Abstract LB-407: Analysis of genetic alterations in esophageal metaplasia: Are goblet cells required for neoplastic risk
Authors: Bandla Santhoshi , Litle Virginia , Watson Thomas J. , Peters Jeffrey H. , Godfrey Tony , Zhou Zhongren 
Published: February 2011

Introduction: Chronic gastroesophageal reflux (GERD) results in metaplastic changes in the esophagus from normal squamous epithelium to a more-acid resistant columnar epithelium with or without goblet cells. In the United States, the presence of goblet cells (intestinal metaplasia: IM) is required for the diagnosis of Barrett's esophagus (BE); the primary risk factor for esophageal adenocarcinoma. Patients with BE are recommended to undergo routine endoscopies to detect progression to dysplasia and cancer. However, several studies indicate that non-goblet cell columnar epithelium (NGCLE) may also be at risk for cancer progression. In Japan and the United Kingdom, the presence of goblet cells is not required for the definition of BE and the recommendation for surveillance. Thus, the current US definition of BE and the guidelines for surveillance are being questioned. Proving the neoplastic potential of NGCLE requires large patient cohorts, repeated endoscopies, and long term follow-up. However, we believe that analysis of genetic changes may provide more immediate information on its possible neoplastic potential. BE is known to harbour frequent genetic alterations including abnormal ploidy, LOH, mutation or methylation of CDKN2A, TP53, FHIT, WWOX, SMAD4 and APC as well as occasional amplification of oncogenes including MYC, GATA6 and ERBB2. Although there is one report of abnormal ploidy in NGCLE, there is no data on specific genetic changes in this tissue. Our study is aimed to address this deficiency and to indirectly assess neoplastic risk of NGCLE.

Materials and Methods: We analyzed genomic DNA from 11 NGCLE and 11 IM samples, using Affymetrix SNP 6.0 arrays. Normal samples from the same patient population were used as our baseline reference. All analysis was done in Nexus 5.0 Copy Number software using a SNPRank segmentation algorithm with log ratio thresholds for single copy gain and single copy loss was set at 0.25 and -0.25 respectively, and the log ratio thresholds for two or more copy gains or copy loss were set at 0.6 and -1.0 respectively.

Results: As previously reported, our IM samples display high frequencies of genomic aberrations including loss of CDKN2A/p16 (36%), FHIT (27%) and gain of Myc (9%) and GATA6 (9%). In contrast, only one of the NGCLE samples was found to have a copy number change, this being at the GATA6 locus. An additional 40 samples are currently being analyzed and sequencing of CDKN2a and TP53 will also be reported.

Conclusion: Results from this study so far indicate that the NGCLE does not harbour the same type or frequency of genetic changes that are observed in IM. If true, these findings would argue against the possibility that NGCLE is at risk for progression directly to cancer and would support the current US definition of BE.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-407.