Long-range epigenetic silencing at 2q14.2 affects most human colorectal cancers and may have application as a non-invasive biomarker of disease

Abstract

Large chromosomal regions can be suppressed in cancer cells as denoted by hypermethylation of neighbouring CpG islands and downregulation of most genes within the region. We have analysed the extent and prevalence of long-range epigenetic silencing at 2q14.2 (the first and best characterised example of coordinated epigenetic remodelling) and investigated its possible applicability as a non-invasive diagnostic marker of human colorectal cancer using different approaches and biological samples. Hypermethylation of at least one of the CpG islands analysed (EN1, SCTR, INHBB) occurred in most carcinomas (90%), with EN1 methylated in 73 and 40% of carcinomas and adenomas, respectively. Gene suppression was a common phenomenon in all the tumours analysed and affected both methylated and unmethylated genes. Detection of methylated EN1 using bisulfite treatment and melting curve (MC) analysis from stool DNA in patients and controls resulted in a predictive capacity of, 44% sensitivity in positive patients (27% of overall sensitivity) and 97% specificity. We conclude that epigenetic suppression along 2q14.2 is common to most colorectal cancers and the presence of a methylated EN1 CpG island in stool DNA might be used as biomarker of neoplastic disease.

Long-Range Epigenetic Silencing Associates with Deregulation of Ikaros Targets in Colorectal Cancer Cells

“…More recently, genome-wide surveys have uncovered other mechanisms. For instance, Frigola and colleagues found coordinated hypermethylation of 12 closely located CpG islands in colorectal cancer (7) and recent data suggest that concurrent hypermethylation of adjacent CpG islands and associated gene repression, also known as long-range epigenetic silencing (LRES), may be a more common phenomenon in cancer than previously recognized (8)(9)(10)(11).…”

“…As mentioned above, recent genome-scale analyses have identified large chromosomal regions containing several CpG island often hypermethylated and transcriptionally repressed termed as LRES (7)(8)(9)(10)(11)18). LRES is frequent in colorectal cancer (7,11).…”

“…LRES is frequent in colorectal cancer (7,11). Given the absence of EZH2 targeting to the Ikaros promoter, we wondered whether its hypermethylation in colorectal cancer is associated with an LRES event.…”

Dynamics of bivalent chromatin domains upon drug induced reactivation and resilencing in cancer cells

“…In previous studies we have shown that LRES affects chromosomal regions 2q14.2 and 5q35.2 in most colorectal cancers. 3,6,30 Although genetic activity is downregulated all along the LRES region, uneven epigenetic profiles are likely to define different chromatin domains. To better characterize the epigenetic regulation of the diverse chromatin domains in LRES we have investigated gene expression and epigenetic profiles in nine and six genes embedded in chromosomal regions 2q14.2 and 5q35.2, respectively, in HCT116 colon cancer cells.…”

Epigenetic Deregulation Across Chromosome 2q14.2 Differentiates Normal from Prostate Cancer and Provides a Regional Panel of Novel DNA Methylation Cancer Biomarkers

“…We have previously shown that gene expression across the 4-Mb chromosomal region 2q14.2 is commonly suppressed in colorectal cancer and this is associated with aberrant DNA and histone methylation (29). Moreover, a hypermethylated gene in the 2q14.2 region, Engrailed-1 (EN1), is a useful diagnostic marker in stool and serum DNA samples in colorectal cancer patients (30). The aim of this study was to investigate the epigenetic state of the 2q14.2 region in prostate cancer and to determine the potential of aberrant methylation of genes within the region in prostate cancer diagnosis and prognosis.…”