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Tumor suppressor and genetic instability during development of esophageal adenocarcinoma
Author(s) -
Yang Youxin,
Ghiran Ionita,
Shields Helen,
Fruehauf Johannes,
Xiang Shuanglin,
Upton Melissa,
LaMont J. Thomas,
Li Chiang J.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a894-a
Subject(s) - dysplasia , chromosome instability , fluorescence in situ hybridization , barrett's esophagus , biology , adenocarcinoma , esophagus , genome instability , cancer research , microsatellite instability , suppressor , cancer , tumor suppressor gene , immunohistochemistry , pathology , chromosome , medicine , gene , carcinogenesis , genetics , immunology , dna , dna damage , allele , anatomy , microsatellite
Genomic instability (GIN) occurs in majority of human solid tumors, particularly in GI cancers. The significance and molecular regulators of GIN remain poorly understood. The roles of p53 and APC in protecting the genomic integrity have been well investigated, largely from studies in vitro. Precancerous Barrett's esophagus (BE) provides an important in vivo model to investigate GIN in human. This study was undertaken to determine GIN in relation to changes in p53 and APC in BE. We analyzed specimens from endoscopic biopsies or esophagectomies in patients with BE (10 cases) or with BE‐associated esophageal 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 tumor suppressor p53 and APC were determined by the sensitive avidin‐biotin immunohistochemistry. Up‐regulation of p53, an indicator of p53 mutations, was observed in BE with high grade dysplasia (HGD), which increased further in BE associated esophageal cancer (EC). The expression of wildtype APC was decreased in BE with HGD and in advanced EC. Chromosomal abnormalities of all probes tested were found in each BE associated EC (100%). Numeric changes of chromosome 7, 11 and 12 were observed in BE stage in 14%, 64% and 43% of cases, respectively. Interestingly, aneusomy of chromosome 11 and 12 were found in BE without pathological dysplasia, in the presence of normal expression of p53 and APC. Our results suggest that GIN is an early event that occurs at precancerous stage prior to changes in tumor suppressor p53 and APC in BE‐associated cancer progression.