Identification of genes uniquely involved in frequent microsatellite instability colon carcinogenesis by expression profiling combined with epigenetic scanning.
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 right-sided tumors. This methylation screening strategy should identify additional genes inactivated by epigenetic silencing in colorectal and other cancers.
Mori
Yuriko
Y
Department of Medicine, Division of Gastroenterology, University of Maryland School of Medicine and Greenebaum Cancer Center and Baltimore Veterans Affairs Hospital, Baltimore, Maryland, USA. ymori001@umaryland.edu
Yin
Jing
J
Sato
Fumiaki
F
Sterian
Anca
A
Simms
Lisa A
LA
Selaru
Florin M
FM
Schulmann
Karsten
K
Xu
Yan
Y
Olaru
Andreea
A
Wang
Suna
S
Deacu
Elena
E
Abraham
John M
JM
Young
Joanne
J
Leggett
Barbara A
BA
Meltzer
Stephen J
SJ
D048868:Adaptor Proteins, Signal Transducing; D000368:Aged; D002352:Carrier Proteins; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism; D018899:CpG Islands; D019175:DNA Methylation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics*; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D009687:Nuclear Proteins; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis / Q000235:genetics; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020691:rab GTP-Binding Proteins / Q000096:biosynthesis / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C516868:PTPRU protein, human; D017027:Protein Tyrosine Phosphatases; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2; C466094:Rab32 protein, human; D000070957:MutL Protein Homolog 1; D020691:rab GTP-Binding Proteins