Genetic variation in insulin pathway genes and distal colorectal adenoma risk
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Insulin, glucose, and other insulin-related proteins that mediate insulin signaling are associated with colorectal neoplasia risk, but associations with common genetic variation in insulin axis genes are less clear. In this study, we used a comprehensive tag single-nucleotide polymorphisms (SNPs) approach to define genetic variation in six insulin axis genes (IGF1, IGF2, IGFBP1, IGFBP3, IRS1, and IRS2) and three genes associated with estrogen signaling (ESR1, ESR2, and PGR).
We assessed associations between SNPs and distal colorectal adenoma (CRA) risk in a case–control study of 1,351 subjects. Cases were individuals with one or more adenomas diagnosed during sigmoidoscopy, and controls were individuals with no adenomas at the sigmoidoscopy exam. We used unconditional logistic regression assuming an additive model to assess SNP-specific risks adjusting for multiple comparisons with P act.
Distal adenoma risk was significantly increased for one SNP in IGF2 [per minor allele OR = 1.41; 95 % confidence interval (CI) = 1.16, 1.67; P act = 0.005] and decreased for an ESR2 SNP (per minor allele OR = 0.78; 95 % CI = 0.66, 0.91; P act = 0.041). There was no statistically significant heterogeneity of these associations by race, sex, BMI, physical activity, or, in women, hormone replacement therapy use. Risk estimates did not differ in the colon versus rectum or for smaller (<1 cm) versus larger (>1 cm) adenomas.
These data suggest that selected genetic variability in IGF2 and ESR2 may be modifiers of CRA risk.
KeywordsColorectal adenoma Tag SNP Insulin axis Estrogen receptors
We would like to thank all the subjects who contributed their time to this study. We would also like to thank Terry Kolb and Jessie Lin for their assistance with data collection, cleaning and management and Anh Diep and for her assistance with biospecimen management. This work was supported by the National Cancer Institute, National Institutes of Health under 1R01 CA096830 and 5P01 CA42710.
Potential conflicts of interest
No authors report any conflict of interest. The content of the manuscript does not necessarily reflect the views or policies of the National Cancer Institute nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.
- 1.Komninou D, Ayonote A, Richie JP Jr, Rigas B (2003) Insulin resistance and its contribution to colon carcinogenesis. Exp Biol Med (Maywood) 228(4):396–405Google Scholar
- 6.Pechlivanis S, Pardini B, Bermejo JL, Wagner K, Naccarati A, Vodickova L, Novotny J, Hemminki K, Vodicka P, Forsti A (2007) Insulin pathway related genes and risk of colorectal cancer: INSR promoter polymorphism shows a protective effect. Endocr Relat Cancer 14(3):733–740PubMedCrossRefGoogle Scholar
- 12.Potter JD, Bostick RM, Grandits GA, Fosdick L, Elmer P, Wood J, Grambsch P, Louis TA (1996) Hormone replacement therapy is associated with lower risk of adenomatous polyps of the large bowel: the Minnesota Cancer Prevention Research Unit Case–Control Study. Cancer Epidemiol Biomarkers Prev 5(10):779–784PubMedGoogle Scholar
- 13.Purdue MP, Mink PJ, Hartge P, Huang WY, Buys S, Hayes RB (2005) Hormone replacement therapy, reproductive history, and colorectal adenomas: data from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial (United States). Cancer Causes Control 16(8):965–973PubMedCrossRefGoogle Scholar
- 19.Yakar S, Nunez NP, Pennisi P, Brodt P, Sun H, Fallavollita L, Zhao H, Scavo L, Novosyadlyy R, Kurshan N, Stannard B, East-Palmer J, Smith NC, Perkins SN, Fuchs-Young R, Barrett JC, Hursting SD, LeRoith D (2006) Increased tumor growth in mice with diet-induced obesity: impact of ovarian hormones. Endocrinology 147(12):5826–5834PubMedCrossRefGoogle Scholar
- 22.Gunter MJ, Hoover DR, Yu H, Wassertheil-Smoller S, Rohan TE, Manson JE, Howard BV, Wylie-Rosett J, Anderson GL, Ho GY, Kaplan RC, Li J, Xue X, Harris TG, Burk RD, Strickler HD (2008) Insulin, insulin-like growth factor-I, endogenous estradiol, and risk of colorectal cancer in postmenopausal women. Cancer Res 68(1):329–337PubMedCrossRefGoogle Scholar
- 24.Rudolph A, Sainz J, Hein R, Hoffmeister M, Frank B, Forsti A, Brenner H, Hemminki K, Chang-Claude J (2011) Modification of menopausal hormone therapy-associated colorectal cancer risk by polymorphisms in sex steroid signaling, metabolism and transport related genes. Endocr Relat Cancer 18(3):371–384PubMedCrossRefGoogle Scholar
- 25.Sainz J, Rudolph A, Hein R, Hoffmeister M, Buch S, von Schonfels W, Hampe J, Schafmayer C, Volzke H, Frank B, Brenner H, Forsti A, Hemminki K, Chang-Claude J (2011) Association of genetic polymorphisms in ESR2, HSD17B1, ABCB1, and SHBG genes with colorectal cancer risk. Endocr Relat Cancer 18(2):265–276PubMedCrossRefGoogle Scholar
- 39.Rinaldi S, Cleveland R, Norat T, Biessy C, Rohrmann S, Linseisen J, Boeing H, Pischon T, Panico S, Agnoli C, Palli D, Tumino R, Vineis P, Peeters PH, van Gils CH, Bueno-de-Mesquita BH, Vrieling A, Allen NE, Roddam A, Bingham S, Khaw KT, Manjer J, Borgquist S, Dumeaux V, Torhild Gram I, Lund E, Trichopoulou A, Makrygiannis G, Benetou V, Molina E, Donate Suarez I, Barricarte Gurrea A, Gonzalez CA, Tormo MJ, Altzibar JM, Olsen A, Tjonneland A, Gronbaek H, Overvad K, Clavel-Chapelon F, Boutron-Ruault MC, Morois S, Slimani N, Boffetta P, Jenab M, Riboli E, Kaaks R (2010) Serum levels of IGF-I, IGFBP-3 and colorectal cancer risk: results from the EPIC cohort, plus a meta-analysis of prospective studies. Int J Cancer 126(7):1702–1715PubMedGoogle Scholar
- 46.Kaneda A, Wang CJ, Cheong R, Timp W, Onyango P, Wen B, Iacobuzio-Donahue CA, Ohlsson R, Andraos R, Pearson MA, Sharov AA, Longo DL, Ko MS, Levchenko A, Feinberg AP (2007) Enhanced sensitivity to IGF-II signaling links loss of imprinting of IGF2 to increased cell proliferation and tumor risk. Proc Natl Acad Sci U S A 104(52):20926–20931PubMedCrossRefGoogle Scholar
- 50.Ito Y, Koessler T, Ibrahim AE, Rai S, Vowler SL, Abu-Amero S, Silva AL, Maia AT, Huddleston JE, Uribe-Lewis S, Woodfine K, Jagodic M, Nativio R, Dunning A, Moore G, Klenova E, Bingham S, Pharoah PD, Brenton JD, Beck S, Sandhu MS, Murrell A (2008) Somatically acquired hypomethylation of IGF2 in breast and colorectal cancer. Hum Mol Genet 17(17):2633–2643PubMedCrossRefGoogle Scholar
- 52.Nakagawa H, Chadwick RB, Peltomaki P, Plass C, Nakamura Y, de La Chapelle A (2001) Loss of imprinting of the insulin-like growth factor II gene occurs by biallelic methylation in a core region of H19-associated CTCF-binding sites in colorectal cancer. Proc Natl Acad Sci U S A 98(2):591–596PubMedCrossRefGoogle Scholar
- 58.Kaaks R, Stattin P, Villar S, Poetsch AR, Dossus L, Nieters A, Riboli E, Palmqvist R, Hallmans G, Plass C, Friesen MD (2009) Insulin-like growth factor-II methylation status in lymphocyte DNA and colon cancer risk in the Northern Sweden Health and Disease cohort. Cancer Res 69(13):5400–5405PubMedCrossRefGoogle Scholar
- 60.Margolis KL, Bonds DE, Rodabough RJ, Tinker L, Phillips LS, Allen C, Bassford T, Burke G, Torrens J, Howard BV (2004) Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women: results from the Women's Health Initiative Hormone Trial. Diabetologia 47(7):1175–1187PubMedCrossRefGoogle Scholar
- 62.Barone M, Tanzi S, Lofano K, Scavo MP, Pricci M, Demarinis L, Papagni S, Guido R, Maiorano E, Ingravallo G, Comelli MC, Francavilla A, Di Leo A (2010) Dietary-induced ERbeta upregulation counteracts intestinal neoplasia development in intact male ApcMin/+ mice. Carcinogenesis 31(2):269–274PubMedCrossRefGoogle Scholar
- 64.Martineti V, Picariello L, Tognarini I, Carbonell Sala S, Gozzini A, Azzari C, Mavilia C, Tanini A, Falchetti A, Fiorelli G, Tonelli F, Brandi ML (2005) ERbeta is a potent inhibitor of cell proliferation in the HCT8 human colon cancer cell line through regulation of cell cycle components. Endocr Relat Cancer 12(2):455–469PubMedCrossRefGoogle Scholar