Loss of imprinting of the insulin-like growth factor II gene occurs by biallelic methylation in a core region of H19-associated CTCF-binding sites in colorectal cancer

Proc Natl Acad Sci U S A. 2001 Jan 16;98(2):591-6. doi: 10.1073/pnas.98.2.591. Epub 2000 Dec 19.

Abstract

We hypothesize that loss of imprinting (LOI) of the insulin-like growth factor II (IGF2) gene is associated with a predisposition to sporadic colorectal cancer. We confirmed a previously known strong correlation between LOI and microsatellite instability and showed that LOI was not a consequence of microsatellite instability or mismatch repair deficiency. LOI of IGF2 correlated strongly with biallelic hypermethylation of a core of five CpG sites in the insulator region of IGF2/H19, which is a known CTCF-binding element. As this methylation-dependent LOI was present in both tumors and normal colonic mucosa, it is possible that hypermethylation creates a field defect predisposing to cancer.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Adenocarcinoma / genetics*
  • Alleles
  • Animals
  • Base Pair Mismatch / genetics
  • Binding Sites
  • CCCTC-Binding Factor
  • Carrier Proteins
  • Colon / metabolism
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics
  • CpG Islands*
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • DNA (Cytosine-5-)-Methyltransferases / physiology
  • DNA Methylation*
  • DNA Repair / genetics
  • DNA-Binding Proteins / metabolism*
  • Enhancer Elements, Genetic
  • Female
  • Gene Expression Regulation, Neoplastic / genetics*
  • Gene Silencing
  • Genes, Regulator*
  • Genes, p16
  • Genetic Predisposition to Disease
  • Genomic Imprinting*
  • Heterozygote
  • Humans
  • Insulin-Like Growth Factor II / genetics*
  • Intestinal Mucosa / metabolism
  • Male
  • Mice
  • Microsatellite Repeats
  • MutL Protein Homolog 1
  • Neoplasm Proteins / genetics
  • Nuclear Proteins
  • Phenotype
  • Promoter Regions, Genetic
  • RNA, Long Noncoding
  • RNA, Untranslated / genetics*
  • Repressor Proteins*
  • Species Specificity
  • Transcription Factors / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • CCCTC-Binding Factor
  • CTCF protein, human
  • Carrier Proteins
  • Ctcf protein, mouse
  • DNA-Binding Proteins
  • H19 long non-coding RNA
  • MLH1 protein, human
  • Mlh1 protein, mouse
  • Neoplasm Proteins
  • Nuclear Proteins
  • RNA, Long Noncoding
  • RNA, Untranslated
  • Repressor Proteins
  • Transcription Factors
  • Insulin-Like Growth Factor II
  • DNA (Cytosine-5-)-Methyltransferases
  • MutL Protein Homolog 1