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Genetic instability (GIN) has been considered as the fundamental process by which normal tissue cells become neoplastic. The cause of GIN remains poorly understood. Precancerous Barrett’s esophagus (BE) provides an important in vivo model to investigate GIN in human. Multilayered epithelium (ME) has been proposed as a precursor of BE. Extracellular matrix (ECM) plays an important role in cancer metastasis. We have previously shown that GIN is an early event that occurs before changes in tumor suppressor p53 and APC during cancer progression in BE. The aim of this study was to determine the changes in ECM in relation to GIN in ME and BE associated adenocarcinoma. We analyzed specimens from endoscopic biopsies or esophagectomies in patients with BE (10 cases, 5 with ME, 5 without ME), and associated adenocarcinoma (10 cases), with normal gastro-esophageal junction (5 cases) as controls. Chromosomal enumeration probe Cep 7, 11, 12, 17 and 18 were detected by fluorescence in situ hybridization (FISH). Expression of heparin sulphate glycosaminoglycan (HS-GAG) chain of heparin sulphate proteoglycan (HSPG), a component of ECM, was determined by the sensitive avidin-biotin immunohistochemistry. We found that strong expression of HS-GAG was detected on cell surfaces both in normal esophageal squamous and gastric columnar epithelial cells. We observed that HS-GAG expression was progressively reduced from Barrett metaplastic specialized epithelium (SE) in 79% to invasive adenocarcinoma (CA) in 100%. We did not found any aneuploidy in our normal controls. In CA stage, however, chromosomal abnormalities of all probes tested were demonstrated. Aneusomy of chromosome 7, 11 and 12 were observed in SE lesions in 14%, 64% and 43% cases, respectively. Among SE lesions with loss expression of HS-GAG, 82% of them appeared aneuploidy of Cep 11. In ME lesions, reduced expression of HS-GAG was found in 80%. Aneuploidy of Cep 11 was detected in 40%. No aneusomy was observed in two ME samples with reduced HS-GAG expression. From SE to CA stage, no aneusomy was found in cases with normal expression of HS-GAG. Interestingly, chromosomal instability is closely associated with loss of HS-GAG expression (P<0.001). In conclusion, alteration in extracellular matrix is an early event and might play a role in developing genetic instability during cancer progression in Barrett’s esophagus.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]