Long-range epigenetic silencing at 2q14.2 affects most human colorectal cancers and may have application as a non-invasive biomarker of disease.
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.
Mayor
R
R
Institut de Medicina Predictiva i Personalitzada del Càncer (IMPPC), Badalona, Catalonia, Spain.
Casadomé
L
L
Azuara
D
D
Moreno
V
V
Clark
S J
SJ
Capellà
G
G
Peinado
M A
MA
D000236:Adenoma / Q000175:diagnosis / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D002277:Carcinoma / Q000175:diagnosis* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D002889:Chromosomes, Human, Pair 2; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000502:physiology*; D005243:Feces / Q000737:chemistry; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing / Q000502:physiology; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D028322:Inhibin-beta Subunits / Q000235:genetics; D025202:Molecular Diagnostic Techniques / Q000379:methods; D009367:Neoplasm Staging; D011379:Prognosis; D016019:Survival Analysis
D014408:Biomarkers, Tumor; C513076:EN1 protein, human; D018398:Homeodomain Proteins; C422402:INHBB protein, human; D028322:Inhibin-beta Subunits