Cell growth and proliferation are central to carcinogenesis. Scientific evidence that growth hormones, and genetic variants that influence these growth hormones, are importantly related to colorectal cancer is increasing. Furthermore, insulin and insulin-like growth factors (IGF), growth hormones that appear to be important for colorectal cancer, are influenced by previously identified risk factors for colorectal cancer such as body size and physical activity. In this study we will use existing lifestyle and metabolic exposure data; known tumor mutational status of microsatellite instability and K-ras mutations; and available germline DNA from an incident colorectal cancer case-control study of approximately 3000 cases and 3000 controls to study how genetic variants that influence growth hormones and cell growth and proliferation relate to development of colorectal cancer and subsequent survival after diagnosis. The study focuses on genetic and environmental interaction. Specific genes examined are molecular variants of genes along insulin pathway, including the IGF1 gene, insulin- like growth factor binding protein-3 (IGFBP3), the insulin receptor substrate gene 1 (IRS-1), the insulin receptor substrate gene-2 (IRS-2); the peroxisome proliferator-activated receptor gamma gene (PPARgamma), apolipoprotein E gene (ApoE), and the vitamin D receptor gene (VDR). We hypothesize that these variants are associated with altered risk of colorectal cancer in conjunction with genetic, diet, and lifestyle factors. Specially, we hypothesize that molecular variants of IGF1, IGFBP3, IRS-1, IRS-2, PPARgamma, ApoE, and VDR interact with dietary such as calcium, vitamin D, sugar, and glycemic index; sunshine exposure, physical activity, aspirin use, and body size to alter risk of colorectal cancer; that molecular variants of IGF1, IGFBP3, IRS-1, IRS-2, PPARgamma, ApoE, and VDR are associated with specific types of mutations in tumors including microsatellite instability and K-ras mutations; and that molecular variants of IGF1, IGFBP3, IRS-1, IRS-2, PPARgamma, ApoE, and VDR are associated with survival after diagnosis. To test the hypothesis that these variants interact with dietary and other factors, it is necessary to have a large sample size, such as the one available. Molecular variants of these genes that are involved in the insulin and growth factor disease pathway will be determined. Statistical analyses will use logistic regression and survival methods. This study builds on a unique existing resource to study genetic and environmental associations with colorectal cancer. It will provide insight into colon cancer etiology and therefore avenues to disease prevention.
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| Slattery, Martha L; Wolff, Roger K; Curtin, Karen et al. (2009) Colon tumor mutations and epigenetic changes associated with genetic polymorphism: insight into disease pathways. Mutat Res 660:12-21 |
| Dong, Linda M; Ulrich, Cornelia M; Hsu, Li et al. (2009) Vitamin D related genes, CYP24A1 and CYP27B1, and colon cancer risk. Cancer Epidemiol Biomarkers Prev 18:2540-8 |
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| Slattery, Martha L; Folsom, Aaron R; Wolff, Roger et al. (2008) Transcription factor 7-like 2 polymorphism and colon cancer. Cancer Epidemiol Biomarkers Prev 17:978-82 |
| Slattery, Martha L; Wolff, Roger K; Herrick, Jennifer et al. (2008) Leptin and leptin receptor genotypes and colon cancer: gene-gene and gene-lifestyle interactions. Int J Cancer 122:1611-7 |
| Slattery, Martha L; Wolff, Roger K; Herrick, Jennifer S et al. (2007) IL6 genotypes and colon and rectal cancer. Cancer Causes Control 18:1095-105 |
| Slattery, Martha L; Herrick, Jennifer; Wolff, Roger K et al. (2007) CDX2 VDR polymorphism and colorectal cancer. Cancer Epidemiol Biomarkers Prev 16:2752-5 |
| Slattery, Martha L (2007) Vitamin D receptor gene (VDR) associations with cancer. Nutr Rev 65:S102-4 |
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