Methylation of APC, TIMP3, and TERT: a new predictive marker to distinguish Barrett's oesophagus patients at risk for malignant transformation.
Barrett's associated oesophageal adenocarcinoma (EAC) is one of the most rapidly increasing malignancies in Western countries. Because of its poor prognosis, management of this disease through screening of Barrett's oesophagus (BE) patients and identification of those with a high risk of developing an adenocarcinoma seems a promising approach. Early molecular markers of malignant transformation might contribute to such screening approaches. Gene promoter methylation analysis was performed on normal, pre-neoplastic, and neoplastic lesions from BE patients. All lesions of interest were sampled by microdissection from formalin-fixed paraffin-embedded tissue sections. We found that, in 27 adenocarcinomas, APC, TIMP3, TERT, CDKN2A, and SFRP1 promoters were methylated in 93%, 65%, 64%, 48%, and 91%, respectively; in contrast MLH1, RASSF1, RARB, CDH1, and FHIT promoters were methylated in less than 5% of the tumours. In BE mucosa from patients who had progressed to adenocarcinoma (12 samples), APC, TIMP3, and TERT promoters were hypermethylated in 100%, 91%, and 92% of cases, whereas in BE mucosa from patients who had not progressed (16 samples) methylation was found only in 36%, 23%, and 17%, respectively. Furthermore, the epigenetic profile of BE with and without EAC differed significantly with, respectively, 81% and 26% of the PCR samples showing promoter hypermethylation for APC, TIMP3, and TERT (p < 0.0001). Promoter methylation of CDKN2A was infrequently detected in BE samples, while SFRP1 methylation was observed in all samples. Our results suggest that promoter methylation profiling of BE using multiple target genes including APC, TIMP3, and TERT might be used as a predictive marker for increased EAC risk.
Clément
Geneviève
G
Institut de Pathologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
Braunschweig
Richard
R
Pasquier
Nathalie
N
Bosman
Fred T
FT
Benhattar
Jean
J
D000230:Adenocarcinoma / Q000737:chemistry / Q000235:genetics / Q000473:pathology*; D001471:Barrett Esophagus / Q000378:metabolism / Q000473:pathology*; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics*; D004938:Esophageal Neoplasms / Q000737:chemistry / Q000235:genetics / Q000473:pathology*; D017491:Genes, APC; D052138:Genes, Neoplasm / Q000235:genetics*; D016147:Genes, Tumor Suppressor; D019942:Genes, p16; D018740:Genetic Heterogeneity; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000032:analysis / Q000235:genetics; D008565:Membrane Proteins / Q000032:analysis / Q000235:genetics; D009363:Neoplasm Proteins / Q000032:analysis / Q000235:genetics; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D012307:Risk Factors; D019098:Telomerase / Q000032:analysis / Q000235:genetics*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000032:analysis / Q000235:genetics*; D000094742:Secreted Frizzled-Related Proteins
D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D019098:Telomerase; D019717:Tissue Inhibitor of Metalloproteinase-3; C117636:SFRP1 protein, human; D000094742:Secreted Frizzled-Related Proteins; C088390:TIMP3 protein, human; C509186:TERT protein, human