Molecular Alterations of Barrett's Esophagus on Microdissected Endoscopic Biopsies

Abstract

SUMMARY:Alterations in proto-oncogenes and tumor suppressor genes play a role in the sequence from Barrett's metaplasia to esophageal adenocarcinoma. The present study aims to ascertain whether molecular abnormalities take place in Barrett's metaplasia and low-grade dysplasia and to correlate them with the histological features of the esophageal mucosa. Forty-one formalin-fixed, paraffin-embedded endoscopic esophageal biopsies were classified according to the type of metaplastic changes (noncolumnar fundic and cardial metaplasia; columnar metaplasia, with and without intestinal features). After microdissection samples were examined for loss of heterozygosity (LOH) using polymorphic markers on 5q (D5S82), corresponding to APC (adenomatous polyposis coli) gene, 13q (CA repeat in intron 2 position 14815 to 14998 of the retinoblastoma gene), 17p (D17S513) corresponding to p53 locus, and for p53 mutations. Molecular alterations including LOH, allelic imbalance, and microsatellite instability could be detected in all types of metaplastic changes and sporadically in the squamous epithelium adjacent to the metaplastic tissue. Molecular alterations involving microsatellites D5S82 and the CA repeat inside the retinoblastoma gene were more frequent in nonintestinal metaplasia whereas those involving the p53 locus took place in columnar intestinal metaplasia and in low-grade dysplasia. Clonal changes were demonstrated in different metaplastic areas in three patients. Genetic alterations comprising LOH and microsatellite instability characterize Barrett's mucosa and appear related to the type of metaplastic change. Some of them precede the development of intestinal metaplasia, suggesting that genetic alterations take place earlier than previously thought. (Lab Invest 2001, 81:241-247).

The dichotomy in carcinogenesis of the distal esophagus and esophagogastric junction: intestinal-type vs cardiac-type mucosa-associated adenocarcinoma

“…These findings support the notion that two different pathways lead to adenocarcinomas of the distal esophagus and esophagogastric junction: one in which intestinal-type epithelium with goblet cells becomes dysplastic (intestinal pathway) and another in which dysplasia arises in cardiac-type glandular mucosa (non-intestinal pathway). [39][40][41] In contrast, an alternative explanation for the lack of intestinal metaplasia in some adenocarcinomas, 39 overgrowth of short segment intestinal metaplasia by large tumors, 17,42 explains neither the absence of intestinal-type mucosa in certain small esophageal adenocarcinomas 43 nor our observation of phenotypic and molecular differences. Thus, adenocarcinomas of the distal esophagus and esophagogastric junction may be stratified based on the presence or absence of background Barrett mucosa, with unique clinicopathological characteristics in either group, but without significant survival differences.…”

Effects of Helicobacter pylori infection on genetic instability, the aberrant CpG island methylation status and the cellular phenotype in Barrett's esophagus in a Japanese population

“…Up to now, only a few reports have investigated the genetic alterations comprising MSI and LOH in BE patients, indicating that genetic alterations take place earlier in the development of SIM. 37,38 We previously found that GIN in SIM and gastric intestinal metaplasia may be associated with BE 39 and gastric carcinogenesis, 31,33 respectively. There have so far been very few reports regarding the alteration of E-cadherin in BE and EAC, [40][41][42] and loss of or reduced E-cadherin expression is considered to play a role in the progression of BE to EAC.…”

Chondrosarcomatous Differentiation in Diffuse-Type Gastric Carcinoma

“…According to previously described methods [5,6], normal and tumor tissues were microdissected under direct light microscopy and digested overnight in a lysis buffer with 5% proteinase K. The DNA was directly tested for BAT25, BAT26, D2S123, D5S346, D17S250, D17S513, and TP53 microsatellites in a silver-stained 9% polyacrylamide gel. Loss of heterozygosity (LOH) was detected if one of the tumor bands decreased 30% below the corresponding normal band intensity.…”