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Background  Tumor development in the human colon is commonly accompanied by epigenetic changes, such as DNA methylation and chromatin modifications. These alterations result in significant, inheritable changes in gene expression that contribute to the selection of tumor cells with enhanced survival potential.    Results  A recent high-throughput gene expression analysis conducted by our group identified numerous genes whose transcription was markedly diminished in colorectal tumors. One of these, the   p rotein- t yrosine  p hosphatase  r eceptor type  R   ( PTPRR ) gene, was dramatically downregulated from the earliest stages of cellular transformation. Here, we show that levels of both major  PTPRR  transcript variants are markedly decreased (compared with normal mucosal levels) in precancerous and cancerous colorectal tumors, as well in colorectal cancer cell lines. The expression of the  PTPRR-1  isoform was inactivated in colorectal cancer cells as a result of  de novo  CpG island methylation and enrichment of transcription-repressive histone-tail marks, mainly H3K27me3.  De novo  methylation of the  PTPRR-1  transcription start site was demonstrated in 29/36 (80%) colorectal adenomas, 42/44 (95%) colorectal adenocarcinomas, and 8/8 (100%) liver metastases associated with the latter tumors.    Conclusions  Epigenetic downregulation of  PTPRR  seems to be an early alteration in colorectal cell transformation, which is maintained during the clonal selection associated with tumor progression. It may represent a preliminary step in the constitutive activation of the RAS/RAF/MAPK/ERK signalling, an effect that will later be consolidated by mutations in genes encoding key components of this pathway.

The protein tyrosine phosphatase receptor type R gene is an early and frequent target of silencing in human colorectal tumorigenesis