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Breast Cancer Research and Treatment
Published in: Breast Cancer Research and Treatment 2/2013

01-04-2013 | Epidemiology

A genome-wide association study to identify genetic susceptibility loci that modify ductal and lobular postmenopausal breast cancer risk associated with menopausal hormone therapy use: a two-stage design with replication

Authors: Rebecca Hein, Dieter Flesch-Janys, Norbert Dahmen, Lars Beckmann, Sara Lindström, Nils Schoof, Kamila Czene, Kirstin Mittelstraß, Thomas Illig, Petra Seibold, Sabine Behrens, Keith Humphreys, Jingmei Li, Jianjun Liu, Janet E. Olson, Xianshu Wang, Susan E. Hankinson, Thérèse Truong, Florence Menegaux, Isabel dos Santos Silva, Nichola Johnson, Shou-Tung Chen, Jyh-Cherng Yu, Argyrios Ziogas, Vesa Kataja, Veli-Matti Kosma, Arto Mannermaa, Hoda Anton-Culver, Chen-Yang Shen, Hiltrud Brauch, Julian Peto, Pascal Guénel, Peter Kraft, Fergus J. Couch, Douglas F. Easton, Per Hall, Jenny Chang-Claude, The GENICA Network

Published in: Breast Cancer Research and Treatment | Issue 2/2013

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Abstract

Menopausal hormone therapy (MHT) is associated with an elevated risk of breast cancer in postmenopausal women. To identify genetic loci that modify breast cancer risk related to MHT use in postmenopausal women, we conducted a two-stage genome-wide association study (GWAS) with replication. In stage I, we performed a case-only GWAS in 731 invasive breast cancer cases from the German case-control study Mammary Carcinoma Risk Factor Investigation (MARIE). The 1,200 single nucleotide polymorphisms (SNPs) showing the lowest P values for interaction with current MHT use (within 6 months prior to breast cancer diagnosis), were carried forward to stage II, involving pooled case-control analyses including additional MARIE subjects (1,375 cases, 1,974 controls) as well as 795 cases and 764 controls of a Swedish case-control study. A joint P value was calculated for a combined analysis of stages I and II. Replication of the most significant interaction of the combined stage I and II was performed using 5,795 cases and 5,390 controls from nine studies of the Breast Cancer Association Consortium (BCAC). The combined stage I and II yielded five SNPs on chromosomes 2, 7, and 18 with joint P values <6 × 10−6 for effect modification of current MHT use. The most significant interaction was observed for rs6707272 (P = 3 × 10−7) on chromosome 2 but was not replicated in the BCAC studies (P = 0.21). The potentially modifying SNPs are in strong linkage disequilibrium with SNPs in TRIP12 and DNER on chromosome 2 and SETBP1 on chromosome 18, previously linked to carcinogenesis. However, none of the interaction effects reached genome-wide significance. The inability to replicate the top SNP × MHT interaction may be due to limited power of the replication phase. Our study, however, suggests that there are unlikely to be SNPs that interact strongly enough with MHT use to be clinically significant in European women.
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Literature
1.
Beral V (2003) Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 362(9382):419–427PubMedCrossRef
2.
Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J (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):321–333PubMedCrossRef
3.
Horwitz K, Clarke C (1998) Estrogens and progestins in mammary development and neoplasia. Introduction. J Mammary Gland Biol Neoplasia 3(1):1–2PubMedCrossRef
4.
Zumoff B (1998) Does postmenopausal estrogen administration increase the risk of breast cancer? Contributions of animal, biochemical, and clinical investigative studies to a resolution of the controversy. Proc Soc Exp Biol Med 217(1):30–37PubMed
5.
Poutanen M, Isomaa V, Peltoketo H, Vihko R (1995) Role of 17 beta-hydroxysteroid dehydrogenase type 1 in endocrine and intracrine estradiol biosynthesis. J Steroid Biochem Mol Biol 55(5–6):525–532PubMedCrossRef
6.
Pawlak KJ, Wiebe JP (2007) Regulation of estrogen receptor (ER) levels in MCF-7 cells by progesterone metabolites. J Steroid Biochem Mol Biol 107(3–5):172–179PubMedCrossRef
7.
8.
Wiebe JP, Souter L, Zhang G (2006) Dutasteride affects progesterone metabolizing enzyme activity/expression in human breast cell lines resulting in suppression of cell proliferation and detachment. J Steroid Biochem Mol Biol 100(4–5):129–140PubMedCrossRef
9.
Collaborative Group on Hormonal Factors in Breast Cancer (1997) Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 350(9084):1047–1059CrossRef
10.
Flesch-Janys D, Slanger T, Mutschelknauss E, Kropp S, Obi N, Vettorazzi E, Braendle W, Bastert G, Hentschel S, Berger J, Chang-Claude J (2008) Risk of different histological types of postmenopausal breast cancer by type and regimen of menopausal hormone therapy. Int J Cancer 123(4):933–941PubMedCrossRef
11.
Chlebowski RT, Anderson GL, Gass M, Lane DS, Aragaki AK, Kuller LH, Manson JE, Stefanick ML, Ockene J, Sarto GE, Johnson KC, Wactawski-Wende J, Ravdin PM, Schenken R, Hendrix SL, Rajkovic A, Rohan TE, Yasmeen S, Prentice RL (2010) Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA 304(15):1684–1692PubMedCrossRef
12.
Li CI (2004) Postmenopausal hormone therapy and the risk of breast cancer: the view of an epidemiologist. Maturitas 49(1):44–50PubMedCrossRef
13.
Newcomb PA, Titus-Ernstoff L, Egan KM, Trentham-Dietz A, Baron JA, Storer BE, Willett WC, Stampfer MJ (2002) Postmenopausal estrogen and progestin use in relation to breast cancer risk. Cancer Epidemiol Biomarkers Prev 11(7):593–600PubMed
14.
Ross RK, Paganini-Hill A, Wan PC, Pike MC (2000) Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin. J Natl Cancer Inst 92(4):328–332PubMedCrossRef
15.
Schairer C, Lubin J, Troisi R, Sturgeon S, Brinton L, Hoover R (2000) Menopausal estrogen and estrogen–progestin replacement therapy and breast cancer risk. JAMA 283(4):485–491PubMedCrossRef
16.
Seeger H, Mueck AO (2008) Are the progestins responsible for breast cancer risk during hormone therapy in the postmenopause? Experimental vs. clinical data. J Steroid Biochem Mol Biol 109(1–2):11–15PubMedCrossRef
17.
Shah NR, Borenstein J, Dubois RW (2005) Postmenopausal hormone therapy and breast cancer: a systematic review and meta-analysis. Menopause 12(6):668–678PubMedCrossRef
18.
Rusner C, Bandemer-Greulich U, Engel J, Stegmaier C, Zawinell A, Holleczek B, Katalinic A, Kuss O, Schmidt-Pokrzywniak A, Schubert-Fritschle G, Tillack A, Stang A (2012) Population-based hormone receptor-specific incidence trends of breast cancer in Germany. Maturitas 73(2):152–157PubMedCrossRef
19.
Sprague BL, Trentham-Dietz A, Cronin KA (2012) A sustained decline in postmenopausal hormone use: results from the National Health and Nutrition Examination Survey, 1999–2010. Obstet Gynecol 120(3):595–603PubMedCrossRef
20.
Canfell K, Banks E, Clements M, Kang YJ, Moa A, Armstrong B (2003) Beral V (2009) Sustained lower rates of HRT prescribing and breast cancer incidence in Australia since. Breast Cancer Res Treat 117(3):671–673CrossRef
21.
Hemminki E, Kyyronen P, Pukkala E (2008) Postmenopausal hormone drugs and breast and colon cancer: nordic countries 1995–2005. Maturitas 61(4):299–304PubMedCrossRef
22.
Barnes KM, Dickstein B, Cutler GB Jr, Fojo T, Bates SE (1996) Steroid treatment, accumulation, and antagonism of P-glycoprotein in multidrug-resistant cells. Biochemistry 35(15):4820–4827PubMedCrossRef
23.
Kim WY, Benet LZ (2004) P-glycoprotein (P-gp/MDR1)-mediated efflux of sex-steroid hormones and modulation of P-gp expression in vitro. Pharm Res 21(7):1284–1293PubMedCrossRef
24.
Campa D, Kaaks R, Le ML, Haiman CA, Travis RC, Berg CD, Buring JE, Chanock SJ, Diver WR, Dostal L, Fournier A, Hankinson SE, Henderson BE, Hoover RN, Isaacs C, Johansson M, Kolonel LN, Kraft P, Lee IM, McCarty CA, Overvad K, Panico S, Peeters PH, Riboli E, Sanchez MJ, Schumacher FR, Skeie G, Stram DO, Thun MJ, Trichopoulos D, Zhang S, Ziegler RG, Hunter DJ, Lindstrom S, Canzian F (2011) Interactions between genetic variants and breast cancer risk factors in the breast and prostate cancer cohort consortium. J Natl Cancer Inst 103(16):1252–1263PubMedCrossRef
25.
Kawase T, Matsuo K, Suzuki T, Hiraki A, Watanabe M, Iwata H, Tanaka H, Tajima K (2009) FGFR2 intronic polymorphisms interact with reproductive risk factors of breast cancer: results of a case control study in Japan. Int J Cancer 125(8):1946–1952PubMedCrossRef
26.
Milne RL, Gaudet MM, Spurdle AB, Fasching PA, Couch FJ, Benitez J, rias Perez JI, Zamora MP, Malats N, Dos SS, I, Gibson LJ, Fletcher O, Johnson N, nton-Culver H, Ziogas A, Figueroa J, Brinton L, Sherman ME, Lissowska J, Hopper JL, Dite GS, Apicella C, Southey MC, Sigurdson AJ, Linet MS, Schonfeld SJ, Freedman DM, Mannermaa A, Kosma VM, Kataja V, Auvinen P, Andrulis IL, Glendon G, Knight JA, Weerasooriya N, Cox A, Reed MW, Cross SS, Dunning AM, Ahmed S, Shah M, Brauch H, Ko YD, Bruning T, Lambrechts D, Reumers J, Smeets A, Wang-Gohrke S, Hall P, Czene K, Liu J, Irwanto AK, Chenevix-Trench G, Holland H, Giles GG, Baglietto L, Severi G, Bojensen SE, Nordestgaard BG, Flyger H, John EM, West DW, Whittemore AS, Vachon C, Olson JE, Fredericksen Z, Kosel M, Hein R, Vrieling A, Flesch-Janys D, Heinz J, Beckmann MW, Heusinger K, Ekici AB, Haeberle L, Humphreys MK, Morrison J, Easton DF, Pharoah PD, Garcia-Closas M, Goode EL, Chang-Claude J (2010) Assessing interactions between the associations of common genetic susceptibility variants, reproductive history and body mass index with breast cancer risk in the breast cancer association consortium: a combined case-control study. Breast Cancer Res. 12(6): R110
27.
Prentice RL, Huang Y, Hinds DA, Peters U, Pettinger M, Cox DR, Beilharz E, Chlebowski RT, Rossouw JE, Caan B, Ballinger DG (2009) Variation in the FGFR2 gene and the effects of postmenopausal hormone therapy on invasive breast cancer. Cancer Epidemiol Biomarkers Prev 18(11):3079–3085PubMedCrossRef
28.
Rebbeck TR, DeMichele A, Tran TV, Panossian S, Bunin GR, Troxel AB, Strom BL (2009) Hormone-dependent effects of FGFR2 and MAP3K1 in breast cancer susceptibility in a population-based sample of post-menopausal African-American and European-American women. Carcinogenesis 30(2):269–274PubMedCrossRef
29.
Travis RC, Reeves GK, Green J, Bull D, Tipper SJ, Baker K, Beral V, Peto R, Bell J, Zelenika D, Lathrop M (2010) Gene–environment interactions in 7610 women with breast cancer: prospective evidence from the Million Women Study. Lancet 375(9732):2143–2151PubMedCrossRef
30.
Hein R, Abbas S, Seibold P, Salazar R, Flesch-Janys D, Chang-Claude J (2012) Polymorphism Thr160Thr in SRD5A1, involved in the progesterone metabolism, modifies postmenopausal breast cancer risk associated with menopausal hormone therapy. Breast Cancer Res Treat 131(2):653–661PubMedCrossRef
31.
The MARIE-GENICA Consortium on Genetic Susceptibility for Menopausal Hormone Therapy Related Breast Cancer Risk (2010) Postmenopausal estrogen monotherapy-associated breast cancer risk is modified by CYP17A1_-34_T > C polymorphism. Breast Cancer Res Treat 120(3):737–744CrossRef
32.
The MARIE-GENICA Consortium6 on Genetic Susceptibility for Menopausal Hormone Therapy7 Related Breast Cancer Risk (2010) Genetic polymorphisms in phase I and phase II enzymes and breast cancer risk associated with menopausal hormone therapy in postmenopausal women. Breast Cancer Res Treat 119(2):463–474CrossRef
33.
The MARIE-GENICA Consortium on Genetic Susceptibility for Menopausal Hormone Therapy Related Breast Cancer Risk (2010) Polymorphisms in the BRCA1 and ABCB1 genes modulate menopausal hormone therapy associated breast cancer risk in postmenopausal women. Breast Cancer Res Treat 120(3):727–736CrossRef
34.
The MARIE-GENICA Consortium on Genetic Susceptibility for Menopausal Hormone Therapy Related Breast Cancer Risk (2010) Polymorphisms in genes of the steroid receptor superfamily modify postmenopausal breast cancer risk associated with menopausal hormone therapy. Int J Cancer 126(12):2935–2946
35.
Nickels S, Truong T, Hein R, et al. (2013) Evidence of gene–environment interactions between common breast cancer susceptibility Loci and Established Environmental Risk Factors. PLoS Genet (accepted for publication)
36.
Piegorsch WW, Weinberg CR, Taylor JA (1994) Non-hierarchical logistic models and case-only designs for assessing susceptibility in population-based case-control studies. Stat Med 13(2):153–162PubMedCrossRef
37.
Wedren S, Lovmar L, Humphreys K, Magnusson C, Melhus H, Syvanen AC, Kindmark A, Landegren U, Fermer ML, Stiger F, Persson I, Baron J, Weiderpass E (2004) Oestrogen receptor alpha gene haplotype and postmenopausal breast cancer risk: a case control study. Breast Cancer Res 6(4):R437–R449PubMedCrossRef
38.
Magnusson C, Baron JA, Correia N, Bergstrom R, Adami HO, Persson I (1999) Breast-cancer risk following long-term oestrogen- and oestrogen–progestin-replacement therapy. Int J Cancer 81(3):339–344PubMedCrossRef
39.
Hunter DJ, Kraft P, Jacobs KB, Cox DG, Yeager M, Hankinson SE, Wacholder S, Wang Z, Welch R, Hutchinson A, Wang J, Yu K, Chatterjee N, Orr N, Willett WC, Colditz GA, Ziegler RG, Berg CD, Buys SS, McCarty CA, Feigelson HS, Calle EE, Thun MJ, Hayes RB, Tucker M, Gerhard DS, Fraumeni JF Jr, Hoover RN, Thomas G, Chanock SJ (2007) A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet 39(7):870–874PubMedCrossRef
40.
de Bakker PI, Yelensky R, Pe’er I, Gabriel SB, Daly MJ, Altshuler D (2005) Efficiency and power in genetic association studies. Nat Genet 37(11):1217–1223PubMedCrossRef
41.
Skol AD, Scott LJ, Abecasis GR, Boehnke M (2006) Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies. Nat Genet 38(2):209–213PubMedCrossRef
42.
R Development Core Team R: A Language and Environment for Statistical Computing [Version 2.12.2.] (2011) R Foundation for Statistical Computing
43.
Sun P, Xia S, Lal B, Eberhart CG, Quinones-Hinojosa A, Maciaczyk J, Matsui W, Dimeco F, Piccirillo SM, Vescovi AL, Laterra J (2009) DNER, an epigenetically modulated gene, regulates glioblastoma-derived neurosphere cell differentiation and tumor propagation. Stem Cells 27(7):1473–1486PubMedCrossRef
44.
Park JR, Jung JW, Seo MS, Kang SK, Lee YS, Kang KS (2010) DNER modulates adipogenesis of human adipose tissue-derived mesenchymal stem cells via regulation of cell proliferation. Cell Prolif 43(1):19–28PubMedCrossRef
45.
Thomas G, Jacobs KB, Kraft P, Yeager M, Wacholder S, Cox DG, Hankinson SE, Hutchinson A, Wang Z, Yu K, Chatterjee N, Garcia-Closas M, Gonzalez-Bosquet J, Prokunina-Olsson L, Orr N, Willett WC, Colditz GA, Ziegler RG, Berg CD, Buys SS, McCarty CA, Feigelson HS, Calle EE, Thun MJ, Diver R, Prentice R, Jackson R, Kooperberg C, Chlebowski R, Lissowska J, Peplonska B, Brinton LA, Sigurdson A, Doody M, Bhatti P, Alexander BH, Buring J, Lee IM, Vatten LJ, Hveem K, Kumle M, Hayes RB, Tucker M, Gerhard DS, Fraumeni JF, Jr., Hoover RN, Chanock SJ, Hunter DJ (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): 579–584
46.
47.
Minakuchi M, Kakazu N, Gorrin-Rivas MJ, Abe T, Copeland TD, Ueda K, Adachi Y (2001) Identification and characterization of SEB, a novel protein that binds to the acute undifferentiated leukemia-associated protein SET. Eur J Biochem 268(5):1340–1351PubMedCrossRef
48.
Aschard H, Lutz S, Maus B, Duell EJ, Fingerlin TE, Chatterjee N, Kraft P, Van SK (2012) Challenges and opportunities in genome-wide environmental interaction (GWEI) studies. Hum Genet 131(10):1591–1613PubMedCrossRef
49.
Dempfle A, Scherag A, Hein R, Beckmann L, Chang-Claude J, Schafer H (2008) Gene–environment interactions for complex traits: definitions, methodological requirements and challenges. Eur J Hum Genet 16(10):1164–1172PubMedCrossRef
50.
Hein R, Beckmann L, Chang-Claude J (2008) Sample size requirements for indirect association studies of gene–environment interactions (G × E). Genet Epidemiol 32(3):235–245PubMedCrossRef
51.
Lindstrom S, Yen YC, Spiegelman D, Kraft P (2009) The impact of gene–environment dependence and misclassification in genetic association studies incorporating gene–environment interactions. Hum Hered 68(3):171–181PubMedCrossRef
52.
Morimoto LM, White E, Newcomb PA (2003) Selection bias in the assessment of gene–environment interaction in case-control studies. Am J Epidemiol 158(3):259–263PubMedCrossRef
53.
Wacholder S, Chatterjee N, Hartge P (2002) Joint effect of genes and environment distorted by selection biases: implications for hospital-based case-control studies. Cancer Epidemiol Biomarkers Prev 11(9):885–889PubMed
54.
Gauderman WJ (2002) Sample size requirements for matched case-control studies of gene–environment interaction. Stat Med 21(1):35–50PubMedCrossRef
55.
Kraft P (2008) Curses—winner’s and otherwise—in genetic epidemiology. Epidemiology 19(5):649–651PubMedCrossRef
Metadata
Title
A genome-wide association study to identify genetic susceptibility loci that modify ductal and lobular postmenopausal breast cancer risk associated with menopausal hormone therapy use: a two-stage design with replication
Authors
Rebecca Hein
Dieter Flesch-Janys
Norbert Dahmen
Lars Beckmann
Sara Lindström
Nils Schoof
Kamila Czene
Kirstin Mittelstraß
Thomas Illig
Petra Seibold
Sabine Behrens
Keith Humphreys
Jingmei Li
Jianjun Liu
Janet E. Olson
Xianshu Wang
Susan E. Hankinson
Thérèse Truong
Florence Menegaux
Isabel dos Santos Silva
Nichola Johnson
Shou-Tung Chen
Jyh-Cherng Yu
Argyrios Ziogas
Vesa Kataja
Veli-Matti Kosma
Arto Mannermaa
Hoda Anton-Culver
Chen-Yang Shen
Hiltrud Brauch
Julian Peto
Pascal Guénel
Peter Kraft
Fergus J. Couch
Douglas F. Easton
Per Hall
Jenny Chang-Claude
The GENICA Network
Publication date
01-04-2013
Publisher
Springer US
Published in
Breast Cancer Research and Treatment / Issue 2/2013
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-013-2443-z

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