Correlation between dysplasia and mutations of six tumor suppressor genes in Barrett's esophagus.

Abstract

Barrett's esophagus (BE) may progress to adenocarcinoma through dysplastic progression. Classification of dysplasia in BE has significant interobserver variability. Our objective was to determine whether genetic alterations in BE correlate with degrees of histologic dysplasia. Fixed tissue from 37 patients with BE and adenocarcinoma was studied for six tumor suppressor genes. Tissues were microdissected and analyzed for loss of heterozygosity. Microdissection of individual crypts showing metaplasia and dysplasia were performed and analyzed for 23 of the 37 patients whose tumors were heterozygous for at least four of the six genes studied. Frequency of alterations for MXI1, hOGG1, p53, MTS1, DCC, and APC were 7 of 32 (22%), 12 of 35 (34%), 12 of 26 (46%), 17 of 30 (57%), 17 of 27 (63%), and 23 of 36 (64%), respectively. Analysis of BE demonstrated that crypts with metaplasia, low-grade dysplasia, and high-grade dysplasia strongly correlated with alterations in tumor suppressor genes (p < 0.0001). This pilot study demonstrates that genetic analysis can be performed on individual crypts in patients with BE, and that alterations may facilitate objective classification of the severity of dysplasia.