007) A genomewide admixture map for Latino populations. Am J Hum Genet 80(6):1024–1036

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  28. Slattery M et al (2012) Genetic variation in genes involved in hormones, inflammation, and energetic factors and breast cancer risk in an admixed population. Carcinogenesis 33(8):1512–1521

  29. Fejerman L et al (2010) European ancestry is positively associated with breast cancer risk in Mexican women. Cancer Epidemiol Biomarkers Prev 19(4):1074–1082

    Article  PubMed  PubMed Central  Google Scholar 

  30. Fejerman L et al (2012) Admixture mapping identifies a locus on 6q25 associated with breast cancer risk in US Latinas. Hum Mol Genet 21(8):1907–1917

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  31. Li CI, Malone KE, Daling JR (2003) Differences in breast cancer stage, treatment, and survival by race and ethnicity. Arch Intern Med 163:49–56

    Article  PubMed  Google Scholar 

  32. Hines LM et al (2010) Comparative analysis of breast cancer risk factors among Hispanic and non-Hispanic white women. Cancer 116(13):3215–3223

    Article  PubMed  PubMed Central  Google Scholar 

  33. Hines LM et al (2011) Ethnic disparities in breast tumor phenotypic subtypes in Hispanic and non-Hispanic white women. J Womens Health (Larchmt) 20(10):1543–1550

    Article  Google Scholar 

  34. Boone SD et al (2014) The joint contribution of tumor phenotype and education to breast cancer survival disparity between Hispanic and non-Hispanic white women. Cancer Causes Control 25(3):273–282

    Article  PubMed  CAS  Google Scholar 

  35. Li R et al (2002) Hormone replacement therapy and breast carcinoma risk in Hispanic and non-Hispanic women. Cancer 95(5):960–968

    Article  PubMed  CAS  Google Scholar 

  36. Gonzalez Burchard E (2005) Latino populations: a unique opportunity for the study of race, genetics, and social environment in epidemiological research. Am J Public Health 95(12):2161–2168

    Article  PubMed  PubMed Central  Google Scholar 

  37. Slattery ML et al (2007) Body size, weight change, fat distribution and breast cancer risk in Hispanic and non-Hispanic white women. Breast Cancer Res Treat 102(1):85–101

    Article  PubMed  Google Scholar 

  38. John EM, Horn-Ross PL, Koo J (2003) Lifetime physical activity and breast cancer risk in a multiethnic population: the San Francisco Bay area breast cancer study. Cancer Epidemiol Biomarkers Prev 12(11 Pt 1):1143–1152

    PubMed  Google Scholar 

  39. John EM et al (2005) Migration history, acculturation, and breast cancer risk in Hispanic women. Cancer Epidemiol Biomarkers Prev 14(12):2905–2913

    Article  PubMed  Google Scholar 

  40. Angeles-Llerenas A et al (2010) Moderate physical activity and breast cancer risk: the effect of menopausal status. Cancer Causes Control 21(4):577–586

    Article  PubMed  Google Scholar 

  41. Carlson CS et al (2004) Selecting a maximally informative set of single-nucleotide polymorphisms for association analyses using linkage disequilibrium. Am J Hum Genet 74(1):106–120

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  42. Stram DO et al (2003) Choosing haplotype-tagging SNPS based on unphased genotype data using a preliminary sample of unrelated subjects with an example from the multiethnic cohort study. Hum Hered 55(1):27–36

    Article  PubMed  Google Scholar 

  43. Collins-Schramm HE et al (2004) Mexican American ancestry-informative markers: examination of population structure and marker characteristics in European Americans, Mexican Americans Amerindians and Asians. Hum Genet 114(3):263–271

    Article  PubMed  Google Scholar 

  44. WHO (1992) International statistical classification of diseases and related health problems (10th revision). World Health Organization, Geneva

  45. Pritchard JK, Stephens M, Donnelly P (2000) Inference of population structure using multilocus genotype data. Genetics 155(2):945–959

    PubMed  CAS  PubMed Central  Google Scholar 

  46. Dubin N, Pasternack BS (1986) Risk assessment for case–control subgroups by polychotomous logistic regression. Am J Epidemiol 123(6):1101–1117

    PubMed  CAS  Google Scholar 

  47. Hosmer D Jr, Lemeshow S (1989) Applied logistic regression. Probability and mathematical statistics. Wiley, New York

    Google Scholar 

  48. Bursac Z et al (2008) Purposeful selection of variables in logistic regression. Source Code Biol Med 3:17

    Article  PubMed  PubMed Central  Google Scholar 

  49. Holm S (1979) A simple sequentially rejective multiple test procedure. Scand J Stat 6:65–70

    Google Scholar 

  50. Nyholt DR (2004) A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other. Am J Hum Genet 74(4):765–769

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  51. Li J, Ji L (2005) Adjusting multiple testing in multilocus analyses using the eigenvalues of a correlation matrix. Heredity (Edinb) 95(3):221–227

    Article  CAS  Google Scholar 

  52. Yue W et al (1998) In situ aromatization enhances breast tumor estradiol levels and cellular proliferation. Cancer Res 58(5):927–932

    PubMed  CAS  Google Scholar 

  53. Talbott KE et al (2008) A CYP19 (aromatase) polymorphism is associated with increased premenopausal breast cancer risk. Breast Cancer Res Treat 111(3):481–487

    Article  PubMed  CAS  Google Scholar 

  54. Zins K et al (2014) Analysis of the rs10046 polymorphism of aromatase (CYP19) in premenopausal onset of human breast cancer. Int J Mol Sci 15(1):712–724

    Article  PubMed  PubMed Central  Google Scholar 

  55. Haiman CA et al (2002) No association between a single nucleotide polymorphism in CYP19 and breast cancer risk. Cancer Epidemiol Biomarkers Prev 11(2):215–216

    PubMed  CAS  Google Scholar 

  56. Haiman CA et al (2000) A tetranucleotide repeat polymorphism in CYP19 and breast cancer risk. Int J Cancer 87(2):204–210

    Article  PubMed  CAS  Google Scholar 

  57. Haiman CA et al (2003) A comprehensive haplotype analysis of CYP19 and breast cancer risk: the multiethnic cohort. Hum Mol Genet 12(20):2679–2692

    Article  PubMed  CAS  Google Scholar 

  58. Reding KW et al (2012) Estrogen-related genes and their contribution to racial differences in breast cancer risk. Cancer Causes Control 23(5):671–681

    Article  PubMed  PubMed Central  Google Scholar 

  59. Yoshimoto N et al (2011) Genetic and environmental predictors, endogenous hormones and growth factors, and risk of estrogen receptor-positive breast cancer in Japanese women. Cancer Sci 102(11):2065–2072

    Article  PubMed  CAS  Google Scholar 

  60. Diergaarde B et al (2008) Polymorphisms in genes involved in sex hormone metabolism, estrogen plus progestin hormone therapy use, and risk of postmenopausal breast cancer. Cancer Epidemiol Biomarkers Prev 17(7):1751–1759

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  61. Johnson AD et al (2008) SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap. Bioinformatics 24(24):2938–2939

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  62. International HapMap C (2003) The International HapMap Project. Nature 426(6968):789–796

    Article  Google Scholar 

  63. Pineda B et al (2013) Associations between aromatase CYP19 rs10046 polymorphism and breast cancer risk: from a case–control to a meta-analysis of 20,098 subjects. PLoS One 8(1):e53902

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  64. Zhang L et al (2009) Association of genetic polymorphisms of ER-alpha and the estradiol-synthesizing enzyme genes CYP17 and CYP19 with breast cancer risk in Chinese women. Breast Cancer Res Treat 114(2):327–338

    Article  PubMed  CAS  Google Scholar 

  65. Miron L et al (2012) Research on aromatase gene (CYP19A1) polymorphisms as a predictor of endocrine therapy effectiveness in breast cancer. Rev Med Chir Soc Med Nat Iasi 116(4):997–1004

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We would also like to acknowledge the contributions of the following individuals to the study: Sandra Edwards for data harmonization oversight; Erica Wolff and Michael Hoffman for laboratory support; Carolina Ortega for her assistance with data management for the Mexico Breast Cancer Study, Jocelyn Koo for data management for the San Francisco Bay Area Breast Cancer Study, Dr. Tim Byers for his contribution to the 4-Corner’s Breast Cancer Study, and Dr. Josh Galanter for assistance in selection of AIMs markers. The Breast Cancer Health Disparities Study was funded by Grant CA14002 from the National Cancer Institute to Dr. Slattery. The San Francisco Bay Area Breast Cancer Study was supported by Grants CA63446 and CA77305 from the National Cancer Institute, Grant DAMD17-96-1-6071 from the U.S. Department of Defense and Grant 7PB-0068 from the California Breast Cancer Research Program. The collection of cancer incidence data used in this study was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885; the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program under contract HHSN261201000036C awarded to the Cancer Prevention Institute of California; and the Centers for Disease Control and Prevention’s National Program of Cancer Registries, under agreement #1U58 DP000807-01 awarded to the Public Health Institute. The 4-Corners Breast Cancer Study was funded by Grants CA078682, CA078762, CA078552, and CA078802 from the National Cancer Institute. The research also was supported by the Utah Cancer Registry, which is funded by contract N01-PC-67000 from the National Cancer Institute, with additional support from the State of Utah Department of Health, the New Mexico Tumor Registry, and the Arizona and Colorado cancer registries, funded by the Centers for Disease Control and Prevention National Program of Cancer Registries and additional state support. The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official view of the National Cancer Institute or endorsement by the State of California Department of Public Health, the National Cancer Institute, and the Centers for Disease Control and Prevention or their Contractors and Subcontractors. The Mexico Breast Cancer Study was funded by Consejo Nacional de Ciencia y Tecnología (CONACyT) (SALUD-2002-C01-7462).

Author information

Authors and Affiliations

  1. Department of Epidemiology and Population Health, James Graham Brown Cancer Center, School of Public Health and Information Sciences, University of Louisville, 485 E. Gray St., Louisville, KY, 40202, USA

    Stephanie D. Boone, Kathy B. Baumgartner, Richard N. Baumgartner & Avonne E. Connor

  2. Department of Bioinformatics and Biostatistics, James Graham Brown Cancer Center, School of Public Health and Information Sciences, University of Louisville, Louisville, KY, USA

    Christina M. Pinkston & Shesh N. Rai

  3. Department of Medicine-Oncology and Hematology, James Graham Brown Cancer Center, School of Medicine, University of Louisville, Louisville, KY, USA

    Elizabeth C. Riley

  4. Department of Biology, University of Colorado, Colorado Springs, Colorado Springs, CO, USA

    Lisa M. Hines

  5. H. Lee Moffit Cancer Center and Research Institute, Tampa, FL, USA

    Anna R. Giuliano

  6. Cancer Prevention Institute of California, Fremont, CA, USA

    Esther M. John

  7. Division of Epidemiology, Department of Health Research and Policy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA

    Esther M. John

  8. Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA, USA

    Mariana C. Stern

  9. Centro de Investigación en Salud Poblacional, Instituto Nacional de Salud Pública, Cuernavaca, Morelos, Mexico

    Gabriela Torres-Mejía

  10. Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA

    Roger K. Wolff & Martha L. Slattery

Authors
  1. Stephanie D. Boone
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kathy B. Baumgartner
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Richard N. Baumgartner
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Avonne E. Connor
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Christina M. Pinkston
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shesh N. Rai
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Elizabeth C. Riley
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Lisa M. Hines
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Anna R. Giuliano
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Esther M. John
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Mariana C. Stern
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Gabriela Torres-Mejía
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Roger K. Wolff
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Martha L. Slattery
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stephanie D. Boone.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (XLSX 16 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Boone, S.D., Baumgartner, K.B., Baumgartner, R.N. et al. Associations between CYP19A1 polymorphisms, Native American ancestry, and breast cancer risk and mortality: the Breast Cancer Health Disparities Study. Cancer Causes Control 25, 1461–1471 (2014). https://doi.org/10.1007/s10552-014-0448-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10552-014-0448-5

Keywords

Search

Navigation