CpG island methylator phenotype in colorectal cancer.

Aberrant methylation of promoter region CpG islands is associated with transcriptional inactivation of tumor-suppressor genes in neoplasia. To understand global patterns of CpG island methylation in colorectal cancer, we have used a recently developed technique called methylated CpG island amplification to examine 30 newly cloned differentially methylated DNA sequences. Of these 30 clones, 19 (63%) were progressively methylated in an age-dependent manner in normal colon, 7 (23%) were methylated in a cancer-specific manner, and 4 (13%) were methylated only in cell lines. Thus, a majority of CpG islands methylated in colon cancer are also methylated in a subset of normal colonic cells during the process of aging. In contrast, methylation of the cancer-specific clones was found exclusively in a subset of colorectal cancers, which appear to display a CpG island methylator phenotype (CIMP). CIMP+ tumors also have a high incidence of p16 and THBS1 methylation, and they include the majority of sporadic colorectal cancers with microsatellite instability related to hMLH1 methylation. We thus define a pathway in colorectal cancer that appears to be responsible for the majority of sporadic tumors with mismatch repair deficiency.

[1]  S. Baylin,et al.  Identification of differentially methylated sequences in colorectal cancer by methylated CpG island amplification. , 1999, Cancer research.

[2]  S. Baylin,et al.  Aging and DNA methylation in colorectal mucosa and cancer. , 1998, Cancer research.

[3]  S N Thibodeau,et al.  Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability. , 1998, Cancer research.

[4]  S. Baylin,et al.  Concordant methylation of the ER and N33 genes in glioblastoma multiforme , 1998, Oncogene.

[5]  J. Herman,et al.  Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[6]  R. White,et al.  Tumor Suppressing Pathways , 1998, Cell.

[7]  J. Herman,et al.  Alterations in DNA methylation: a fundamental aspect of neoplasia. , 1998, Advances in cancer research.

[8]  J. Herman,et al.  Association between CpG island methylation and microsatellite instability in colorectal cancer. , 1997, Cancer research.

[9]  P. Laird,et al.  COBRA: a sensitive and quantitative DNA methylation assay. , 1997, Nucleic acids research.

[10]  M. Slattery,et al.  Microsatellite instability in colorectal adenomas. , 1997, Gastroenterology.

[11]  L. Harris,et al.  Cytoplasmic sequestration of an O6-methylguanine-DNA methyltransferase enhancer binding protein in DNA repair-deficient human cells. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[12]  T. Bestor,et al.  Formation of methylation patterns in the mammalian genome. , 1997, Mutation research.

[13]  M. Loda,et al.  Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. , 1997, Cancer research.

[14]  J C Reed,et al.  Somatic Frameshift Mutations in the BAX Gene in Colon Cancers of the Microsatellite Mutator Phenotype , 1997, Science.

[15]  A. de la Chapelle,et al.  Mutations predisposing to hereditary nonpolyposis colorectal cancer. , 1997, Advances in cancer research.

[16]  K. Kinzler,et al.  Lessons from Hereditary Colorectal Cancer , 1996, Cell.

[17]  S. Baylin,et al.  Methylation of the estrogen receptor CpG island in lung tumors is related to the specific type of carcinogen exposure. , 1996, Cancer research.

[18]  T. Iwama,et al.  Molecular nature of colon tumors in hereditary nonpolyposis colon cancer, familial polyposis, and sporadic colon cancer. , 1996, Gastroenterology.

[19]  S. Baylin,et al.  De novo methylation of CpG island sequences in human fibroblasts overexpressing DNA (cytosine-5-)-methyltransferase , 1996, Molecular and cellular biology.

[20]  B. Andrews,et al.  Binding to the yeast SwI4,6-dependent cell cycle box, CACGAAA, is cell cycle regulated in vivo. , 1996, Nucleic acids research.

[21]  J. Herman,et al.  Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers. , 1995, Cancer research.

[22]  K. Kinzler,et al.  Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. , 1995, Science.

[23]  R. Weinberg,et al.  Suppression of intestinal neoplasia by DNA hypomethylation , 1995, Cell.

[24]  A. Kamb,et al.  Cell-cycle regulators and cancer. , 1995, Trends in genetics : TIG.

[25]  K. A. Walker,et al.  Epigenetic Gene Inactivation Induced by a Cis-acting Methylation Center (*) , 1995, The Journal of Biological Chemistry.

[26]  A. Bird,et al.  Sp1 sites in the mouse aprt gene promoter are required to prevent methylation of the CpG island. , 1994, Genes & development.

[27]  Z. Siegfried,et al.  Spl elements protect a CpG island from de novo methylation , 1994, Nature.

[28]  K. Dameron,et al.  Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. , 1994, Science.

[29]  P. Jones,et al.  Ubiquitous and tenacious methylation of the CpG site in codon 248 of the p53 gene may explain its frequent appearance as a mutational hot spot in human cancer , 1994, Molecular and cellular biology.

[30]  S. Baylin,et al.  Methylation of the oestrogen receptor CpG island links ageing and neoplasia in human colon , 1994, Nature Genetics.

[31]  M. Turker,et al.  A cis-acting element accounts for a conserved methylation pattern upstream of the mouse adenine phosphoribosyltransferase gene. , 1993, The Journal of biological chemistry.

[32]  A. Bird,et al.  High levels of De Novo methylation and altered chromatin structure at CpG islands in cell lines , 1990, Cell.

[33]  P. Holt,et al.  Colonic proliferation is increased in senescent rats. , 1988, Gastroenterology.

[34]  L. Roncucci,et al.  The influence of age on colonic epithelial cell proliferation , 1988, Cancer.

[35]  M. Lipkin.  Biomarkers of increased susceptibility to gastrointestinal cancer: new application to studies of cancer prevention in human subjects. , 1988, Cancer research.

[36]  M. Frommer,et al.  CpG islands in vertebrate genomes. , 1987, Journal of molecular biology.

[37]  A. Bird.  CpG-rich islands and the function of DNA methylation , 1986, Nature.