Diet and DNA methylation in colon mucosa and adenomas

Summary

Principal Investigator: Jean Pierre Issa
Abstract: [unreadable] DESCRIPTION (provided by applicant): [unreadable] DNA methylation within promoter-associated CpG islands marks and/or mediates epigenetic silencing in human cells. In normal colon, aberrant DNA methylation arises as a function of age and has been proposed as a mechanism contributing to age-related risk for colorectal tumors. Separately, a subset of colorectal tumors is characterized by intense hypermethylation of multiple genes, a process termed CpG Island Methylator Phenotype (CIMP). The factors that initiate and/or modulate age-related methylation and CIMP remain unknown. Based on preliminary data suggesting that dietary (fiber, folate) and/or lifestyle factors (alcohol, smoking) could modulate these processes, we propose the following hypotheses: (1) dietary factors influence the methylation status of genes in normal colon epithelium, (2) dietary factors influence the prevalence of CIMP in colorectal tumors and (3) Constitutive polymorphisms (MTHFR) modify the interactions between diet and hypermethylation in the colon. To test these hypotheses, we will use the unique resource of a wellcharacterized patient population enrolled in a trial of the prevention of colorectal adenomas by folate supplementation. Our specific aims are: (1) To determine associations between diet (folate, fiber, fat) and gene-specific DNA methylation (for multiple genes), as well as global DNA methylation (Alu methylation) in colon mucosa biopsies, controlling for MTHFR genotype, (2) to determine associations between diet (folate, fiber, fat) and CIMP status in colonic adenomas, controlling for MTHFR genotype and (3) to determine the effect of folate supplementation on DNA methylation (gene-specific and global) in colon mucosa and colon adenomas. These studies should provide definitive information on interactions between diet and DNA methylation in human colorectal mucosa and cancer. [unreadable] [unreadable]
Funding Period: 2004-07-13 - 2008-04-30
more information: NIH RePORT

Top Publications

  1. pmc LINE-1 hypomethylation in cancer is highly variable and inversely correlated with microsatellite instability
    Marcos R H Estecio
    Department of Leukemia, University of Texas M D Anderson Cancer Center, Houston, Texas, United States of America
    PLoS ONE 2:e399. 2007
  2. pmc DNA methylation profiles of primary colorectal carcinoma and matched liver metastasis
    Kazuo Konishi
    Department of Leukemia, Division of Cancer Medicine, The University of Texas M D Anderson Cancer Center, Houston, Texas, United States of America
    PLoS ONE 6:e27889. 2011
  3. pmc Frequent alteration of MLL3 frameshift mutations in microsatellite deficient colorectal cancer
    Yoshiyuki Watanabe
    Department of Leukemia, The University of Texas M D Anderson Cancer Center, Houston, Texas, United States of America
    PLoS ONE 6:e23320. 2011
  4. pmc Association between folate levels and CpG Island hypermethylation in normal colorectal mucosa
    Kristin Wallace
    Department of Medicine, Dartmouth Medical School, Evergreen Center, Lebanon, NH 03756, USA
    Cancer Prev Res (Phila) 3:1552-64. 2010
  5. pmc Widespread and tissue specific age-related DNA methylation changes in mice
    Shinji Maegawa
    Department of Leukemia, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA
    Genome Res 20:332-40. 2010
  6. pmc Concordant DNA methylation in synchronous colorectal carcinomas
    Kazuo Konishi
    Department of Leukemia, The University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA
    Cancer Prev Res (Phila) 2:814-22. 2009
  7. pmc Targeting DNA methylation
    Jean Pierre J Issa
    Department of Leukemia and Center for Cancer Epigenetics, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
    Clin Cancer Res 15:3938-46. 2009
  8. pmc Sensitive and specific detection of early gastric cancer with DNA methylation analysis of gastric washes
    Yoshiyuki Watanabe
    Department of Leukemia, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA
    Gastroenterology 136:2149-58. 2009
  9. pmc Global DNA hypomethylation (LINE-1) in the normal colon and lifestyle characteristics and dietary and genetic factors
    Jane C Figueiredo
    Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
    Cancer Epidemiol Biomarkers Prev 18:1041-9. 2009
  10. pmc An Sp1/Sp3 binding polymorphism confers methylation protection
    Yanis A Boumber
    Department of Leukemia, MD Anderson Cancer Center, University of Texas, Houston, Texas, United States of America
    PLoS Genet 4:e1000162. 2008

Scientific Experts

  • Lanlan Shen
  • JOHN ANTHONY BARON
  • Jean Pierre J Issa
  • Kazuo Konishi
  • Yoshiyuki Watanabe
  • Jaroslav Jelinek
  • Marcos R H Estecio
  • Fumio Itoh
  • Shinji Maegawa
  • Woonbok Chung
  • Ryan J Castoro
  • Hyun Soo Kim
  • Kristin Wallace
  • Saira Ahmed
  • Yi Guo
  • Yanis A Boumber
  • Kimie Kondo
  • Saira S Ahmed
  • Minoru Toyota
  • Stanley R Hamilton
  • Mee Yon Cho
  • Michio Imawari
  • Randala Hamdan
  • Robert W Haile
  • A Joan Levine
  • Gail McKeown-Eyssen
  • Maria V Grau
  • Yutaka Kondo
  • Xinli Chen
  • Jane C Figueiredo
  • Alberto J Montero
  • Marcos R Estecio
  • Tetsuya Hiraishi
  • Ritsuko Oikawa
  • Brittany North
  • George Hinkal
  • Shoudan Liang
  • Dennis Ahnen
  • Li Zhang
  • Jiang Gui
  • Lawrence A Donehower
  • Elizabeth L Barry
  • Jiexin Zhang
  • Nianxiang Zhang
  • Mari Kogo
  • Kazuhiro Kaneko
  • Ki Tae Suk
  • Toshihumi Takano
  • Robert S Bresalier
  • Carmen Tellez
  • Xuqi Chen
  • Ketan Doshi
  • Pearlly S Yan
  • Stephen J Meltzer
  • Eloiza H Tajara
  • Ashraf E K Ibrahim
  • Noam Harpaz
  • Vazganush Gharibyan
  • Rong He
  • Allen S Yang
  • Tim H M Huang
  • Suna Wang
  • Marcos Estecio
  • Emile M Youssef
  • Li Mao
  • C Marcela Diaz-Montero

Detail Information

Publications18

  1. pmc LINE-1 hypomethylation in cancer is highly variable and inversely correlated with microsatellite instability
    Marcos R H Estecio
    Department of Leukemia, University of Texas M D Anderson Cancer Center, Houston, Texas, United States of America
    PLoS ONE 2:e399. 2007
    ..This study was performed to determine the relationship between DNA hypomethylation, hypermethylation and microsatellite instability in cancer...
  2. pmc DNA methylation profiles of primary colorectal carcinoma and matched liver metastasis
    Kazuo Konishi
    Department of Leukemia, Division of Cancer Medicine, The University of Texas M D Anderson Cancer Center, Houston, Texas, United States of America
    PLoS ONE 6:e27889. 2011
    ..The contribution of DNA methylation to the metastatic process in colorectal cancers (CRCs) is unclear...
  3. pmc Frequent alteration of MLL3 frameshift mutations in microsatellite deficient colorectal cancer
    Yoshiyuki Watanabe
    Department of Leukemia, The University of Texas M D Anderson Cancer Center, Houston, Texas, United States of America
    PLoS ONE 6:e23320. 2011
    ..Mutations in MLL3 were found in a whole genome analysis of colorectal cancer but have not been confirmed by a separate study...
  4. pmc Association between folate levels and CpG Island hypermethylation in normal colorectal mucosa
    Kristin Wallace
    Department of Medicine, Dartmouth Medical School, Evergreen Center, Lebanon, NH 03756, USA
    Cancer Prev Res (Phila) 3:1552-64. 2010
    ..These data have important implications regarding the safety of supplementary folate administration in healthy adults, given the hypothesis that methylation in normal mucosa may predispose to colorectal neoplasia...
  5. pmc Widespread and tissue specific age-related DNA methylation changes in mice
    Shinji Maegawa
    Department of Leukemia, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA
    Genome Res 20:332-40. 2010
    ..We conclude that epigenetic deregulation is a common feature of aging in mammals...
  6. pmc Concordant DNA methylation in synchronous colorectal carcinomas
    Kazuo Konishi
    Department of Leukemia, The University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA
    Cancer Prev Res (Phila) 2:814-22. 2009
    ..Screening for and secondary prevention of colon cancer should take this fact into account...
  7. pmc Targeting DNA methylation
    Jean Pierre J Issa
    Department of Leukemia and Center for Cancer Epigenetics, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
    Clin Cancer Res 15:3938-46. 2009
    ..But the idea of stably changing gene expression in vivo has transformative potential in cancer therapy and beyond...
  8. pmc Sensitive and specific detection of early gastric cancer with DNA methylation analysis of gastric washes
    Yoshiyuki Watanabe
    Department of Leukemia, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA
    Gastroenterology 136:2149-58. 2009
    ..We hypothesized that methylation analysis of DNA recovered from gastric washes could be used to detect gastric cancer...
  9. pmc Global DNA hypomethylation (LINE-1) in the normal colon and lifestyle characteristics and dietary and genetic factors
    Jane C Figueiredo
    Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
    Cancer Epidemiol Biomarkers Prev 18:1041-9. 2009
    ..Little is known about the relationships between global hypomethylation and lifestyle, demographics, dietary measures, and genetic factors...
  10. pmc An Sp1/Sp3 binding polymorphism confers methylation protection
    Yanis A Boumber
    Department of Leukemia, MD Anderson Cancer Center, University of Texas, Houston, Texas, United States of America
    PLoS Genet 4:e1000162. 2008
    ..Our finding demonstrates that, in some genes, hypermethylation in cancer is dictated by protein-DNA interactions at the promoters and provides a novel mechanism by which genetic polymorphisms can influence an epigenetic state...
  11. ncbi Drug sensitivity prediction by CpG island methylation profile in the NCI-60 cancer cell line panel
    Lanlan Shen
    Department of Leukemia, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA
    Cancer Res 67:11335-43. 2007
    ..Our results confirm that epigenetic profiles are useful in identifying molecular mediators for cancer drug sensitivity (pharmaco-epigenomics)...
  12. pmc Integrated genetic and epigenetic analysis identifies three different subclasses of colon cancer
    Lanlan Shen
    Department of Leukemia, University of Texas M D Anderson Cancer Center, Houston, TX 77030
    Proc Natl Acad Sci U S A 104:18654-9. 2007
    ..Together, our integrated genetic and epigenetic analysis reveals that colon cancers correspond to three molecularly distinct subclasses of disease...
  13. pmc Genome-wide profiling of DNA methylation reveals a class of normally methylated CpG island promoters
    Lanlan Shen
    Department of Leukemia, The University of Texas at M D Anderson Cancer Center, Houston, Texas, USA
    PLoS Genet 3:2023-36. 2007
    ....
  14. pmc Association between DNA methylation and shortened survival in patients with advanced colorectal cancer treated with 5-fluorouracil based chemotherapy
    Lanlan Shen
    The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
    Clin Cancer Res 13:6093-8. 2007
    ..We sought to determine the prognostic significance of CIMP in advanced colorectal cancer patients treated with 5-fluorouracil (5-FU) in an Eastern Cooperative Oncology Group clinical trial...
  15. ncbi Targeting aberrant chromatin structure in colorectal carcinomas
    Kazuo Konishi
    Department of Leukemia, University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA
    Cancer J 13:49-55. 2007
    ..Drugs that inhibit DNA methylation and histone deacetylation are in use in the clinic and should be tested in colorectal malignancy...
  16. ncbi Rare CpG island methylator phenotype in ulcerative colitis-associated neoplasias
    Kazuo Konishi
    Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
    Gastroenterology 132:1254-60. 2007
    ..Whether this translates into hypermethylation in UC-associated cancers (UC-Cs) is not known...
  17. ncbi Epigenetic inactivation of EGFR by CpG island hypermethylation in cancer
    Alberto J Montero
    Division of Hematology Oncology, Medical University of South Carolina, Charleston, South Carolina, USA
    Cancer Biol Ther 5:1494-501. 2006
    ..In conclusion, EGFR is hypermethylated and silenced in a subset of solid tumor cell lines and primary tumor specimens, and cotreatment with decitabine and gefitinib has an additive effect only in EGFR methylated breast cancer cell lines...
  18. ncbi DNA methylation as a therapeutic target in cancer
    Jean Pierre J Issa
    University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
    Clin Cancer Res 13:1634-7. 2007
    ..These drugs have now been approved for clinical use in the United States in the treatment of myelodysplastic syndrome, thus opening the floodgate for a whole new approach to cancer therapy--epigenetic therapy...