Abstract
Several studies suggest that higher circulating insulin-like growth factor I (IGF-I) levels are associated with premenopausal breast cancer risk. Breast cancer risk and circulating IGF-I concentration appear to be partly heritable, thus genetic variation at IGF1 could influence IGF-I levels and breast cancer risk. We investigated the association of IGF1 CA repeat variants with premenopausal breast cancer risk using a family-based design. The study sample included 840 families from the Ontario Familial Breast Cancer Registry (OFBCR) and the Australian Breast Cancer Family Registry (ABCFR). Three CA repeat variants, at 5′, 3′, and in intron 2 were genotyped (5′CA, 3′CA, In2CA). We found several nominally significant associations. The 5′CA-21 allele (P = 0.03) and In2CA-212 allele (P = 0.04) were associated with lower risk, and the In2CA-216 allele with higher risk (P = 0.04) for the combined ABCFR–OFBCR. These associations were not significant after taking into account multiple comparisons. In2CA-216 was more strongly associated with risk when we used a recessive instead of an additive model (P = 0.01). 5′CA alleles of repeat length 18–20 were associated with higher risk (P = 0.02), and 5′CA alleles of >20 repeats were associated with lower risk (P = 0.01). These associations were significant in the OFBCR (In2CA-216 recessive, P = 0.02; 5′CA 18–20 and >20 allele grouping, P = 0.01) but not strongly supported by the ABCFR (In2CA-216 recessive, P = 0.14; 5′CA 18–20, P = 0.25; 5′CA >20, P = 0.20). The associations we found could be due to chance as many comparisons were made. Our results do not strongly support an association between these IGF1 variants and breast cancer risk.
Similar content being viewed by others
References
Hadsell DL (2003) The insulin-like growth factor system in normal mammary gland function. Breast Dis 17:3–14
Kleinberg DL (1998) Role of IGF-I in normal mammary development. Breast Cancer Res Treat 47(3):201–208. doi:10.1023/A:1005998832636
Baglietto L, English DR, Hopper JL, Morris HA, Tilley WD, Giles GG (2007) Circulating insulin-like growth factor-I and binding protein-3 and the risk of breast cancer. Cancer Epidemiol Biomarkers Prev 16(4):763–768. doi:10.1158/1055-9965.EPI-06-0960
Renehan AG, Harvie M, Howell A (2006) Insulin-like growth factor (IGF)-I, IGF binding protein-3, and breast cancer risk: 8 years on. Endocr Relat Cancer 13(2):273–278. doi:10.1677/erc.1.01219
Renehan AG, Zwahlen M, Minder C, O’Dwyer ST, Shalet SM, Egger M (2004) Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis. Lancet 363(9418):1346–1353. doi:10.1016/S0140-6736(04)16044-3
Shi R, Yu H, McLarty J, Glass J (2004) IGF-I and breast cancer: a meta-analysis. Int J Cancer 111(3):418–423. doi:10.1002/ijc.20233
Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M, Pukkala E, Skytthe A, Hemminki K (2000) Environmental and heritable factors in the causation of cancer–analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med 343(2):78–85. doi:10.1056/NEJM200007133430201
Harrela M, Koistinen H, Kaprio J, Lehtovirta M, Tuomilehto J, Eriksson J, Toivanen L, Koskenvuo M, Leinonen P, Koistinen R et al (1996) Genetic and environmental components of interindividual variation in circulating levels of IGF-I, IGF-II, IGFBP-1, and IGFBP-3. J Clin Invest 98(11):2612–2615. doi:10.1172/JCI119081
Hong Y, Pedersen N, Brismar K, Hall K, de Faire U (1996) Quantitative genetic analyses of insulin-like growth factor I (IGF-I), IGF-binding protein-1, and insulin levels in middle-aged and elderly twins. J Clin Endocrinol Metab 81(5):1791–1797. doi:10.1210/jc.81.5.1791
Gonzalez-Zuloeta Ladd AM, Liu F, Houben MP, Arias Vasquez A, Siemes C, Janssens AC, Coebergh JW, Hofman A, Janssen JA, Stricker BH et al (2007) IGF-1 CA repeat variant and breast cancer risk in postmenopausal women. Eur J Cancer 43(11):1718–1722. doi:10.1016/j.ejca.2007.04.026
Cleveland RJ, Gammon MD, Edmiston SN, Teitelbaum SL, Britton JA, Terry MB, Eng SM, Neugut AI, Santella RM, Conway K (2005) IGF1 CA repeat polymorphisms, lifestyle factors and breast cancer risk in the long island breast cancer study project. Carcinogenesis 27(4):758–765. doi:10.1093/carcin/bgi294
Wagner K, Hemminki K, Israelsson E, Grzybowska E, Soderberg M, Pamula J, Pekala W, Zientek H, Mielzynska D, Siwinska E et al (2005) Polymorphisms in the IGF-1 and IGFBP 3 promoter and the risk of breast cancer. Breast Cancer Res Treat 92(2):133–140. doi:10.1007/s10549-005-2417-x
Wen W, Gao YT, Shu XO, Yu H, Cai Q, Smith JR, Zheng W (2005) Insulin-like growth factor-I gene polymorphism and breast cancer risk in Chinese women. Int J Cancer 113(2):307–311. doi:10.1002/ijc.20571
DeLellis K, Ingles S, Kolonel L, McKean-Cowdin R, Henderson B, Stanczyk F, Probst-Hensch NM (2003) IGF1 genotype, mean plasma level and breast cancer risk in the Hawaii/Los Angeles multiethnic cohort. Br J Cancer 88(2):277–282. doi:10.1038/sj.bjc.6600728
Missmer SA, Haiman CA, Hunter DJ, Willett WC, Colditz GA, Speizer FE, Pollak MN, Hankinson SE (2002) A sequence repeat in the insulin-like growth factor-1 gene and risk of breast cancer. Int J Cancer 100(3):332–336. doi:10.1002/ijc.10473
Figer A, Karasik YP, Baruch RG, Chetrit A, Papa MZ, Sade RB, Rizel S, Friedman E (2002) Insulin-like growth factor I polymorphism and breast cancer risk in Jewish women. Isr Med Assoc J 4(10):759–762
Yu H, Li BD, Smith M, Shi R, Berkel HJ, Kato I (2001) Polymorphic CA repeats in the IGF-I gene and breast cancer. Breast Cancer Res Treat 70(2):117–122. doi:10.1023/A:1012947027213
Slattery ML, Sweeney C, Wolff R, Herrick J, Baumgartner K, Giuliano A, Byers T (2007) Genetic variation in IGF1, IGFBP3, IRS1, IRS2 and risk of breast cancer in women living in Southwestern United States. Breast Cancer Res Treat 104(2):197–209. doi:10.1007/s10549-006-9403-9
Al-Zahrani A, Sandhu MS, Luben RN, Thompson D, Baynes C, Pooley KA, Luccarini C, Munday H, Perkins B, Smith P et al (2005) IGF1 and IGFBP3 tagging polymorphisms are associated with circulating levels of IGF1, IGFBP3 and risk of breast cancer. Hum Mol Genet 15(1):1–10. doi:10.1093/hmg/ddi398
Patel AV, Cheng I, Canzian F, Le Marchand L, Thun MJ, Berg CD, Buring J, Calle EE, Chanock S, Clavel-Chapelon F et al (2008) IGF-1, IGFBP-1, and IGFBP-3 Polymorphisms predict circulating IGF levels but not breast cancer risk: findings from the breast and prostate cancer cohort consortium (BPC3). PLoS One 3(7):e2578
Deming SL, Ren Z, Cai Q, Shu XO, Wen W, Long JR, Gao YT, Zheng W (2008) IGF-I and IGF-II genetic variation and breast cancer risk in Chinese women: results from the Shanghai breast cancer study. Cancer Epidemiol Biomarkers Prev 17(1):255–257. doi:10.1158/1055-9965.EPI-07-2588
Fehringer G, Ozcelik H, Knight JA, Paterson AD, Boyd NF (2008) Association between IGF1 CA microsatellites and mammographic density, anthropometric measures, and circulating IGF-I levels in premenopausal Caucasian women. Breast Cancer Res Treat. doi:10.1007/s10549-008-0146-7
John EM, Hopper JL, Beck JC, Knight JA, Neuhausen SL, Senie RT, Ziogas A, Andrulis IL, Anton-Culver H, Boyd N et al (2004) The breast cancer family registry: an infrastructure for cooperative multinational, interdisciplinary and translational studies of the genetic epidemiology of breast cancer. Breast Cancer Res 6(4):R375–R389. doi:10.1186/bcr801
Sutherland HJ, Lacroix J, Knight J, Andrulis IL, Boyd NF (2001) The cooperative familial registry for breast cancer studies: design and first year recruitment rates in Ontario. J Clin Epidemiol 54(1):93–98. doi:10.1016/S0895-4356(00)00263-8
Benson G (1999) Tandem repeats finder: a program to analyze DNA sequences. Nucleic Acids Res 27(2):573–580. doi:10.1093/nar/27.2.573
The Centre for Applied Genomics, Hospital for Sick Children. Toronto, Canada http://www.tcag.ca
Couillault C (2002) Pedagree: a program for detecting autosomal marker Mendelian incompatibilities in pedigree data. Version 1.00. http://pedagree.free.fr
Guo SW, Thompson EA (1992) Performing the exact test of Hardy-Weinberg proportion for multiple alleles. Biometrics 48(2):361–372. doi:10.2307/2532296
Liu K, Muse S (2005) PowerMarker: an integrated analysis environment for genetic marker analysis. Bioinformatics 21(9):2128–2129. doi:10.1093/bioinformatics/bti282
Laird NM, Horvath S, Xu X (2000) Implementing a unified approach to family-based tests of association. Genet Epidemiol 19(suppl 1):S36–S42. doi:10.1002/1098-2272(2000)19:1+<::AID-GEPI6>3.0.CO;2-M
Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J Roy Statist Soc Ser B Methodol 57(1):289–300
Lange C, DeMeo D, Silverman EK, Weiss ST, Laird NM (2004) PBAT: tools for family-based association studies. Am J Hum Genet 74(2):367–369. doi:10.1086/381563
Vaessen N, Heutink P, Janssen JA, Witteman JC, Testers L, Hofman A, Lamberts SW, Oostra BA, Pols HA, van Duijn CM (2001) A polymorphism in the gene for IGF-I: functional properties and risk for type 2 diabetes and myocardial infarction. Diabetes 50(3):637–642. doi:10.2337/diabetes.50.3.637
Takacs I, Koller DL, Peacock M, Christian JC, Hui SL, Conneally PM, Johnston CC Jr, Foroud T, Econs MJ (1999) Sibling pair linkage and association studies between bone mineral density and the insulin-like growth factor I gene locus. J Clin Endocrinol Metab 84(12):4467–4471. doi:10.1210/jc.84.12.4467
Rosen CJ, Kurland ES, Vereault D, Adler RA, Rackoff PJ, Craig WY, Witte S, Rogers J, Bilezikian JP (1998) Association between serum insulin growth factor-I (IGF-I) and a simple sequence repeat in IGF-I gene: implications for genetic studies of bone mineral density. J Clin Endocrinol Metab 83(7):2286–2290. doi:10.1210/jc.83.7.2286
Chen TM, Kuo PL, Hsu CH, Tsai SJ, Chen MJ, Lin CW, Sun HS (2007) Microsatellite in the 3′ untranslated region of human fibroblast growth factor 9 (FGF9) gene exhibits pleiotropic effect on modulating FGF9 protein expression. Hum Mutat 28(1):98. doi:10.1002/humu.9471
Gebhardt F, Zanker KS, Brandt B (1999) Modulation of epidermal growth factor receptor gene transcription by a polymorphic dinucleotide repeat in intron 1. J Biol Chem 274(19):13176–13180. doi:10.1074/jbc.274.19.13176
Tae HJ, Luo X, Kim KH (1994) Roles of CCAAT/enhancer-binding protein and its binding site on repression and derepression of acetyl-CoA carboxylase gene. J Biol Chem 269(14):10475–10484
Canzian F, McKay JD, Cleveland RJ, Dossus L, Biessy C, Rinaldi S, Landi S, Boillot C, Monnier S, Chajes V et al (2006) Polymorphisms of genes coding for insulin-like growth factor 1 and its major binding proteins, circulating levels of IGF-I and IGFBP-3 and breast cancer risk: results from the EPIC study. Br J Cancer 94(2):299–307. doi:10.1038/sj.bjc.6602936
Setiawan VW, Cheng I, Stram DO, Penney KL, Le Marchand L, Altshuler D, Kolonel LN, Hirschhorn J, Henderson BE, Freedman ML (2006) Igf-I genetic variation and breast cancer: the multiethnic cohort. Cancer Epidemiol Biomarkers Prev 15(1):172–174. doi:10.1158/1055-9965.EPI-05-0625
Easton DF, Pooley KA, Dunning AM, Pharoah PD, Thompson D, Ballinger DG, Struewing JP, Morrison J, Field H, Luben R et al (2007) Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447(7148):1087–1093. doi:10.1038/nature05887
Acknowledgments
We thank Hamdi Jarjanazi and Keith Wong for their contributions to this study. This work was supported by the National Cancer Institute, National Institutes of Health under RFA-CA-06-503 and through cooperative agreements with members of the Breast Cancer Family Registry and P·I.s [including P·I.s from Cancer Care Ontario (U01 CA69467) and University of Melbourne (U01 CA69638)]. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centres in the CFR, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the CFR.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Fehringer, G., Boyd, N.F., Knight, J.A. et al. Family-based genetic association study of insulin-like growth factor I microsatellite markers and premenopausal breast cancer risk. Breast Cancer Res Treat 118, 415–424 (2009). https://doi.org/10.1007/s10549-009-0336-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10549-009-0336-y