Expression Profiling Combined with Epigenetic Scanning Microsatellite Instability Colon Carcinogenesis by Identification of Genes Uniquely Involved in Frequent Updated

Gene silencing through CpG island hypermethylation has been associated with genesis or progression of frequent microsatellite instability (MSI-H) cancers. To identify novel methylation sites unique to MSI-H colon cancers in an unbiased fashion, we conducted a global expression profiling-based methylation target search. We identified 81 genes selectively down-regulated in MSI-H cancers using cDNA microarray analysis of 41 primary colon cancers. Forty six of these 81 genes contained CpG islands overlapping their 5 untranslated regions. Initial screening of six genes in 57 primary colon cancers detected the following gene with MSI-H cancer-specific hypermethylation: RAB32, a ras family member and A-kinase-anchoring protein, was methylated in 14 of 25 (56%) MSI-H cancers but in none of 32 non-MSI-H cancers or 23 normal colonic specimens. RAB32 hypermethylation correlated with RAB32 mRNA down-regulation and with hMLH1 hypermethylation. In addition, the protein-tyrosine phosphatase receptor type O gene, PTPRO, was frequently methylated in rightsided tumors. This methylation screening strategy should identify additional genes inactivated by epigenetic silencing in colorectal and other cancers.

[1]  Yue-zhong Wu,et al.  Suppression of the protein tyrosine phosphatase receptor type O gene (PTPRO) by methylation in hepatocellular carcinomas , 2003, Oncogene.

[2]  B. Leggett,et al.  The impact of microsatellite instability on the molecular phenotype of colorectal tumors. , 2003, Cancer research.

[3]  M. Perucho,et al.  Genetics supersedes epigenetics in colon cancer phenotype. , 2003, Cancer cell.

[4]  Rui Qiao,et al.  BRAF oncogenic mutations correlate with progression rather than initiation of human melanoma. , 2003, Cancer research.

[5]  S. Ross.  Diet and DNA Methylation Interactions in Cancer Prevention , 2003, Annals of the New York Academy of Sciences.

[6]  F. Sato,et al.  Pharmacologic unmasking of epigenetically silenced tumor suppressor genes in esophageal squamous cell carcinoma. , 2002, Cancer cell.

[7]  S. Toyooka,et al.  Aberrant methylation of the HPP1 gene in ulcerative colitis-associated colorectal carcinoma. , 2002, Cancer research.

[8]  K. Kinzler,et al.  Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status , 2002, Nature.

[9]  John D. Scott,et al.  Rab32 is an A-kinase anchoring protein and participates in mitochondrial dynamics , 2002, The Journal of cell biology.

[10]  P. Stork,et al.  Crosstalk between cAMP and MAP kinase signaling in the regulation of cell proliferation. , 2002, Trends in cell biology.

[11]  B. Leggett,et al.  Features of colorectal cancers with high-level microsatellite instability occurring in familial and sporadic settings: parallel pathways of tumorigenesis. , 2001, The American journal of pathology.

[12]  S. Groshen,et al.  Hypermethylated APC DNA in plasma and prognosis of patients with esophageal adenocarcinoma. , 2000, Journal of the National Cancer Institute.

[13]  Scar,et al.  Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. , 2000, The New England journal of medicine.

[14]  J. Herman,et al.  DNA hypermethylation in tumorigenesis: epigenetics joins genetics. , 2000, Trends in genetics : TIG.

[15]  J. Herman,et al.  CpG island methylator phenotype in colorectal cancer. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

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

[17]  Susan S. Taylor,et al.  Phosphorylation and inactivation of BAD by mitochondria-anchored protein kinase A. , 1999, Molecular cell.

[18]  S. Papa,et al.  cAMP‐dependent protein kinase and phosphoproteins in mammalian mitochondria. An extension of the cAMP‐mediated intracellular signal transduction , 1999, FEBS letters.

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

[20]  Y. Hosoya,et al.  Establishment of methylation-sensitive-representational difference analysis and isolation of hypo- and hypermethylated genomic fragments in mouse liver tumors. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[21]  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.

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

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

[24]  Darryl Shibata,et al.  Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis , 1993, Nature.

[25]  S N Thibodeau,et al.  Microsatellite instability in cancer of the proximal colon. , 1993, Science.