ABSTRACT
The main risk factor for esophageal dysplasia and adenocarcinoma (DAC) is Barrett's esophagus (BE), characterized by intestinal metaplasia. The critical genomic mechanisms that lead to progression of nondysplastic BE to DAC remain poorly understood and require analyses of longitudinal patient cohorts and high-resolution assays. We tested BE tissues from 74 patients, including 42 nonprogressors from two separate groups of 21 patients each and 32 progressors (16 in a longitudinal cohort before DAC/preprogression-BE and 16 with temporally concurrent but spatially separate DAC/concurrent-BE). We interrogated genome-wide somatic copy number alterations (SCNAs) at the exon level with high-resolution SNP arrays in DNA from formalin-fixed samples histologically confirmed as nondysplastic BE. The most frequent abnormalities were SCNAs involving FHIT exon 5, CDKN2A/B or both in 88% longitudinal BE progressors to DAC vs. 24% in both nonprogressor groups (p = 0.0004). Deletions in other genomic regions were found in 56% of preprogression-BE but only in one nonprogressor-BE (p = 0.0004). SCNAs involving FHIT exon 5 and CDKN2A/B were also frequently detected in BE temporally concurrent with DAC. TP53 losses were detected in concurrent-BE but not earlier in preprogression-BE tissues of patients who developed DAC. CDKN2A/p16 immunohistochemistry showed significant loss of expression in BE of progressors vs. nonprogressors, supporting the genomic data. Our data suggest a role for CDKN2A/B and FHIT in early progression of BE to dysplasia and adenocarcinoma that warrants future mechanistic research. Alterations in CDKN2A/B and FHIT by high-resolution assays may serve as biomarkers of increased risk of progression to DAC when detected in BE tissues.
Subject(s)
Adenocarcinoma/pathology , Barrett Esophagus/genetics , Biomarkers, Tumor/genetics , Esophageal Mucosa/pathology , Esophageal Neoplasms/pathology , Precancerous Conditions/genetics , Acid Anhydride Hydrolases/genetics , Adult , Aged , Barrett Esophagus/pathology , Cyclin-Dependent Kinase Inhibitor p15/genetics , Cyclin-Dependent Kinase Inhibitor p16/genetics , DNA Copy Number Variations , Disease Progression , Exons/genetics , Female , Humans , In Situ Hybridization, Fluorescence , Longitudinal Studies , Male , Middle Aged , Neoplasm Proteins/genetics , Polymorphism, Single Nucleotide , Precancerous Conditions/pathology , Tumor Suppressor Protein p53/geneticsABSTRACT
Objective To investigate the effect of Smo siRNA on the aggressive capability of human esophageal carcinoma EC9706 cells.Methods EC9706 cells were transfected by Smo siRNA.The expressions of Smo and Glil protein in experimental and control groups were detected with immunocytochemistry.The expressions of Smo and Gli1 mRNA in experimental and control groups were detected with in situ hybridization.The change of aggressive capability in all groups was detected by Boyden chamber in vitro.Results Compared with control group,there was a significant decrease in the protein and mRNA levels of Smo and Gli1 in every specific siRNA transfection group with three different concentration (P ＜ 0.05).The aggressive capability of EC9706 cells was significantly weakened after the transfection (P ＜ 0.05).Conclusions Smo siRNA can inhibit the expressions of Smo and Gli1 genes in EC9706 cells,and can also weaken the aggressive capability of EC9706 cells.
