Molecular Epidemiology of Colorectal Adenomas

Summary

Principal Investigator: Robert Haile
Abstract: Our overall objective is to conduct more directed studies of main effects of genes and gene-gene and gene environment interactions within selected metabolic pathways of interest in the etiology of colorectal adenomas, accepted precursors of colorectal cancer (CRC). In the parent study for this application, we have DNA and risk factor data on 1,610 subjects (778 cases and 832 controls). We have the following specific aims: 1) Study selected genes and environmental factors relevant to a folate-related pathway. Specifically, we propose to study MTHFR, MTRR, ADH3, which may affect folate metabolism, and XRCC1, XRCC3, OGG1, and MGMT, which may be involved in DNA repair of damage associated with folate metabolism. In addition, we have data already in hand on RBC folates, homocysteine, and DNA methylation that will be incorporated into statistical analyses of these data where appropriate. 2) Study genes that may be involved in the metabolism or transport of bile acids. Specifically, we propose to study SLC10A2, the gene encoding the ilieal sodium-dependent bile acid transporter (ISBT), along with the VDR and EPHX1 genes. We will also conduct analyses to investigate if the main effects of these genes appear to be modified by selected environmental factors that have been hypothesized to affect risk of colorectal adenomas or cancer via an effect on bile acids. 3) To characterize systematically in vitro all non-synonymous SNPs in selected genes of epidemiologic interest, such as EPHXl (alias mEH) and MTHFR, by site-directed mutagenesis of the cloned enzyme, overexpression and appropriate assays, and to characterize systematically in vitro all SNPs in the 5' and 3' UTRs (untranslated region) of selected genes of epidemiologic interest in appropriate reporter constructs, e.g. expressing modified firefly luciferase. Our rationale for selecting alleles to be characterized is described in the Study Design and Methods section; 4) As a statistical method to better analyze complex metabolic pathways is further developed by Drs. Thomas and Cortessis, we will apply this method to data generated by this study.
Funding Period: 2003-08-01 - 2007-07-31
more information: NIH RePORT

Top Publications

  1. pmc Cancer risks for the relatives of colorectal cancer cases with a methylated MLH1 promoter region: data from the Colorectal Cancer Family Registry
    A Joan Levine
    Department of Preventive Medicine, Genetic Epidemiology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA
    Cancer Prev Res (Phila) 5:328-35. 2012
  2. ncbi Genetic variation in insulin pathway genes and distal colorectal adenoma risk
    A Joan Levine
    Department of Preventive Medicine, Genetic Epidemiology, University of Southern California Keck School of Medicine, NRT 1450 Biggy Street Room 1509A, Los Angeles, CA 90033, USA
    Int J Colorectal Dis 27:1587-95. 2012
  3. pmc Genetic variation in the base excision repair pathway, environmental risk factors, and colorectal adenoma risk
    Roman Corral
    Department of Preventive Medicine, Keck School of Medicine of USC, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, United States of America
    PLoS ONE 8:e71211. 2013
  4. pmc Variation in folate pathway genes and distal colorectal adenoma risk: a sigmoidoscopy-based case-control study
    A Joan Levine
    Department of Preventive Medicine, Genetic Epidemiology, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA
    Cancer Causes Control 22:541-52. 2011
  5. ncbi XRCC1 and XRCC3 polymorphisms and their role as effect modifiers of unsaturated fatty acids and antioxidant intake on colorectal adenomas risk
    Mariana C Stern
    Department of Preventive Medicine, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA
    Cancer Epidemiol Biomarkers Prev 14:609-15. 2005
  6. ncbi XRCC1, XRCC3, and XPD polymorphisms as modifiers of the effect of smoking and alcohol on colorectal adenoma risk
    Mariana C Stern
    University of Southern California Norris Comprehensive Cancer Center, Keck School of Medicine, 1441 Eastlake Avenue, Room 5421A, Los Angeles, CA 90089, USA
    Cancer Epidemiol Biomarkers Prev 15:2384-90. 2006

Scientific Experts

Detail Information

Publications6

  1. pmc Cancer risks for the relatives of colorectal cancer cases with a methylated MLH1 promoter region: data from the Colorectal Cancer Family Registry
    A Joan Levine
    Department of Preventive Medicine, Genetic Epidemiology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA
    Cancer Prev Res (Phila) 5:328-35. 2012
    ....
  2. ncbi Genetic variation in insulin pathway genes and distal colorectal adenoma risk
    A Joan Levine
    Department of Preventive Medicine, Genetic Epidemiology, University of Southern California Keck School of Medicine, NRT 1450 Biggy Street Room 1509A, Los Angeles, CA 90033, USA
    Int J Colorectal Dis 27:1587-95. 2012
    ....
  3. pmc Genetic variation in the base excision repair pathway, environmental risk factors, and colorectal adenoma risk
    Roman Corral
    Department of Preventive Medicine, Keck School of Medicine of USC, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, United States of America
    PLoS ONE 8:e71211. 2013
    ..Our findings strengthen the role of oxidative damage induced by key lifestyle and dietary risk factors in colorectal adenoma formation. ..
  4. pmc Variation in folate pathway genes and distal colorectal adenoma risk: a sigmoidoscopy-based case-control study
    A Joan Levine
    Department of Preventive Medicine, Genetic Epidemiology, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA
    Cancer Causes Control 22:541-52. 2011
    ..Folate-associated one-carbon metabolism (FOCM) is an important pathway in colorectal neoplasia risk but data on genetic variation in this pathway are largely limited to studies of single SNPs in selected genes...
  5. ncbi XRCC1 and XRCC3 polymorphisms and their role as effect modifiers of unsaturated fatty acids and antioxidant intake on colorectal adenomas risk
    Mariana C Stern
    Department of Preventive Medicine, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA
    Cancer Epidemiol Biomarkers Prev 14:609-15. 2005
    ....
  6. ncbi XRCC1, XRCC3, and XPD polymorphisms as modifiers of the effect of smoking and alcohol on colorectal adenoma risk
    Mariana C Stern
    University of Southern California Norris Comprehensive Cancer Center, Keck School of Medicine, 1441 Eastlake Avenue, Room 5421A, Los Angeles, CA 90089, USA
    Cancer Epidemiol Biomarkers Prev 15:2384-90. 2006
    ..04). Our data suggest that the effects of smoking and alcohol may vary depending on the genetic background of proteins that participate in the base excision repair and nucleotide excision repair pathways...