Analysis of somatic DNA methylation alterations of genes encoding cell surface metallopeptidases in colorectal cancer

Abstract

The genome of cancer cells accumulates numerous genetic and epigenetic somatic alterations ultimately conferring capabilities for unrestrained growth, invasion of local tissues, migration, and colonization of distant organs. Many of these new capabilities require the disruption of the cell-to-cell interactions between the cancer cell and its microenvironment. These interactions are mediated, among other factors, by the activity of extracellular enzymes that reshape not only the extracellular compartment of the cancer cells but also that of the neighboring non-cancerous stroma cells. Cell surface metallopeptidases play a crucial role in this process, by cleaving and modifying fundamental components of the extracellular compartment. The transcriptional profile of cell surface metallopeptidases becomes deregulated in several human cancers by genetic and epigenetic alterations, contributing to the tumor phenotype. In this article, we describe two common strategies to analyze somatic epigenetic alterations of cell surface metallopeptidases, i.e., high-resolution single locus analysis and high-throughput multi-loci analysis, presenting several illustrative analyses performed on our CRC collection. These analyses demonstrate that cell surface metallopeptidases, particularly those belonging to the ADAMTS gene family, frequently undergo somatic DNA hypermethylation in CRC suggesting the existence of an underlying mechanism or a strong selection process favoring the transcriptional silencing of these genes.