Genetic Study of Prostaglandin Synthesis/EGFR and Risk of Colorectal Neoplasia

Summary

Principal Investigator: Cornelia Ulrich
Abstract: [unreadable] DESCRIPTION (provided by applicant): Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) are effective chemopreventive agents against colorectal adenomas, precursors of colorectal cancer. NSAIDs exert their chemopreventive effects through the inhibition of the cyclooxygenases (COX)1 and 2, key enzymes in the prostaglandin synthesis pathway. Initial studies suggest that genetic variation in prostaglandin synthesis can affect colorectal carcinogenesis. One of the main downstream products of the COX enzymes is prostaglandin E2 (PGE2). PGE2 is the most upregulated prostaglandin in colorectal cancer, and experimental studies directly implicate PGE2 in the development of colorectal neoplasia. Recent studies have shown that PGE2 signaling can activate epidermal growth factor receptor (EGFR) signaling, a second pathway of key importance in olorectal carcinogenesis. This study will evaluate the association between colorectal adenomas and genetic variability in enzymes, receptors, and signaling molecules in the prostaglandin/EGFR pathways. We will focus on proteins that: a) regulate PGE2 levels (prostaglandin E synthase (PGES) and 15- hydroxyprostaglandin dehydrogenase (PGDN); b) bind to PGE2 at the cell surface (receptors EP1, EP2, and EP4); or c) are involved in PGE2 cross-talk with EGFR signaling (Src and EGFR). We will genotype individuals in an existing case-control study of 540 adenoma cases and 640 polyp-free controls. Participants were recruited through gastroenterology practices in Minnesota and information on health status, family history, dietary intake, physical activity, and NSAID use has been obtained. All patients underwent a full colonoscopy and completed questionnaires prior to diagnosis. Several of the target genes have been resequenced for polymorphism discovery (PGES, EP1, 2, and 4, EGFR) and resequencing of the other target genes (PGDN, Src) is underway. We propose a study design that maximizes available information regarding genetic variability in the prostaglandin/EGFR pathways by examining common haplotypes with tag SNPs, as well as specific candidate polymorphisms. As a secondary aim, interactions with NSAID use will be investigated to determine responses of genetically-defined subgroups. Gene-gene interactions will also be evaluated, providing a comprehensive analysis of the role of genetic variation in this pathway. This study uses a cost-effective approach to address the research question of genetic variability in the prostaglandin/EGFR pathways and risk of colorectal neoplasia. It builds on past successful collaborations, as well as promising preliminary data, and provides training for a new investigator. This study of genetic variation in the prostaglandin/EGFR pathway will provide insights into the complex process of colorectal carcinogenesis, and increase understanding of the pharmacogenetics of NSAID chemoprevention. [unreadable] [unreadable] [unreadable]
Funding Period: 2006-07-07 - 2008-06-30
more information: NIH RePORT

Top Publications

  1. pmc Genetic variation in the lipoxygenase pathway and risk of colorectal neoplasia
    Sarah E Kleinstein
    Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
    Genes Chromosomes Cancer 52:437-49. 2013
  2. pmc Glutathione peroxidase tagSNPs: associations with rectal cancer but not with colon cancer
    Ulrike Haug
    Division of Preventive Oncology, German Cancer Research Center, Heidelberg, Germany
    Genes Chromosomes Cancer 51:598-605. 2012
  3. pmc A review of gene-drug interactions for nonsteroidal anti-inflammatory drug use in preventing colorectal neoplasia
    J T Cross
    Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
    Pharmacogenomics J 8:237-47. 2008
  4. pmc Genetic variation in prostaglandin E2 synthesis and signaling, prostaglandin dehydrogenase, and the risk of colorectal adenoma
    Elizabeth M Poole
    Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington, USA
    Cancer Epidemiol Biomarkers Prev 19:547-57. 2010

Detail Information

Publications4

  1. pmc Genetic variation in the lipoxygenase pathway and risk of colorectal neoplasia
    Sarah E Kleinstein
    Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
    Genes Chromosomes Cancer 52:437-49. 2013
    ..Genetic variability in ALOXs may affect risk of colorectal neoplasia, particularly for rectal cancer. Additionally, genetic variability in FLAP and ALOX15 may modify the protective effect of NSAID use against colorectal neoplasia...
  2. pmc Glutathione peroxidase tagSNPs: associations with rectal cancer but not with colon cancer
    Ulrike Haug
    Division of Preventive Oncology, German Cancer Research Center, Heidelberg, Germany
    Genes Chromosomes Cancer 51:598-605. 2012
    ....
  3. pmc A review of gene-drug interactions for nonsteroidal anti-inflammatory drug use in preventing colorectal neoplasia
    J T Cross
    Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
    Pharmacogenomics J 8:237-47. 2008
    ..Reliable detection of gene-NSAID interactions will require greater sample sizes, consistent definitions of NSAID use and evaluation of clinical trial subjects of chemoprevention studies...
  4. pmc Genetic variation in prostaglandin E2 synthesis and signaling, prostaglandin dehydrogenase, and the risk of colorectal adenoma
    Elizabeth M Poole
    Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington, USA
    Cancer Epidemiol Biomarkers Prev 19:547-57. 2010
    ..Prostaglandins are metabolites of omega-6 and omega-3 polyunsaturated fatty acids; their biosynthesis is the primary target of nonsteroidal anti-inflammatory drugs (NSAID), which reduce colorectal neoplasia risk...