Abstract
The transcription factor 7-like 2 (TCF7L2) gene is part of the Wnt/β-catenin signaling pathway and plays a critical role in cell development and growth regulation. TCF7L2 variants rs12255372 and rs7903146 have been associated with risk of Type 2 diabetes. Few epidemiological studies have examined the association between TCF7L2 and breast cancer risk. We investigated the associations between 25 TCF7L2 single nucleotide polymorphisms (SNPs) and breast cancer in Hispanic and non-Hispanic white (NHW) women from the 4-Corner’s Breast Cancer Study, the San Francisco Bay Area Breast Cancer Study, and the Mexico Breast Cancer Study. A total of 4,703 Hispanic (2,093 cases, 2,610 controls) and 3,031 NHW (1,431 cases, 1,600 controls) women were included. Odds ratios (OR) and 95 % confidence intervals (CI) were calculated using logistic regression to estimate the association between the TCF7L2 SNPs and breast cancer risk. We also examined effect modification by self-reported ethnicity, genetic admixture, and diabetes history. After adjusting for multiple comparisons, four TCF7L2 SNPs were significantly associated with breast cancer overall: rs7903146 (ORTT 1.24; 95 % CI 1.03–1.49), rs3750805 (ORAT/TT 1.15; 95 % CI 1.03–1.28), rs7900150 (ORAA 1.23; 95 % 1.07–1.42), and rs1225404 (ORCC 0.82; 95 % 0.70–0.94). Among women with a history of diabetes, the TT genotype of rs3750804 increased breast cancer risk (OR, 2.46; 95 % CI 1.28–4.73). However, there was no association among women without a diabetes history (OR, 1.06; 95 % CI 0.85–1.32). We did not find significant interactions by ethnicity or by genetic admixture. Findings support an association between TCF7L2 and breast cancer and history of diabetes modifies this association for specific variants.
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Ravindranath A, O’Connell A, Johnston PG, El-Tanani MK (2008) The role of LEF/TCF factors in neoplastic transformation. Curr Mol Med 8(1):38–50
Grant SF, Thorleifsson G, Reynisdottir I, Benediktsson R, Manolescu A, Sainz J, Helgason A, Stefansson H, Emilsson V, Helgadottir A, Styrkarsdottir U, Magnusson KP, Walters GB, Palsdottir E, Jonsdottir T, Gudmundsdottir T, Gylfason A, Saemundsdottir J, Wilensky RL, Reilly MP, Rader DJ, Bagger Y, Christiansen C, Gudnason V, Sigurdsson G, Thorsteinsdottir U, Gulcher JR, Kong A, Stefansson K (2006) Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet 38(3):320–323. doi:10.1038/ng1732
Bodhini D, Radha V, Dhar M, Narayani N, Mohan V (2007) The rs12255372(G/T) and rs7903146(C/T) polymorphisms of the TCF7L2 gene are associated with type 2 diabetes mellitus in Asian Indians. Metab Clin Exp 56(9):1174–1178. doi:10.1016/j.metabol.2007.04.012
Tong Y, Lin Y, Zhang Y, Yang J, Liu H, Zhang B (2009) Association between TCF7L2 gene polymorphisms and susceptibility to type 2 diabetes mellitus: a large Human Genome Epidemiology (HuGE) review and meta-analysis. BMC Med Genet 10:15. doi:10.1186/1471-2350-10-15
Zhang C, Qi L, Hunter DJ, Meigs JB, Manson JE, van Dam RM, Hu FB (2006) Variant of transcription factor 7-like 2 (TCF7L2) gene and the risk of type 2 diabetes in large cohorts of U.S. women and men. Diabetes 55(9):2645–2648. doi:10.2337/db06-0643
Korner A, Kiess W, Stumvoll M, Kovacs P (2008) Polygenic contribution to obesity: genome-wide strategies reveal new targets. Front Horm Res 36:12–36. doi:10.1159/0000115335
Smith U (2007) TCF7L2 and type 2 diabetes—we WNT to know. Diabetologia 50(1):5–7. doi:10.1007/s00125-006-0521-z
Gebeshuber CA, Sladecek S, Grunert S (2007) Beta-catenin/LEF-1 signalling in breast cancer–central players activated by a plethora of inputs. Cells Tissues Organs 185(1–3):51–60. doi:10.1159/000101303
Brown AM (2001) Wnt signaling in breast cancer: have we come full circle? Breast Cancer Res 3(6):351–355
Howe LR, Brown AM (2004) Wnt signaling and breast cancer. Cancer Biol Ther 3(1):36–41
Polakis P (2012) Wnt signaling in cancer. Cold Spring Harbor Perspect Biol 4(5). doi:10.1101/cshperspect.a008052
Chung GG, Zerkowski MP, Ocal IT, Dolled-Filhart M, Kang JY, Psyrri A, Camp RL, Rimm DL (2004) Beta-catenin and p53 analyses of a breast carcinoma tissue microarray. Cancer 100(10):2084–2092. doi:10.1002/cncr.20232
Geyer FC, Lacroix-Triki M, Savage K, Arnedos M, Lambros MB, MacKay A, Natrajan R, Reis-Filho JS (2011) Beta-catenin pathway activation in breast cancer is associated with triple-negative phenotype but not with CTNNB1 mutation. Mod Pathol 24(2):209–231. doi:10.1038/modpathol.2010.205
Khramtsov AI, Khramtsova GF, Tretiakova M, Huo D, Olopade OI, Goss KH (2010) Wnt/beta-catenin pathway activation is enriched in basal-like breast cancers and predicts poor outcome. Am J Pathol 176(6):2911–2920. doi:10.2353/ajpath.2010.091125
Burwinkel B, Shanmugam KS, Hemminki K, Meindl A, Schmutzler RK, Sutter C, Wappenschmidt B, Kiechle M, Bartram CR, Frank B (2006) Transcription factor 7-like 2 (TCF7L2) variant is associated with familial breast cancer risk: a case-control study. BMC Cancer 6:268. doi:10.1186/1471-2407-6-268
Goode EL, Szabo C, Prokunina-Olsson L, Vierkant RA, Fredericksen ZS, Collins FS, White KL, Schmidt M, Fridley BL, Couch FJ (2009) No association between a candidate TCF7L2 variant and risk of breast or ovarian cancer. BMC Cancer 9:312. doi:10.1186/1471-2407-9-312
Naidu R, Yip CH, Taib NA (2011) Genetic variations in transcription factor 7-like 2 (TCF7L2) gene: association of TCF7L2 rs12255372(G/T) or rs7903146(C/T) with breast cancer risk and clinico-pathological parameters. Med Oncol. doi:10.1007/s12032-011-9837-8
Slattery M, John E, Torres-Mejia G, Lundgreen A, Herrick J, Baumgartner K, Hines L, Stern M, Wolff R (2012) Genetic variation in genes involved in hormones, inflammation, and energetic factors and breast cancer risk in an admixed population. Carcinogenesis. doi:10.1093/carcin/bgs163
Slattery ML, Sweeney C, Edwards S, Herrick J, Baumgartner K, Wolff R, Murtaugh M, Baumgartner R, Giuliano A, Byers T (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. doi:10.1007/s10549-006-9292-y
Angeles-Llerenas A, Ortega-Olvera C, Perez-Rodriguez E, Esparza-Cano JP, Lazcano-Ponce E, Romieu I, Torres-Mejia G (2010) Moderate physical activity and breast cancer risk: the effect of menopausal status. Exerc Sport Sci Rev 21(4):577–586. doi:10.1007/s10552-009-9487-8
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 Biomark Prev 12(11 Pt 1):1143–1152
John EM, Phipps AI, Davis A, Koo J (2005) Migration history, acculturation, and breast cancer risk in Hispanic women. Cancer Epidemiol Biomark Prev 14(12):2905–2913. doi:10.1158/1055-9965.EPI-05-0483
Falush D, Stephens M, Pritchard JK (2003) Inference of population structure using multilocus genotype data: linked loci and correlated allele frequencies. Genetics 164(4):1567–1587
Pritchard JK, Stephens M, Donnelly P (2000) Inference of population structure using multilocus genotype data. Genetics 155(2):945–959
Long JC, Williams RC, Urbanek M (1995) An E–M algorithm and testing strategy for multiple-locus haplotypes. Am J Hum Genet 56(3):799–810
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):79–91
Hosmer D, Lemeshow S (1989) Applied logistic regression. Wiley, New York
Flom PL (2010) Multinomial and ordinal logistic regression using PROC LOGISTIC.9. National Development and Research Institutes, Inc., New York
Hosmer DWaL S (2000) Applied logistic regression, 2nd edn. Wiley, New York
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. doi:10.1086/383251
Li J, Ji L (2005) Adjusting multiple testing in multilocus analyses using the eigenvalues of a correlation matrix. Heredity 95(3):221–227. doi:10.1038/sj.hdy.6800717
Holm S (1979) A simple sequentially rejective multiple test procedure. Scand J Stat 6(2):65–70
Arif JM, Al-Saif AM, Al-Karrawi MA, Al-Sagair OA (2011) Causative relationship between diabetes mellitus and breast cancer in various regions of Saudi Arabia: an overview. Asian Pac J Cancer Prev 12(3):589–592
Khachatryan L, Scharpf R, Kagan S (2011) Influence of diabetes mellitus type 2 and prolonged estrogen exposure on risk of breast cancer among women in Armenia. Health Care Women Int 32(11):953–971. doi:10.1080/07399332.2011.569041
Larsson SC, Mantzoros CS, Wolk A (2007) Diabetes mellitus and risk of breast cancer: a meta-analysis. Int J Cancer 121(4):856–862. doi:10.1002/ijc.22717
Liao S, Li J, Wei W, Wang L, Zhang Y, Wang C, Sun S (2011) Association between diabetes mellitus and breast cancer risk: a meta-analysis of the literature. Asian Pac J Cancer Prev 12(4):1061–1065
Lipscombe LL, Goodwin PJ, Zinman B, McLaughlin JR, Hux JE (2006) Diabetes mellitus and breast cancer: a retrospective population-based cohort study. Breast Cancer Res Treat 98(3):349–356. doi:10.1007/s10549-006-9172-5
Michels KB, Solomon CG, Hu FB, Rosner BA, Hankinson SE, Colditz GA, Manson JE (2003) Type 2 diabetes and subsequent incidence of breast cancer in the Nurses’ Health Study. Diabetes Care 26(6):1752–1758
Schott S, Schneeweiss A, Sohn C (2010) Breast cancer and diabetes mellitus. Exp Clin Endocrinol Diabetes 118(10):673–677. doi:10.1055/s-0030-1254116
Vona-Davis L, Howard-McNatt M, Rose DP (2007) Adiposity, type 2 diabetes and the metabolic syndrome in breast cancer. Obes Rev 8(5):395–408. doi:10.1111/j.1467-789X.2007.00396.x
Wolf I, Sadetzki S, Gluck I, Oberman B, Ben-David M, Papa MZ, Catane R, Kaufman B (2006) Association between diabetes mellitus and adverse characteristics of breast cancer at presentation. Eur J Cancer 42(8):1077–1082. doi:10.1016/j.ejca.2006.01.027
Rollison DE, Giuliano AR, Sellers TA, Laronga C, Sweeney C, Risendal B, Baumgartner KB, Byers T, Slattery ML (2008) Population-based case-control study of diabetes and breast cancer risk in Hispanic and non-Hispanic White women living in US southwestern states. Am J Epidemiol 167(4):447–456. doi:10.1093/aje/kwm322
MacDonald BT, Tamai K, He X (2009) Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell 17(1):9–26. doi:10.1016/j.devcel.2009.06.016
Fejerman L, John EM, Huntsman S, Beckman K, Choudhry S, Perez-Stable E, Burchard EG, Ziv E (2008) Genetic ancestry and risk of breast cancer among U.S. Latinas. Cancer Res 68(23):9723–9728. doi:10.1158/0008-5472.CAN-08-2039
Ooi SL, Martinez ME, Li CI (2011) Disparities in breast cancer characteristics and outcomes by race/ethnicity. Breast Cancer Res Treat 127(3):729–738. doi:10.1007/s10549-010-1191-6
Acknowledgments
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 state-wide 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-Corner’s 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). 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, Carolyn 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, Dr. Josh Galanter for assistance in selection of AIMs markers for the study, Dr. Elad Ziv for his input into the study, and Drs. Sue Ingles and Wei Wang for their contribution to the study.
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Connor, A.E., Baumgartner, R.N., Baumgartner, K.B. et al. Associations between TCF7L2 polymorphisms and risk of breast cancer among Hispanic and non-Hispanic White women: the Breast Cancer Health Disparities Study. Breast Cancer Res Treat 136, 593–602 (2012). https://doi.org/10.1007/s10549-012-2299-7
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DOI: https://doi.org/10.1007/s10549-012-2299-7