Cancer Causes & Control

, Volume 21, Issue 6, pp 897–908 | Cite as

Genetic variation in sex-steroid receptors and synthesizing enzymes and colorectal cancer risk in women

  • Jennifer Lin
  • Robert Y. L. Zee
  • Kuang-Yu Liu
  • Shumin M. Zhang
  • I-Min Lee
  • JoAnn E. Manson
  • Edward Giovannucci
  • Julie E. Buring
  • Nancy R. Cook
Original paper

Abstract

Objectives

Several lines of evidence have suggested that female hormones may lower the risk for developing colorectal cancer. However, the mechanisms by which sex hormones affect colorectal cancer development remain unknown. We sought to determine whether the association may be under genetic control by evaluating genetic variation in estrogen receptors (ESR1 and ESR2), progesterone receptor (PGR), aromatase cytochrome 450 enzyme (CYP19A1), and 17 beta-hydroxysteroid dehydrogenase type 2 gene (HSD17B2).

Methods

We included 158 incident cases of colorectal cancer and 563 randomly chosen control subjects from 28,345 women in the Women’s Health Study aged 45 or older who provided blood samples and had no history of cancer or cardiovascular disease at baseline in 1993. All cases and controls were Caucasians of European descent. A total of 63 tagging and putative functional SNPs in the 5 genes were included for analysis. Unconditional logistic regression was used to estimate odds ratio (ORs) and 95% confidence intervals (CIs).

Results

There was no association between variation in ESR1, ESR2, PGR, CYP19A1 and HSD17B2 and colorectal cancer risk after correction for multiple comparisons (p values after correction ≥0.25). There was also no association with any of the haplotypes examined (p ≥ 0.15) and no evidence of joint effects of variants in the 5 genes (p ≥ 0.51).

Conclusion

Our data offer insufficient support for an association between variation in ESR1, ESR2, PGR, CYP19A1, and HSD17B2 and risk for developing colorectal cancer.

Keywords

Sex hormone genes Colorectal cancer Estrogen receptors Progesterone receptor HSD17B2 CYP19A1 

Notes

Acknowledgments

The work was supported by grants CA112529 and CA47988, and from the National Cancer Institute, and grant HL43851 and HL080467 from the National Heart, Lung, and Blood Institute. We would like to thank the entire staff of the WHS under the leadership of David Gordon, as well as Mary Breen, Susan Burt, Marilyn Chown, Georgina Friedenberg, Inge Judge, Jean Mac-Fadyean, Geneva McNair, David Potter, Claire Ridge, and Harriet Samuelson. We also acknowledge the Endpoints Committee of the WHS (Dr. Wendy Y Chen, Jim Taylor, and Til Stürmer) and Anna Klevak for technical assistance with the manuscript.

Supplementary material

10552_2010_9518_MOESM1_ESM.pdf (42 kb)
Supplementary material 1 (PDF 41 kb)

References

  1. 1.
    Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T et al (2008) Cancer statistics, 2008. CA Cancer J Clin 58(2):71–96CrossRefPubMedGoogle Scholar
  2. 2.
    Froggatt NJ, Green J, Brassett C, Evans DG, Bishop DT, Kolodner R et al (1999) A common MSH2 mutation in English and North American HNPCC families: origin, phenotypic expression, and sex specific differences in colorectal cancer. J Med Genet 36(2):97–102PubMedGoogle Scholar
  3. 3.
    Ochiai M, Watanabe M, Kushida H, Wakabayashi K, Sugimura T, Nagao M (1996) DNA adduct formation, cell proliferation and aberrant crypt focus formation induced by PhIP in male and female rat colon with relevance to carcinogenesis. Carcinogenesis 17(1):95–98CrossRefPubMedGoogle Scholar
  4. 4.
    Odagiri E, Jibiki K, Kato Y, Nakamura S, Oda S, Demura R et al (1985) Steroid receptors in dimethylhydrazine-induced colon carcinogenesis. Cancer 56(11):2627–2634CrossRefPubMedGoogle Scholar
  5. 5.
    Gershbein LL (1993) Action of estrogen and adrenocorticoids on adenocarcinoma induction by 1,2-dimethylhydrazine in male rats. Res Commun Chem Pathol Pharmacol 81(1):117–120PubMedGoogle Scholar
  6. 6.
    Calle EE, Miracle-McMahill HL, Thun MJ, Heath CW Jr (1995) Estrogen replacement therapy and risk of fatal colon cancer in a prospective cohort of postmenopausal women. J Natl Cancer Inst 87(7):517–523CrossRefPubMedGoogle Scholar
  7. 7.
    Potter JD, McMichael AJ (1983) Large bowel cancer in women in relation to reproductive and hormonal factors: a case-control study. J Natl Cancer Inst 71(4):703–709PubMedGoogle Scholar
  8. 8.
    Kune GA, Kune S, Watson LF (1989) Children, age at first birth, and colorectal cancer risk data from the Melbourne Colorectal Cancer Study. Am J Epidemiol 129(3):533–542PubMedGoogle Scholar
  9. 9.
    Singh S, Langman MJ (1995) Oestrogen and colonic epithelial cell growth. Gut 37(6):737–739CrossRefPubMedGoogle Scholar
  10. 10.
    Narisawa T, Magadia NE, Weisburger JH, Wynder EL (1974) Promoting effect of bile acids on colon carcinogenesis after intrarectal instillation of N-methyl-N′-nitro-N-nitrosoguanidine in rats. J Natl Cancer Inst 53(4):1093–1097PubMedGoogle Scholar
  11. 11.
    McMichael AJ, Potter JD (1985) Host factors in carcinogenesis: certain bile-acid metabolic profiles that selectively increase the risk of proximal colon cancer. J Natl Cancer Inst 75(2):185–191PubMedGoogle Scholar
  12. 12.
    McMichael AJ, Potter JD (1980) Reproduction, endogenous and exogenous sex hormones, and colon cancer: a review and hypothesis. J Natl Cancer Inst 65(6):1201–1207PubMedGoogle Scholar
  13. 13.
    Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML et al (2002) Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. Jama 288(3):321–333CrossRefPubMedGoogle Scholar
  14. 14.
    Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H et al (2004) Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. Jama 291(14):1701–1712CrossRefPubMedGoogle Scholar
  15. 15.
    Gunter MJ, Hoover DR, Yu H, Wassertheil-Smoller S, Rohan TE, Manson JE et al (2008) Insulin, insulin-like growth factor-I, endogenous estradiol, and risk of colorectal cancer in postmenopausal women. Cancer Res 68(1):329–337CrossRefPubMedGoogle Scholar
  16. 16.
    Clendenen TV, Koenig KL, Shore RE, Levitz M, Arslan AA, Zeleniuch-Jacquotte A (2009) Postmenopausal levels of endogenous sex hormones and risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev 18(1):275–281CrossRefPubMedGoogle Scholar
  17. 17.
    Giovannucci E (2002) Obesity, gender, and colon cancer. Gut 51(2):147CrossRefPubMedGoogle Scholar
  18. 18.
    Enmark E, Gustafsson JA (1999) Oestrogen receptors—an overview. J Intern Med 246(2):133–138CrossRefPubMedGoogle Scholar
  19. 19.
    Campbell-Thompson M, Lynch IJ, Bhardwaj B (2001) Expression of estrogen receptor (ER) subtypes and ERbeta isoforms in colon cancer. Cancer Res 61(2):632–640PubMedGoogle Scholar
  20. 20.
    Kono S, Honjo S, Todoroki I, Nishiwaki M, Hamada H, Nishikawa H et al (1998) Glucose intolerance and adenomas of the sigmoid colon in Japanese men (Japan). Cancer Causes Control 9(4):441–446CrossRefPubMedGoogle Scholar
  21. 21.
    Jassam N, Bell SM, Speirs V, Quirke P (2005) Loss of expression of oestrogen receptor beta in colon cancer and its association with Dukes’ staging. Oncol Rep 14(1):17–21PubMedGoogle Scholar
  22. 22.
    Issa JP, Ottaviano YL, Celano P, Hamilton SR, Davidson NE, Baylin SB (1994) Methylation of the oestrogen receptor CpG island links ageing and neoplasia in human colon. Nat Genet 7(4):536–540CrossRefPubMedGoogle Scholar
  23. 23.
    Di Leo A, Linsalata M, Cavallini A, Messa C, Russo F (1992) Sex steroid hormone receptors, epidermal growth factor receptor, and polyamines in human colorectal cancer. Dis Colon Rectum 35(4):305–309CrossRefPubMedGoogle Scholar
  24. 24.
    Singh S, Sheppard MC, Langman MJ (1993) Sex differences in the incidence of colorectal cancer: an exploration of oestrogen and progesterone receptors. Gut 34(5):611–615CrossRefPubMedGoogle Scholar
  25. 25.
    Oshima CT, Wonraht DR, Catarino RM, Mattos D, Forones NM (1999) Estrogen and progesterone receptors in gastric and colorectal cancer. Hepatogastroenterology 46(30):3155–3158PubMedGoogle Scholar
  26. 26.
    Berta L, Fronticelli Baldelli C, Fazzari A, Radice E, Bargoni A, Frairia R et al (2003) Sex steroid receptors, secondary bile acids and colorectal cancer. A possible mechanism of interaction. Panminerva Med 45(4):261–266PubMedGoogle Scholar
  27. 27.
    Kaklamanos IG, Bathe OF, Franceschi D, Lazaris AC, Davaris P, Glinatsis M et al (1999) Expression of receptors for estrogen and progesterone in malignant colonic mucosa as a prognostic factor for patient survival. J Surg Oncol 72(4):225–229CrossRefPubMedGoogle Scholar
  28. 28.
    Fiorelli G, Picariello L, Martineti V, Tonelli F, Brandi ML (1999) Estrogen synthesis in human colon cancer epithelial cells. J Steroid Biochem Mol Biol 71(5–6):223–230CrossRefPubMedGoogle Scholar
  29. 29.
    Means GD, Mahendroo MS, Corbin CJ, Mathis JM, Powell FE, Mendelson CR et al (1989) Structural analysis of the gene encoding human aromatase cytochrome P-450, the enzyme responsible for estrogen biosynthesis. J Biol Chem 264(32):19385–19391PubMedGoogle Scholar
  30. 30.
    Clemons M, Goss P (2001) Estrogen and the risk of breast cancer. N Engl J Med 344(4):276–285CrossRefPubMedGoogle Scholar
  31. 31.
    Speer G, Cseh K, Winkler G, Takacs I, Barna I, Nagy Z et al (2001) Oestrogen and vitamin D receptor (VDR) genotypes and the expression of ErbB-2 and EGF receptor in human rectal cancers. Eur J Cancer 37(12):1463–1468CrossRefPubMedGoogle Scholar
  32. 32.
    Slattery ML, Sweeney C, Murtaugh M, Ma KN, Wolff RK, Potter JD et al (2005) Associations between ERalpha, ERbeta, and AR genotypes and colon and rectal cancer. Cancer Epidemiol Biomarkers Prev 14(12):2936–2942CrossRefPubMedGoogle Scholar
  33. 33.
    Bethke L, Webb E, Sellick G, Rudd M, Penegar S, Withey L et al (2007) Polymorphisms in the cytochrome P450 genes CYP1A2, CYP1B1, CYP3A4, CYP3A5, CYP11A1, CYP17A1, CYP19A1 and colorectal cancer risk. BMC Cancer 7:123CrossRefPubMedGoogle Scholar
  34. 34.
    Tomlinson I, Webb E, Carvajal-Carmona L, Broderick P, Kemp Z, Spain S et al (2007) A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21. Nat Genet 39(8):984–988CrossRefPubMedGoogle Scholar
  35. 35.
    Zanke BW, Greenwood CM, Rangrej J, Kustra R, Tenesa A, Farrington SM et al (2007) Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24. Nat Genet 39(8):989–994CrossRefPubMedGoogle Scholar
  36. 36.
    Tomlinson IP, Webb E, Carvajal-Carmona L, Broderick P, Howarth K, Pittman AM et al (2008) A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3. Nat Genet 40(5):623–630CrossRefPubMedGoogle Scholar
  37. 37.
    Tenesa A, Farrington SM, Prendergast JG, Porteous ME, Walker M, Haq N et al (2008) Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21. Nat Genet 40(5):631–637CrossRefPubMedGoogle Scholar
  38. 38.
    Jaeger E, Webb E, Howarth K, Carvajal-Carmona L, Rowan A, Broderick P et al (2008) Common genetic variants at the CRAC1 (HMPS) locus on chromosome 15q13.3 influence colorectal cancer risk. Nat Genet 40(1):26–28CrossRefPubMedGoogle Scholar
  39. 39.
    Broderick P, Carvajal-Carmona L, Pittman AM, Webb E, Howarth K, Rowan A et al (2007) A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk. Nat Genet 39(11):1315–1317CrossRefPubMedGoogle Scholar
  40. 40.
    Zhang SM, Buring JE, Lee IM, Cook NR, Ridker PM (2005) C-reactive protein levels are not associated with increased risk for colorectal cancer in women. Ann Intern Med 142(6):425–432PubMedGoogle Scholar
  41. 41.
    Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21(2):263–265CrossRefPubMedGoogle Scholar
  42. 42.
    Haiman CA, Stram DO, Pike MC, Kolonel LN, Burtt NP, Altshuler D et al (2003) A comprehensive haplotype analysis of CYP19 and breast cancer risk: the Multiethnic Cohort. Hum Mol Genet 12(20):2679–2692CrossRefPubMedGoogle Scholar
  43. 43.
    Pearce CL, Hirschhorn JN, Wu AH, Burtt NP, Stram DO, Young S et al (2005) Clarifying the PROGINS allele association in ovarian and breast cancer risk: a haplotype-based analysis. J Natl Cancer Inst 97(1):51–59PubMedGoogle Scholar
  44. 44.
    Cox DG, Bretsky P, Kraft P, Pharoah P, Albanes D, Altshuler D et al (2008) Haplotypes of the estrogen receptor beta gene and breast cancer risk. Int J Cancer 122(2):387–392CrossRefPubMedGoogle Scholar
  45. 45.
    Fallin D, Schork NJ (2000) Accuracy of haplotype frequency estimation for biallelic loci, via the expectation-maximization algorithm for unphased diploid genotype data. Am J Hum Genet 67(4):947–959CrossRefPubMedGoogle Scholar
  46. 46.
    Zaykin DV, Westfall PH, Young SS, Karnoub MA, Wagner MJ, Ehm MG (2002) Testing association of statistically inferred haplotypes with discrete and continuous traits in samples of unrelated individuals. Hum Hered 53(2):79–91CrossRefPubMedGoogle Scholar
  47. 47.
    Kraft P, Cox DG, Paynter RA, Hunter D, De Vivo I (2005) Accounting for haplotype uncertainty in matched association studies: a comparison of simple and flexible techniques. Genet Epidemiol 28(3):261–272CrossRefPubMedGoogle Scholar
  48. 48.
    Ritchie MD, Hahn LW, Moore JH (2003) Power of multifactor dimensionality reduction for detecting gene-gene interactions in the presence of genotyping error, missing data, phenocopy, and genetic heterogeneity. Genet Epidemiol 24(2):150–157CrossRefPubMedGoogle Scholar
  49. 49.
    Hahn LW, Ritchie MD, Moore JH (2003) Multifactor dimensionality reduction software for detecting gene-gene and gene-environment interactions. Bioinformatics 19(3):376–382CrossRefPubMedGoogle Scholar
  50. 50.
    Moore JH (2004) Computational analysis of gene-gene interactions using multifactor dimensionality reduction. Expert Rev Mol Diagn 4(6):795–803CrossRefPubMedGoogle Scholar
  51. 51.
    Benjamini Y, Yekutieli D (2005) Quantitative trait loci analysis using the false discovery rate. Genetics 171(2):783–790CrossRefPubMedGoogle Scholar
  52. 52.
    Hankinson SE, Willett WC, Manson JE, Colditz GA, Hunter DJ, Spiegelman D et al (1998) Plasma sex steroid hormone levels and risk of breast cancer in postmenopausal women. J Natl Cancer Inst 90(17):1292–1299CrossRefPubMedGoogle Scholar
  53. 53.
    Zeleniuch-Jacquotte A, Bruning PF, Bonfrer JM, Koenig KL, Shore RE, Kim MY et al (1997) Relation of serum levels of testosterone and dehydroepiandrosterone sulfate to risk of breast cancer in postmenopausal women. Am J Epidemiol 145(11):1030–1038PubMedGoogle Scholar
  54. 54.
    Kaaks R, Rinaldi S, Key TJ, Berrino F, Peeters PH, Biessy C et al (2005) Postmenopausal serum androgens, oestrogens and breast cancer risk: the European prospective investigation into cancer and nutrition. Endocr Relat Cancer 12(4):1071–1082CrossRefPubMedGoogle Scholar
  55. 55.
    Haiman CA, Dossus L, Setiawan VW, Stram DO, Dunning AM, Thomas G 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):1893–1897CrossRefPubMedGoogle Scholar
  56. 56.
    Dunning AM, Dowsett M, Healey CS, Tee L, Luben RN, Folkerd E et al (2004) Polymorphisms associated with circulating sex hormone levels in postmenopausal women. J Natl Cancer Inst 96(12):936–945PubMedCrossRefGoogle Scholar
  57. 57.
    Easton DF, Pooley KA, Dunning AM, Pharoah PD, Thompson D, Ballinger DG et al (2007) Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447(7148):1087–1093CrossRefPubMedGoogle Scholar
  58. 58.
    Hunter DJ, Kraft P, Jacobs KB, Cox DG, Yeager M, Hankinson SE et al (2007) A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet 39(7):870–874CrossRefPubMedGoogle Scholar
  59. 59.
    Schumacher FR, Feigelson HS, Cox DG, Haiman CA, Albanes D, Buring J et al (2007) A common 8q24 variant in prostate and breast cancer from a large nested case-control study. Cancer Res 67(7):2951–2956CrossRefPubMedGoogle Scholar
  60. 60.
    Stacey SN, Manolescu A, Sulem P, Rafnar T, Gudmundsson J, Gudjonsson SA et al (2007) Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet 39(7):865–869CrossRefPubMedGoogle Scholar
  61. 61.
    Thomas G, Jacobs KB, Kraft P, Yeager M, Wacholder S, Cox DG et al (2009) A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1). Nat Genet 41(5):579–584CrossRefPubMedGoogle Scholar
  62. 62.
    Zheng W, Long J, Gao YT, Li C, Zheng Y, Xiang YB et al (2009) Genome-wide association study identifies a new breast cancer susceptibility locus at 6q25.1. Nat Genet 41(3):324–328CrossRefPubMedGoogle Scholar
  63. 63.
    Dunning AM, Healey CS, Baynes C, Maia AT, Scollen S, Vega A et al (2009) Association of ESR1 gene tagging SNPs with breast cancer risk. Hum Mol Genet 18(6):1131–1139CrossRefPubMedGoogle Scholar
  64. 64.
    Chung CC, Magalhaes W, Gonzalez-Bosquet J, Chanock SJ (2009) Genome-wide association studies in cancer—current and future directions. CarcinogenesisGoogle Scholar
  65. 65.
    Watters JJ, Campbell JS, Cunningham MJ, Krebs EG, Dorsa DM (1997) Rapid membrane effects of steroids in neuroblastoma cells: effects of estrogen on mitogen activated protein kinase signalling cascade and c-fos immediate early gene transcription. Endocrinology 138(9):4030–4033CrossRefPubMedGoogle Scholar
  66. 66.
    Gilad LA, Bresler T, Gnainsky J, Smirnoff P, Schwartz B (2005) Regulation of vitamin D receptor expression via estrogen-induced activation of the ERK 1/2 signaling pathway in colon and breast cancer cells. J Endocrinol 185(3):577–592CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  • Jennifer Lin
    • 1
  • Robert Y. L. Zee
    • 1
  • Kuang-Yu Liu
    • 2
  • Shumin M. Zhang
    • 1
  • I-Min Lee
    • 1
    • 3
  • JoAnn E. Manson
    • 1
    • 3
  • Edward Giovannucci
    • 3
    • 4
  • Julie E. Buring
    • 1
    • 3
    • 5
  • Nancy R. Cook
    • 1
    • 3
  1. 1.Division of Preventive Medicine, Department of MedicineBrigham and Women’s Hospital and Harvard Medical SchoolBostonUSA
  2. 2.Department of Anesthesiology, Perioperative and Pain MedicineBrigham and Women’s Hospital and Harvard Medical SchoolBostonUSA
  3. 3.Department of EpidemiologyHarvard School of Public HealthBostonUSA
  4. 4.Department of NutritionHarvard School of Public HealthBostonUSA
  5. 5.Department of Ambulatory Care and PreventionBrigham and Women’s Hospital and Harvard Medical SchoolBostonUSA

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