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VWA2  encodes AMACO, a secreted protein up-regulated in most colorectal carcinomas (CRC), constituting a promising biomarker. The mechanism responsible for its aberrant up-regulation has not been previously described. In this work, we analyzed  VWA2  DNA methylation in over 400 primary CRCs. No epigenetic alterations were found in its promoter-associated CpG island. However, the region located downstream of the transcriptional start site was hypomethylated in most CRCs. ChIP-Seq revealed increased levels of the active mark H3K4me3 and reduction of the repressive mark H3K27me3. In contrast, several CRC cell lines exhibited hypermethylation of  VWA2 . 5-AZA-2-deoxycitidine treatment led to transcriptional activation of  VWA2 , supporting a functional link between DNA methylation and transcription.  VWA2  expression in primary CRCs correlated with that of Myc and Myc-target genes. Transcriptional up-regulation of  VWA2  is extremely frequent (78%) and strong (average fold change >15) in CRC, but not in other types of cancer.  VWA2  undergoes hypomethylation in the majority of CRCs. This alteration could partly underlie the previously reported over-expression of AMACO. Co-expression profiling suggests that  VWA2  might be a constituent of a larger oncogenic transcriptional program regulated by c-Myc. Up-regulation of  VWA2  is virtually exclusive of CRC, reinforcing its potential as a specific biomarker.

Epigenetic and transcriptional dysregulation of VWA2 associated with a MYC-driven oncogenic program in colorectal cancer