Growth Factors and Colon Cancer

Summary

Principal Investigator: MARTHA OR MARTY SLATTERY
Abstract: 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.
Funding Period: 2001-08-01 - 2008-07-31
more information: NIH RePORT

Top Publications

  1. pmc Genetic variation in C-reactive protein in relation to colon and rectal cancer risk and survival
    Martha L Slattery
    Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT 84108, USA
    Int J Cancer 128:2726-34. 2011
  2. pmc IL6 genotypes and colon and rectal cancer
    Martha L Slattery
    School of Medicine, University of Utah, Salt Lake City, UT 84108, USA
    Cancer Causes Control 18:1095-105. 2007
  3. pmc Vitamin D receptor gene (VDR) associations with cancer
    Martha L Slattery
    Department of Epidemiology, University of Utah School of Medicine, 30 North 1900 East, AC 230, Salt Lake City, UT 84117, USA
    Nutr Rev 65:S102-4. 2007
  4. pmc Leptin and leptin receptor genotypes and colon cancer: gene-gene and gene-lifestyle interactions
    Martha L Slattery
    Department of Medicine, University of Utah, Salt Lake City, UT, USA
    Int J Cancer 122:1611-7. 2008
  5. pmc CDX2 VDR polymorphism and colorectal cancer
    Martha L Slattery
    Department of Medicine, University of Utah, 375 Chipeta Way, Salt Lake City, UT 84108, USA
    Cancer Epidemiol Biomarkers Prev 16:2752-5. 2007
  6. pmc Transcription factor 7-like 2 polymorphism and colon cancer
    Martha L Slattery
    Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84108, USA
    Cancer Epidemiol Biomarkers Prev 17:978-82. 2008
  7. pmc Oncogenetic tree model of somatic mutations and DNA methylation in colon tumors
    Carol Sweeney
    Health Sciences Center, University of Utah, Salt Lake City, UT, USA
    Genes Chromosomes Cancer 48:1-9. 2009
  8. pmc Colon tumor mutations and epigenetic changes associated with genetic polymorphism: insight into disease pathways
    Martha L Slattery
    Department of Medicine, University of Utah, Salt Lake City, UT 84108, USA
    Mutat Res 660:12-21. 2009
  9. pmc Vitamin D related genes, CYP24A1 and CYP27B1, and colon cancer risk
    Linda M Dong
    Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
    Cancer Epidemiol Biomarkers Prev 18:2540-8. 2009
  10. pmc Assessing tumor mutations to gain insight into base excision repair sequence polymorphisms and smoking in colon cancer
    Karen Curtin
    Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, 84132, USA
    Cancer Epidemiol Biomarkers Prev 18:3384-8. 2009

Scientific Experts

Detail Information

Publications22

  1. pmc Genetic variation in C-reactive protein in relation to colon and rectal cancer risk and survival
    Martha L Slattery
    Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT 84108, USA
    Int J Cancer 128:2726-34. 2011
    ..These data suggest that genetic variation in the CRP gene influences risk of both colon and rectal cancer development...
  2. pmc IL6 genotypes and colon and rectal cancer
    Martha L Slattery
    School of Medicine, University of Utah, Salt Lake City, UT 84108, USA
    Cancer Causes Control 18:1095-105. 2007
    ..This study provides further support for inflammation-related factors in the etiology of CRC. Other studies are needed to explore other genes in this and other inflammation-related pathways...
  3. pmc Vitamin D receptor gene (VDR) associations with cancer
    Martha L Slattery
    Department of Epidemiology, University of Utah School of Medicine, 30 North 1900 East, AC 230, Salt Lake City, UT 84117, USA
    Nutr Rev 65:S102-4. 2007
  4. pmc Leptin and leptin receptor genotypes and colon cancer: gene-gene and gene-lifestyle interactions
    Martha L Slattery
    Department of Medicine, University of Utah, Salt Lake City, UT, USA
    Int J Cancer 122:1611-7. 2008
    ..VDR polymorphisms interacted with all LEP and LEPR polymorphisms. These data support an association between LEP and colon cancer. They also suggest that the mechanisms linking leptin to colon cancer may be independent of energy balance...
  5. pmc CDX2 VDR polymorphism and colorectal cancer
    Martha L Slattery
    Department of Medicine, University of Utah, 375 Chipeta Way, Salt Lake City, UT 84108, USA
    Cancer Epidemiol Biomarkers Prev 16:2752-5. 2007
    ..71; 95% CI, 0.52-0.97) but not colon cancer. These data suggest that haplotype analysis that encompasses different domains of the VDR gene might further our understanding of associations between the VDR gene and colon and rectal cancer...
  6. pmc Transcription factor 7-like 2 polymorphism and colon cancer
    Martha L Slattery
    Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84108, USA
    Cancer Epidemiol Biomarkers Prev 17:978-82. 2008
    ..78; 95% CI, 0.62-0.98) in a dose-response fashion (P for linear trend across genotypes = 0.03). These data suggest that colon cancer risk associated with the rs7903146 TCF7L2 polymorphism is modified by use of aspirin/NSAIDs...
  7. pmc Oncogenetic tree model of somatic mutations and DNA methylation in colon tumors
    Carol Sweeney
    Health Sciences Center, University of Utah, Salt Lake City, UT, USA
    Genes Chromosomes Cancer 48:1-9. 2009
    ..The oncogenetic tree model assumptions are appropriate for the observed heterogeneity of colon tumors, and the model produces a useful visual schematic of the sequence of events in pathways of colon carcinogenesis...
  8. pmc Colon tumor mutations and epigenetic changes associated with genetic polymorphism: insight into disease pathways
    Martha L Slattery
    Department of Medicine, University of Utah, Salt Lake City, UT 84108, USA
    Mutat Res 660:12-21. 2009
    ..The important modifying effects of aspirin/NSAIDs on associations with genetic polymorphisms reinforce the underlying role of inflammation in the etiology of colon cancer...
  9. pmc Vitamin D related genes, CYP24A1 and CYP27B1, and colon cancer risk
    Linda M Dong
    Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
    Cancer Epidemiol Biomarkers Prev 18:2540-8. 2009
    ..As this is the first study to evaluate these genes in relation to colon cancer, additional studies are needed to confirm these results...
  10. pmc Assessing tumor mutations to gain insight into base excision repair sequence polymorphisms and smoking in colon cancer
    Karen Curtin
    Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, 84132, USA
    Cancer Epidemiol Biomarkers Prev 18:3384-8. 2009
    ..02-1.9). These findings point to the importance of studying tumor mutations when examining DNA repair polymorphisms and cigarette smoke exposure to identify potentially relevant associations with colorectal cancer...
  11. ncbi Vitamin D receptor gene polymorphisms, dietary promotion of insulin resistance, and colon and rectal cancer
    Maureen A Murtaugh
    Health Research Center, Department of Family and Preventive Medicine, University of Utah, Salt Lake City, UT 84108, USA
    Nutr Cancer 55:35-43. 2006
    ....
  12. ncbi Haplotype analysis of common vitamin D receptor variants and colon and rectal cancers
    Carol Sweeney
    Health Research Center, Department of Family and Preventive Medicine, University of Utah, Salt Lake City, 84108, USA
    Cancer Epidemiol Biomarkers Prev 15:744-9. 2006
    ..In this analysis, haplotypes of the VDR influenced risk of colon cancer, but haplotype variables had only slightly better ability to explain case-control differences than genotype variables...
  13. ncbi Energy balance, insulin-related genes and risk of colon and rectal cancer
    Martha L Slattery
    Health Research Center, University of Utah, Salt Lake City, UT 84108, USA
    Int J Cancer 115:148-54. 2005
    ..Obesity, physical activity and energy intake appear to alter risk of colorectal cancer; however, the risk appears to be minimally influenced by genetic variants evaluated...
  14. ncbi Associations between apoE genotype and colon and rectal cancer
    Martha L Slattery
    Health Research Center, University of Utah, Salt Lake City, UT 84108, USA
    Carcinogenesis 26:1422-9. 2005
    ....
  15. ncbi PPARgamma, energy balance, and associations with colon and rectal cancer
    Martha L Slattery
    Health Research Center, University of Utah, Salt Lake City 84108, USA
    Nutr Cancer 51:155-61. 2005
    ..These data do not support the hypothesis that the P12A PPARgamma polymorphism is associated with colon or rectal cancer through regulation of energy balance...
  16. ncbi Interactions of peroxisome proliferator-activated receptor {gamma} and diet in etiology of colorectal cancer
    Maureen A Murtaugh
    Health Research Center, Department of Family and Preventive Medicine, University of Utah, Suite A, 375 Chipeta Way, Salt Lake City, UT 84101, USA
    Cancer Epidemiol Biomarkers Prev 14:1224-9. 2005
    ....
  17. ncbi Insulin-like growth factor pathway polymorphisms associated with body size in Hispanic and non-Hispanic white women
    Carol Sweeney
    Health Research Center, Family and Preventive Medicine, University of Utah, Suite A, 375 Chipeta Way, Salt Lake City, UT 84108, USA
    Cancer Epidemiol Biomarkers Prev 14:1802-9. 2005
    ..These results provide evidence that IGF pathway polymorphisms have functional effects on growth and central obesity and indicate that genotype-phenotype relationships are ethnic specific...
  18. ncbi Associations between ERalpha, ERbeta, and AR genotypes and colon and rectal cancer
    Martha L Slattery
    Health Research Center, School of Medicine, University of Utah, 375 Chipeta Way, Suite A, Salt Lake City, UT 84108, USA
    Cancer Epidemiol Biomarkers Prev 14:2936-42. 2005
    ..71; 95% CI, 2.89-15.6). Our results suggest that the ERbeta gene is more important than ERalpha in the etiology of colorectal cancer...
  19. ncbi Associations between vitamin D, vitamin D receptor gene and the androgen receptor gene with colon and rectal cancer
    Martha L Slattery
    University of Utah, Health Research Center, Salt Lake City, USA
    Int J Cancer 118:3140-6. 2006
    ..05) relative to men with fewer than 23 CAG repeats of the AR gene. These data provide support for the role of vitamin D and sunshine exposure in the etiology of colorectal cancer and suggest that AR gene may modulate the association...
  20. ncbi Polymorphisms in insulin-related genes predispose to specific KRAS2 and TP53 mutations in colon cancer
    Wade S Samowitz
    Department of Pathology, University of Utah, Salt Lake City, UT 84108, USA
    Mutat Res 595:117-24. 2006
    ....
  21. ncbi PPARgamma and colon and rectal cancer: associations with specific tumor mutations, aspirin, ibuprofen and insulin-related genes (United States)
    Martha L Slattery
    Health Research Center, University of Utah, Salt Lake City, 84108, USA
    Cancer Causes Control 17:239-49. 2006
    ..These data suggest that PPARgamma may be associated with many aspects of colorectal cancer including insulin- and inflammation-related mechanisms...
  22. ncbi The CYP1A1 genotype may alter the association of meat consumption patterns and preparation with the risk of colorectal cancer in men and women
    Maureen A Murtaugh
    Health Research Center, Department of Family and Preventive Medicine, University of Utah, Salt Lake City, UT 84101, USA
    J Nutr 135:179-86. 2005
    ..Genetic susceptibility may modify the associations of some meat or meat preparation factors with the risk of colorectal cancer...