Genomic instability in precancerous lesions before inactivation of tumor suppressors p53 and APC in patients.
The etiology and significance of genomic instability (GIN), a hallmark of human cancers, remains controversial. The paradigm that inactivation of tumor suppressors [e.g. p53 or adenomatous polyposis coli (APC) genes] leads to GIN is largely based on experiments in vitro and in animal models. It remains unclear whether GIN is a cause or a result of cancer, particularly in patients. Precancerous Barrett's esophagus (BE) provides a clinical model to investigate GIN in cancer progression. We analyzed specimens from endoscopic biopsies or esophagectomies in patients with BE (ten cases, including five cases with multilayered epithelium (ME)), BE-associated esophageal adenocarcinoma (ten cases), or with normal gastro-esophageal junction (five cases). Chromosomal enumeration probe Cep 7, 11, 12, 17 and 18 were detected by fluorescence in situ hybridization (FISH). Expression of p53 and APC were determined by immunohistochemistry. Increased p53 expression, a measurement of p53 mutations, was observed in BE with high grade dysplasia (HGD) and in BE-associated esophageal cancer (EC). The expression of wild type APC was decreased in BE with HGD and in advanced EC. Chromosomal abnormalities were found in all EC samples. Numeric changes of chromosome 7, 11 and 12 were observed in BE in 14%, 64% and 43% of cases, respectively. Aneusomy of chromosome 11 and 12 were found in ME and in BE without dysplasia, in the presence of normal expression pattern of p53 and APC. Our results suggest that GIN is an early event that occurs at precancerous stages prior to changes in tumor suppressor genes (p53 and APC) in BE-associated tumorigenesis in patients, suggesting that GIN may serve as a causative link between chronic inflammation and cancer.
Yang
Youxin
Y
Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. yyang@BIDMC.harvard.edu
Fruehauf
Johannes
J
Xiang
Shuanglin
S
Li
Chiang J
CJ
D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism*; D002877:Chromosomes, Human; D015870:Gene Expression; D042822:Genomic Instability; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D011230:Precancerous Conditions / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D025601:Adenomatous Polyposis Coli Protein; D016159:Tumor Suppressor Protein p53