Submitted on August 18, 2005
Accepted on December 6, 2005
Gain of Allelic Gene Expression for Insulin-like Growth Factor 2 Occurs Frequently in Barrett's Esophagus
Linda A. Feagins1, Nathan Susnow1, Hui Ying Zhang1, Stephanie Pearson1, Charles Owen1, William F. Schmalstieg1, Lance S. Terada2, Stuart J. Spechler2, Ruben D. Ramirez3, and Rhonda F. Souza4*
1 Department of Medicine, University of Texas Southwestern Medical School, Dallas, TX, USA
2 Department of Medicine, University of Texas Southwestern Medical School, Dallas, TX, USA; Department of Medicine, Dallas VA Medical Center, Dallas, TX, USA
3 Department of Medicine, University of Texas Southwestern Medical School, Dallas, TX, USA; Department of Medicine, Dallas VA Medical Center, Dallas, TX, USA; Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA
4 Department of Medicine, University of Texas Southwestern Medical School, Dallas, TX, USA; Department of Medicine, Dallas VA Medical Center, Dallas, TX, USA; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA
* To whom correspondence should be addressed. E-mail: rhonda.souza{at}verizon.net.
The insulin-like growth factor 2 (IGF2) gene normally exhibits genomic imprinting, a DNA modification that allows the expression of only one of the two inherited alleles. With loss of imprinting (LOI), there is a gain of allelic gene expression (GOAGE) due to IGF2 being expressed by both alleles. GOAGE for IGF2 has been demonstrated in a number of malignancies and in normal epithelia surrounding malignancies, but not in epithelia without associated neoplasia. We hypothesized that non-neoplastic Barrett's epithelium might have GOAGE for IGF2 that could facilitate its progression to neoplasia. Endoscopic biopsies were taken from metaplastic esophageal, normal gastric, and normal duodenal epithelia in 43 patients with Barrett's esophagus. Genomic DNAs were analyzed by PCR followed by ApaI digestion or allele-specific PCR to identify an ApaI polymorphism of IGF2. cDNAs from patients with the ApaI polymorphism were analyzed for IGF2 GOAGE using exon connection PCR followed by a secondary nested PCR and ApaI digestion. We found that 13 of 43 (30%) samples of Barrett's metaplasia contained the ApaI polymorphism and were thus informative for IGF2, and sufficient material was available for GOAGE analysis in 9 of those 13 cases; GOAGE for IGF2 was demonstrated in 5 (56%) of those 9 cases. All patients with GOAGE in Barrett's metaplasia also demonstrated GOAGE in their gastric and duodenal epithelia. In contrast, patients without GOAGE in Barrett's metaplasia also had no GOAGE in their gastric and duodenal epithelia. We conclude that, in patients with Barrett's esophagus, GOAGE for IGF2 is found frequently in the metaplastic esophageal epithelium as well as in normal gastric and duodenal epithelia.
